Modern Dietary Fat Intakes in Disease Promotion (Nutrition and Health)

Modern Dietary Fat Intakes in Disease Promotion

Nutrition and Health Adrianne Bendich, PhD, FACN, Series Editor

For other titles published in this series, go to www.springer.com/series/7659

Modern Dietary Fat Intakes in Disease Promotion Edited by

Fabien De Meester, phd DMF Ltd Company, Marche/Famenne, Belgium

Sherma Zibadi, md, phd University of Arizona, College of Medicine, Sarver Heart Center, Tucson, AZ and

Ronald Ross Watson, phd University of Arizona, Mel and Enid Zuckerman College of Public Health, Tucson, AZ

Editors Fabien De Meester, PhD Managing Director DMF Ltd Company Luxembourg Str 46 6900 Marche/Famenne Belgium [email protected]

Sherma Zibadi, MD, PhD University of Arizona Mel & Enid Zuckerman College of Public Health P.O. Box 245163 Tucson, AZ 85724-5163 USA [email protected]

Ronald Ross Watson, PhD Department of Health Promotion Sciences University of Arizona Health Sciences Center 1295 N. Martin Ave. P.O. Box 245155 Tucson, AZ 85724-5155 USA [email protected]

Series Editor Adrianne Bendich, PhD, FACN GlaxoSmithKline Consumer Healthcare Parsippany, NJ USA

ISBN 978-1-60327-570-5 e-ISBN 978-1-60327-571-2 DOI 10.1007/978-1-60327-571-2 Springer New York Dordrecht Heidelberg London Library of Congress Control Number: 2010921817 © Springer Science+Business Media, LLC 2010 All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Humana Press, c/o Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Humana Press is part of Springer Science+Business Media (www.springer.com)

Series Preface

The Nutrition and Health series of books have had great success because each volume has the consistent overriding mission of providing health professionals with texts that are essential because each includes (1) a synthesis of the state of the science, (2) timely, in-depth reviews by the leading researchers in their respective fields, (3) extensive, up-to-date fully annotated reference lists, (4) a detailed index, (5) relevant tables and figures, (6) identification of paradigm shifts and the consequences, (7) virtually no overlap of information between chapters, but targeted, inter-chapter referrals, (8) suggestions of areas for future research, and (9) balanced, data-driven answers to patient as well as health professionals questions which are based upon the totality of evidence rather than the findings of any single study. The series volumes are not the outcome of a symposium. Rather, each editor has the potential to examine a chosen area with a broad perspective, both in subject matter and in the choice of chapter authors. The editor(s), whose training(s) is (are) both research and practice oriented, has(ve) the opportunity to develop a primary objective for their book, define the scope and focus, and then invite the leading authorities to be part of their initiative. The authors are encouraged to provide an overview of the field, discuss their own research, and relate the research findings to potential human health consequences. Because each book is developed de novo, the chapters are coordinated so that the resulting volume imparts greater knowledge than the sum of the information contained in the individual chapters. Modern Dietary Fat Intakes in Disease Promotion, edited by Fabien De Meester, Sherma Zibadi, and Ronald Ross Watson, clearly exemplifies the goals of the Nutrition and Health series. The editors are leaders in their fields of expertise. Fabien De Meester, Ph.D., was until recently President and CEO of BNLfood. He recently decided to step down from his position at BNLfood to establish a new and innovative international platform of DMF (Development & Management Frontiers) companies focused on educational aspects of the Columbus Concept as the new standard in lipid nutrition. Dr. De Meester and Dr. Watson have published a recent volume for Humana Press entitled Wild-Type Food in Health Promotion and Disease Prevention: the Columbus Concept. Dr. De Meester has published over 50 research articles, patents, and communications on topics related to organic chemistry, enzymology, biochemistry, molecular biology, food science, and business, and has organized a series of international workshops on the Columbus Concept. Dr. Sherma Zibadi, M.D., Ph.D., has completed postgraduate training in medicine and has concentrated on metabolic diseases. Dr. Watson is a well-known editor of more than 65 volumes on a wide range of biomedically related nutrition topics over the past 25 years and has published over 250 peer-reviewed research articles. He is professor of Public Health at the University of Arizona and the director of the NIH-funded Alcohol Research Center. The book chapters are logically organized to provide the reader with a basic understanding of the interactions between behavioral aspects of eating and the critical importance of what we v

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eat with specific emphasis on the types and qualities of the fats that are consumed. The volume is divided into five sections including the section on the behavioral aspects of eating; a second section on dietary fats; the third section examines the clinical relevance of fats and cardiovascular disease. The fourth section contains novel chapters on the potential for contaminants in fats and oils to increase risk of illnesses. The fifth section looks at dietary and pharmaceutical approaches to modify fat-induced disease and ill-health. Each section contains chapters that address treatment options as well as prevention strategies. This logical sequence of chapters provides the latest information on the current standards of practice for clinicians, related health professionals including the dietician, nurse, pharmacist, physical therapist, behaviorist, psychologist, and others involved in the team effort required for successful treatment of lipid disorders, cardiac and cerebrovascular diseases as well as conditions that adversely affect normal metabolic processes. This comprehensive volume also has great value for academicians involved in the education of graduate students and post-doctoral fellows, medical students and allied health professionals who plan to interact with patients with lipid disorders as well as those who are overweight or obese. Cutting edge discussions of the roles of growth factors, hormones, cellular and nuclear receptors, adipose tissue, and all of the cells directly involved in fat metabolism are included in well-organized chapters that put the molecular aspects into clinical perspective. Of great importance, the editor and authors have provided chapters that balance the most technical information with discussions of its importance for clients and patients as well as graduate and medical students, health professionals, and academicians. There are numerous chapters that are devoted to the treatment of obesity and its related comorbidities. These include an overview of current treatment options as well as a discussion of future treatments that are already in development. Critical to any weight reduction program is exercise, and there is a comprehensive chapter on the role of physical activity, exercise, and nutrition in weight control. The importance of a team approach to the treatment of obesity as a chronic disease is extensively discussed in chapters on social interactions, lifestyles as well as behavioral modification in the treatment of obesity. Unique to this volume are chapters that examine the development of obesity in Asian populations including an examination of factors including social class and genetics. Specific treatment modalities are reviewed in separate chapters on pharmacotherapies, combination therapies, potential for behavioral interventions, and the effects of different fat types on feelings of hunger and satiety. Each of these chapters presents an objective evaluation of the treatment and identifies the positives and negatives that have been seen during clinical studies as well as cumulative data derived from clinical practice. There is a clear, data-driven message throughout the volume that there are important debates that are ongoing between researchers concerning the value of weight reduction, statins, fish consumption, consumption of meats, and the use of feedlots versus free-range feeding of domesticated animals. There are also thought-provoking chapters that examine whether all saturated fats are “bad” and whether there are sufficient studies to warrant a recommendation of consumption of conjugated linoleic acid; there are two novel chapters on the effects of modifying milk fats and/or other dairy constituents. Of particular interest to the consumer and the patient are answers to their questions about food contaminants. Chapters examine the health effects of inadequate storage, processing, and/or cooking of foods including those with potentially oxidizable fats. Another chapter reviews the complex area of mycotoxins that have been in the human food supply since the beginning of civilization. Women of child-bearing potential are anxious to know about the benefits and/or

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risks of eating fish that are rich in long-chain polyunsaturated fats, yet may also contain contaminants from the sea. Two in-depth chapters provide guidance to the reader in the value of fish consumption. Detailed tables and figures assist the reader in comprehending the complexities of the chemistry of fats and their effects on eating behaviors. Modulators of eating responses and the role of Western diets in the development of the diseases associated with overconsumption of total calories, total fats, specific fats, and other dietary constituents are covered in the last section that also includes discussions of chronic fatigue syndrome, attention-deficit hyperactivity, insulin resistance and type 2 diabetes, micronutrients including selenium, folic acid, and vitamins B12 and B6; chapters include discussions of the relevance of bioactive compounds such as polyphenols, resveratrol, tocotrienols, phytosterols, soy, sulfur compounds from cruciferous vegetables, and other relevant plant constituents. Thus, this volume is focused on answering questions commonly asked by clients and patients about why some diets do not work and why some “professional” sources advocate certain products that are available over the counter but may not “work.” The over-riding goal of this volume is to provide the health professional with balanced documentation and awareness that their clients’/patients’ metabolic conditions are complex states that transcend the simplistic view of just losing a few pounds. Hallmarks of the 29 chapters include bulleted key points at the beginning of each chapter, complete definitions of terms with the abbreviations fully defined for the reader, and consistent use of terms between chapters. There are more than 75 relevant tables, graphs, and figures as well as over 2,200 up-to-date references; all chapters include a conclusion section that provides the highlights of major findings. The volume contains a highly annotated index and within chapters, readers are referred to relevant information in other chapters. This important text provides practical, data-driven resources based upon the totality of the evidence to help the reader understand the basics, treatments, and preventive strategies that are involved in balancing the fats in one’s diet as well as within one’s body. The overarching goal of the editors is to provide fully referenced information to health professionals so that they may have a balanced perspective on the value of various treatment options that are available today as well as in the foreseeable future. In conclusion, Modern Dietary Fat Intake in Disease Promotion, edited by Fabien De Meester, Sherma Zibadi, and Ronald Ross Watson, provides health professionals in many areas of research and practice with the most up-to-date, well-referenced, and easy-to-understand volume on the importance of identifying and treating as well as providing strategies to prevent the development of chronic, serious metabolic diseases. This volume will serve the reader as the most authoritative resource in the field to date and is a very welcome addition to the Nutrition and Health series. Adrianne Bendich, Ph.D., FACN Parsippany, NJ

Preface

Modern Dietary Fat Intakes in Disease Promotion is the follow-up book to the original one published in 2008 under the running title Wild-Type Food in Health Promotion and Disease Prevention: The Columbus Concept, 2008 Humana Press Inc, ISBN 978-1-58829-668-9, E-ISBN 978-1-59745-330-1. It shifts focus from examining the beneficial effects of dietary fat intake to targeting the disease-promoting aspects of fat in the human diet. A review of both disease promotion and disease prevention reveals many diet–health relationships and paradoxes reported regularly in the scientific literature. Perhaps the most frequently neglected family of essential nutrients in contemporary diets is polyunsaturated fatty acids or PUFAs. Their two subgroups omega-6 and omega-3 compete against each other for substrates, intermediaries, and end products in many biological pathways involved in physiological inflammatory processes. A consensus is growing in the modern scientific community about their public health burden through the promotion of chronic degenerative diseases whose incidences and severity continue to increase. Recent attempts at increasing dietary omega-3 fatty acids in foods to reduce disease have met with limited enthusiasm and acceptance by producers, retailers, and consumers—essentially due to the oxidative instability of these acids. Simultaneously, there is a return to plant and animal foods that reflect the wild standard—in other words, which include healthy omega-6/3 fatty acids with an ω6:ω3 PUFA ratio of 1:1 and/or a 25% proportion of ω6 highly unsaturated fatty acids (HUFAs). The goal is to have more balance in blood serum/plasma total lipids in association with a balanced mixture of naturally occurring antioxidant vitamins and minerals. This is the basis of the Columbus Concept, referred to as a new standard in lipid nutrition; it implies a reduction in the relative contribution of omega-6 fatty acids and favors an absolute increase in the contribution of omega-3 fatty acids to the modern dietary pattern. Modern Dietary Fat Intakes in Disease Promotion was a challenging but critical book to edit and publish, as the twentieth century has seen food become readily available due to remarkable advances in agricultural and food-processing technologies. There are both benefits and adverse health consequences to removing cholesterol and omega-3 fats from natural foods, hydrogenating PUFAs from vegetable and fish oils/fats by chemical means, designing high-fat/carbohydrate empty-calorie diets, and spreading around non-biodegradable agrochemicals and pesticides. Such practices today appear to belong to a regrettable era of (1) free-market excitement, probably fueled by a lack of humility in recognizing the historical importance of humanity’s adjustment to wild-type foods, and (2) over-confidence in scientific knowledge. Now, at the beginning of the twenty-first century, we have learned from the cholesterol craze that nature-designed foods may not need to be altered to improve their beneficial health effects, save perhaps in subgroups of the world population that are genetically predisposed to specific diseases and for whom a ix

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nutrigenetic/genomic approach is more appropriate. Therefore, the twenty-first century appears to be focusing on nutritional sciences based on wisdom and the following basic principles: 1. Appropriate balanced intake of essential nutrients. 2. Energy intake = energy expenditure. 3. Whole foods and/or least-processed foods including the following: a. Non-chemically hydrogenated saturated and mono-unsaturated fats for cooking. b. Cold-pressed, non-refined, antioxidant-rich polyunsaturated oils for dressing. c. Extracted, refined, antioxidant-rich highly unsaturated oils for supplementing. Modern Dietary Fat Intakes in Disease Promotion calls for a three-level grasp of the feed– food–fork value chain that includes the following reviewed critical aspects: 1. Behavior: social, cultural, economic, and educational aspects. 2. Composition: fat/protein, triglycerides/phospholipids, and omega-6/-3 ratios. 3. Contamination: peroxides, agrochemicals, and microorganisms.

Volume Contents The first chapters include discussions of the behavioral aspects of eating. Wilczy´nska-Kwiatek, De Meester, Singh, and Łapi´nski review nutrition as modified by behavior on brain function. They point out that the high-carbohydrate diets promoted by Western food guidelines are associated with clinical manifestations of affective disorders leading to depression. This disease is ranked by WHO as the leading degenerative disease in developed countries. A parallel is made between the increased intake of carbohydrate-rich, refined, grain-based fast foods and lower proportional intake of essential nutrients including omega-3 fats, antioxidant vitamins, and minerals. This observation led the authors to review the effects of dietary essential nutrients, primarily omega-3 fatty acids, on psychological function and mental health. The authors found strong evidence that EPA (eicosapentaenoic acid, C20:5ω3) is a promising dietary supplement for the prevention of mental decay in healthy individuals. Puri adds two papers on the potential role of modern lifestyles in myalgic encephalomyelitis and attention-deficit hyperactivity disorder. He shows how a deficiency of and/or imbalance between omega-6 and omega-3 at the tissue level—caused by Western diets and environmental (viral infection, organophosphate) factors— could lead to the rising prevalence of neuron-degenerative diseases in the Western world. Puri concludes that a change in diet should be considered by physicians prior to prescribing a synthetic drug to children and adults newly diagnosed with such disorders. Going and Hingle review data that correlate the health effects of diet and exercise. They define the beneficial influences of regular-to-moderate physical activity and moderate energy-dense, nutrient-rich diets to help control weight and regulate metabolism. O’Hara and Gregg emphasize that focusing health recommendations only on body weight (the weight-centered health paradigm) may not be health promoting. First, it is ineffective as a means to improving health or controlling body weight, and second, the attitudes, behaviors, and practices arising from such a paradigm are harmful to health and well-being. In particular, this paradigm is associated with dissatisfaction, dieting,

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discrimination, and death. Dokken and Boucher test the hypothesis that excessive caloric intake of any kind versus any specific dietary components, including fats, explains the strong relationship between obesity associated with insulin resistance and type 2 diabetes. Dube and Stanton report on the social context of dietary behavior. They suggest that a multi-faceted approach targeting the home-cooking role model, increasing the availability of fruits and vegetables, and decreasing the availability of snacks is necessary to encourage lifetime healthy dietary practices in children and adults, lower the burden on health-care systems, and to reduce health disparities. Bartholomew and Jowers review strategies for modifying school-based foods and conclude that restricting access to calorie-dense foods by manipulating the price structures of their healthy counterparts (i.e., salad bars versus snack foods) has great potential for success. Singh, Rastogi, Goyal, Vajpayee, Fedacko, Pella, and De Meester review data suggesting that populations of developing countries are more sensitive to modern chronic diseases of affluence than are those of developed countries, suggesting a maladaptive process in the latter. They cite data showing that southeast Asians suffer more diabetes and coronary artery disease than do Caucasians, especially at younger ages, whereas their fat intake is less than 25% and obtained from plant rather than animal food. Vaghefi, Watkins, and Brown define how modern Western low-cost and time-saving diets are finding their ways throughout the planet through economic development and technological progress. The high fat content and the low nutritional value of such diets are discussed from the standpoint of their contribution to promoting diseases globally. There are important chapters that review the composition of fats, oils, and other constituents in the diet. Vituru and Gormley explain how the oil-seed industry resulted from the ability to hydrogenate oil produced by extraction from seeds. This generalized processing of plant fats thereafter led to the appearance of trans-unsaturated fats and the disappearance of ω3 fats in the twentieth-century diet, a double trend that mirrors the dramatic global increase in modern degenerative diseases. Crawford, Lehane, and Ghebremeskel revisit health effects as modified by dietary animal fat. Feeding intensively reared, domesticated animals with growth-promoting oil grains has facilitated artificially fat animals presenting high fat/protein and increased omega6/3 and triglyceride/phospholipid ratios in their carcasses. Using such animals as food has little in common with using wild animals or game historically as food—and is a possible modulator of human physiology from an evolutionary standpoint. Surai, Pappas, Karadas, Papazyan, and Fisinin point out that modern, land-based agriculture has washed essential micronutrients away from the food supply. Their review focuses on the removal of selenium as a striking example of a lost essential mineral in plants due to low soil pH and high concentrations of sulfur and phosphorus from the massive use of fertilizer. Enrichment of chickens, cattle, and pig feed with selenomethionine appears to be a sustainable transitory solution to the problem until soil composition can be restored, which is appropriate to animal/man feeding requirements. Sabetisoofyani, Larson, and Watson address the primary role of homocysteine in the inception and progression of endothelial dysfunction with accelerated atherosclerosis from both a dietary perspective (a deficiency in essential B vitamins) and a genomic perspective (mutations in cystathione βsynthase or 5,10-methylenetetrahydrofolate reductase). Ravnskov’s review summarizes much of his lifetime effort at re-establishing the facts behind lipid nutrition. He concludes that cholesterol and saturated fats are not primary risk factors of cardiovascular disease, claiming that both the market place and limited understanding of research on fats and cholesterol have helped encourage previous misconceptions about cholesterol and heart disease. Ravnskov calls for an urgent revision of modern dietary guidelines based on a more educated approach to dietary lipids.

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Jahreis and Hengst provide evidence that dietary fats do not represent a health issue per se. They suggest that fats obtained from ruminants fed grass-type, omega-3-rich fodder promote positive effects on established risk factors of CVD. Jacques, Leblanc, and Bergeron review the different options available to the dairy industry for increasing the understanding of both scientists and the lay public about the health roles of certain fats, particularly in terms of the many misconceptions about cholesterol and saturated fats. Modifications of milk-fat composition through cow feeding, enzymatic inter-esterification, and physical fractionation appear to be among the most promising options. De Lorgeril corroborates Ravnskov’s review by summarizing recent cholesterol-lowering (absorption, synthesis) trials. He concludes with a similar recommendation that medical (in addition to food) guidelines should be carefully re-examined. He describes how reducing blood cholesterol increases atherosclerotic progression as measured by changes in carotid intima-media thickness. Sharma, Singh, and Katz explain the role of statins in modern and modernizing societies where blood cholesterol and triglyceride lowering has become a health-care priority, notwithstanding the potential side effects of such a preventive approach in what they refer to as cardiovascular incapability. Careful selection as to statin types and dosage appears to minimize their side effects on hepatic and renal functions, muscular impairments, and other physical properties while providing sought-after preventive benefits. Vasanthi, Kartal-Özer, Azzi, and Das summarize the recent literature on the efficacy and mechanisms of popular cholesterol-lowering dietary supplements. Zibadi, Larson, and Watson explore how obesity induces maladaptive remodeling of the cardiac muscle through alterations in myocyte shape and number and the extracellular matrix, resulting in cardiac hypertrophy and fibrosis. Leptin, an adipokine overproduced in obesity, appears to play a major role in the remodeling process and therefore to provide an avenue of treating obesity and other hyperleptinemic-related cardiac dysfunctions. Cordova et al. present the genetically modified rodent animal models that are developed to test the maladaptive remodeling hypothesis in the human obesity, cardiac structural, and functional changes relationship. Togni presents the non-deficiency malnutrition syndrome that results from the characteristic load of empty calories in advanced Western diets. In this context, he shows that plant extracts including polyphenols may be recommended as dietary supplements. Kelley, Hubbard, and Erickson review the currently available literature on the influence of conjugated linoleic acid (CLA) isomers on human body composition and tumorigenesis. They conclude that at present it is too early for CLA to be labeled as a health-promoting dietary supplement. Vemuri and Kelley warn that t10,c12-CLA may cause lipodystrophy, insulin resistance, non-alcoholic fatty liver disease, fat mass, and increased body weight in animals and humans. A unique feature of this volume is the extensive information pertaining to major sources of food contaminants. Surai and Fisinin describe how food processing can affect dietary lipids and eventually promote ill-health effects when not protected from peroxidation. They emphasize the need for improving the conditions of food processing, storage, and cooking at a time when fat hydrogenation is increasingly perceived as detrimental to foods. Surai, Mezes, Fotina, and Denev report on the global endemic contamination of the feed–food–fork chain by fungal metabolites: mycotoxins. These food contaminants have detrimental biological effects on both animal and human health through their organ toxicity, including immunomodulation, neurotoxicity, mutagenicity, carcinogenicity, and teratogenicity. As 25% of the current world crop production is potentially contaminated, it is essential to find sustainable solutions to this fungal-persistent presence in the animal and human food chain. Sioen, De Henauw, and Van Camp review a conflict of interest in establishing dietary recommendations for fish as a source of long-chain, ω3 fatty acids. Modern agro-food and environmental practices translate into loading oceans with all kinds

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of persistent and potentially toxic residues that accumulate in fish, in particular fish fats. Their statistical evaluation proposes a balance that can be approached in terms of nutritional benefits versus toxicological aspects of fish consumption. Covaci and Dirtu extend this discussion to naturally produced, organo-brominated compounds from marine micro-organisms present in fish and fish fats. Their review presents evidence that refined fish-oil dietary supplements might be a suitable alternative to fish consumption. The Columbus Concept, defined by this book and the previous one, still has a long way to go to establish itself in the market place. The way lipid standards are taught and implemented in dietary and medical practices within culinary and medical schools, agro-food and pharmaceutical industries, and legislatures has to be changed. In the balance, the burden and cost of chronic diseases on both modern and modernizing societies is exploding, and currently there is no single critical environmental factor identified other than a dietary omega-6/3 PUFA imbalance. Fabien De Meester Marche/Famenne, Belgium Sherma Zibadi Tucson, AZ Ronald Ross Watson Tucson, AZ

Acknowledgments Modern Dietary Fat Intakes in Disease Promotion is positioned as a complementary rationale to the previously published Wild-Type Food in Health Promotion and Disease Prevention: The Columbus Concept. As with the previous volume, this book is the result of long-term, committed teamwork aimed at translating an ever more robust new standard in lipid nutrition into a market reality. In 2008, the Sixth International Congress on the Columbus Concept (ICCC) coincided with the Second Congress of the International Society of Nutrigenetics & Nutrigenomics (ISNN) in Geneva, Switzerland, where a satellite session on dietary PUFAs and cholesterol was organized and sponsored by the Columbus Paradigm Institute (www.columbus-concept.com), a BNLfood company. A special note of thanks should be extended to Artemis P Simopoulos from the Center for Genetics, Nutrition, and Health (CGNH, Washington DC) for her continuous support for the development of the Columbus Concept. Dr. De Meester extends his most sincere gratitude to all contributors of this second tome on the Columbus Concept and confirms his uncompromised support to taking it to market for the health benefits of human societies at large. In this respect, he wishes to emphasize the outstanding contributions of Michael Crawford, Michel de Lorgeril, Ram B. Singh, Peter Surai, Basant Puri, Uffe Ravnskov, and Ronald Ross Watson to the Columbus venture so far. Dr. Watson acknowledges the vital work of our editorial assistants Bethany L. Stevens and Leslie Dupont. Bethany has kept the editors and the authors on task over most of the previous 2 years, answering questions, reviewing manuscripts, dealing with idiosyncrasies of the publishing process, and providing calm assurance that the work would get done. Without her efforts the book would not have appeared and certainly would not have achieved its current quality. Leslie was instrumental in reviewing and editing the preface and Chapter 1.

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Dr. De Meester and Dr. Watson also appreciate the continuing financial support for the editing team efforts by BNLfood and others developing the Columbus concept. Finally, the volume editors would like to extend their appreciation to Humana Publishing Company and their staff for providing a professional platform of communication for new, challenging ideas and hypotheses in nutritional sciences and to the series editor Adrianne Bendich, on the one hand, for her personal input in positioning the book toward the right audience and, on the other, her incisive and pertinent comments, suggestions, and recommendations for improving the content, coherence, and presentation.

Acknowledgments

The work of editorial assistant Bethany L. Stevens in communicating with authors, working with the manuscripts and the publisher was critical to the successful completion of the book and is much appreciated. Her daily responses to queries and collection of manuscripts and documents were extremely helpful. Support for her work was graciously provided by DMF Ltd Company Belgium. Finally Nguyen T. Nga of the Arizona Health Sciences library was instrumental in finding the authors and their addresses in the early stages of the book’s preparation.

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Contents

Part I

Behavioral Aspects of Eating

1 Western Diet and Behavior: The Columbus Concept . . . . . . . . . . . . . . . Agnieszka Wilczy´nska-Kwiatek, Fabien De Meester, Ram B. Singh, and Łukasz Łapi´nski 2 The Social Context of Dietary Behaviors: The Role of Social Relationships and Support on Dietary Fat and Fiber Intake . . . . . . . . . . Anish R. Dube and Cassandra A. Stanton 3

Social Class, Food Intakes and Risk of Coronary Artery Disease in the Developing World: The Asian Paradox . . . . . . . . . . . . . . . . . . . Ram B. Singh, S.S. Rastogi, R.K. Goyal, S. Vajpayee, Jan Fedacko, Daniel Pella, and Fabien De Meester

4 Social, Cultural, Economical, and Practical Factors . . . . . . . . . . . . . . . Simin B. Vaghefi, Julia Watkins, and Karri Brown Part II 5

3

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Dietary Fats

Partially Hydrogenated Fats in the US Diet and Their Role in Disease . . . . . James J. Gormley and Vijaya Juturu

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6 Fatty Acid Ratios in Free-Living and Domestic Animals . . . . . . . . . . . . . Michael A. Crawford, Y. Wang, C. Lehane, and K. Ghebremeskel

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7 Is Saturated Fat Bad? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Uffe Ravnskov

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8

9

Alteration of Human Body Composition and Tumorigenesis by Isomers of Conjugated Linoleic Acid . . . . . . . . . . . . . . . . . . . . . . Nirvair S. Kelley, Neil E. Hubbard, and Kent L. Erickson

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Insulin Resistance and Non-alcoholic Fatty Liver Disease Induced by Conjugated Linoleic Acid in Humans . . . . . . . . . . . . . . . . . . . . . Madhuri Vemuri and Darshan S. Kelley

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Contents

Part III Fats and Cardiovascular Disease 10 Dietary Fat Intake: Promotion of Disease in Carotid Artery Disease: Lipid Lowering Versus Side Effects of Statins . . . . . . . . . . . . . . . . . . Rakesh Sharma, Ram B. Singh, Robert J. Moffatt, and Jose Katz

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11 Recent Cholesterol-Lowering Drug Trials: New Data, New Questions . . . . . Michel de Lorgeril

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12

Leptin and Obesity: Role in Cardiac Structure and Dysfunction . . . . . . . . Sherma Zibadi, Douglas F. Larson, and Ronald Ross Watson

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Cardiac Structural and Functional Changes in Genetically Modified Models of Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Felina Cordova, Sherma Zibadi, Douglas F. Larson, and Ronald Ross Watson

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Fat-Modified Dairy Products and Blood Lipids in Humans . . . . . . . . . . . Gerhard Jahreis and Christin Hengst

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15 Modified Milk Fat Reduces Plasma Triacylglycerol Concentrations: Health and Disease Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hélène Jacques, Nadine Leblanc, and Nathalie Bergeron

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Dietary Supplements, Cholesterol and Cardiovascular Disease . . . . . . . . . Hannah R. Vasanthi, Nesrin Kartal-Özer, Angelo Azzi, and Dipak K. Das

Part IV 17

Contaminants in Fats and Oils: Role in Illness

Ill Health Effects of Food Lipids: Consequences of Inadequate Food Processing, Storage and Cooking . . . . . . . . . . . . . . . . . . . . . . . . . Peter Surai and V.I. Fisinin

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18 Mycotoxins in Human Diet: A Hidden Danger . . . . . . . . . . . . . . . . . . Peter Surai, Miklos Mezes, T.I. Fotina, and S.D. Denev

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19 Nutrition–Toxicological Dilemma on Fish Consumption . . . . . . . . . . . . . Isabelle Sioen, Stefaan De Henauw, and Johan Van Camp

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Anthropogenic and Naturally Produced Contaminants in Fish Oil: Role in Ill Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Adrian Covaci and Alin C. Dirtu

Part V

Dietary and Pharmaceutical Approaches to Modify Fat-Induced Disease and Ill-Health

21 Do Modern Western Diets Play a Role in Myalgic Encephalomyelitis? . . . . . Basant K. Puri 22

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The Role of Modern Western Diets in Attention-Deficit Hyperactivity Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Basant K. Puri

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The Role of Dietary Fat in Insulin Resistance and Type 2 Diabetes . . . . . . . Betsy Dokken and Jackie Boucher

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Strategies to Modify School-Based Foods to Lower Obesity and Disease Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . John B. Bartholomew and Esbelle M. Jowers

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Selenium Enigma: Health Implications of an Inadequate Supply . . . . . . . . Peter Surai, A.C. Pappas, F. Karadas, T.T. Papazyan, and V.I. Fisinin

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26 Homocysteine: Role in Cardiovascular Disease . . . . . . . . . . . . . . . . . . Arash Sabetisoofyani, Douglas F. Larson, and Ronald Ross Watson

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27

Dietary Plant Extracts to Modify Effects of High Fat Modern Diets in Health Promotion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stefano Togni

28 Don’t Diet: Adverse Effects of the Weight Centered Health Paradigm . . . . . Lily O’Hara and Jane Gregg 29

417 431

Physical Activity in Diet-Induced Disease Causation and Prevention in Women and Men . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Scott Going and Melanie Hingle

443

Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

455

Contributors

Angelo Azzi Vascular Biology Laboratory, JM USDA-HNRCA, Tufts University, Boston, MA, USA John B. Bartholomew Department of Kinesiology and Health Education, The University of Texas, 1 University Station, D3700, Austin, TX 78712-1204, USA Nathalie Bergeron College of Pharmacy, Touro University California, 1310 Johnson Lane, Mare Island, Vallejo, CA 94592 USA Jackie Boucher Minneapolis Heart Institute Foundation, 920 East 28th Street, Suite 100, Minneapolis, MN 55407, USA, [email protected] Karri Brown Department of Nutrition and Dietetics, College of Health, University of North Florida, Jacksonville, FL, USA Felina Cordova Mel and Enid Zuckerman College of Public Health, University of Arizona, 1295 N. Martin, Tucson, AZ 85724-5155, USA Adrian Covaci Department of Pharmaceutical Sciences, Toxicological Center, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium M.A. Crawford Institute of Brain Chemistry and Human Nutrition, London Metropolitan University, London, England Dipak K. Das Cardiovascular Research Center, University of Connecticut School of Medicine, Farmington, CT, USA Stefaan De Henauw Department of Public Health, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium Michel De Lorgeril Laboratoire TIMC-IMAG, UMR 5525, Cœur and Nutrition, Faculté de Médecine, Université Joseph Fourier—Grenoble 1, CNRS, Grenoble, France; Domaine de la Merci, 38706 La Tronche, France Fabien De Meester Managing Director, DMF Ltd Company, Luxembourg Str 46, 6900 Marche/Famenne, Belgium, [email protected] S.D. Denev Trakia University, Stara Zagora, Bulgaria xxi

xxii

Contributors

Alin C. Dirtu Department of Pharmaceutical Sciences, Toxicological Center, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium; Department of Chemistry, “Al. I. Cuza” University of Iasi, Carol I Bvd., No. 11, 700506, Iasi, Romania Betsy B. Dokken Department of Medicine, Section of Endocrinology, Diabetes and Hypertension, University of Arizona, 1656 East Mabel St, Tucson, AZ, USA, [email protected] Anish R. Dube Program in Public Health at Brown University, Providence, RI, USA Kent L. Erickson Department of Cell Biology and Human Anatomy, School of Medicine, University of California, One Shields Ave., Davis, CA 95616-8643, USA, [email protected] Jan Fedacko PJ Safaric University, Kosice, Slovakia V.I. Fisinin All-Russian Research and Technology Institute of Poultry Production, Sergiev Posad, Russia T.I. Fotina Sumy National Agrarian University, Sumy, Ukraine K. Ghebremeskel Institute of Brain Chemistry and Human Nutrition, London Metropolitan University, London, England Scott Going Department of Nutritional Sciences, The University of Arizona, 2549 N Santa Rita Ave, #1, Tucson, AZ 85719, USA, [email protected] James J. Gormley Gormley NPI Consulting, Riverdale, NY 10463, USA, gormleyconsulting.blogspot.com R.K. Goyal Government Medical College, MS University of Baroda, Surat, Gujarat, India Jane Gregg Health Promotion, School of Health and Sport Sciences, University of the Sunshine Coast, Sippy Downs, QLD, Australia Christin Hengst Department of Nutritional Physiology, Institute of Nutrition, Friedrich Schiller University, Dornburger Str. 24, D-07743 Jena, Germany, [email protected] Melanie Hingle USDA-ARS Children’s Nutrition Research Center, Baylor College of Medicine, Houston, TX, USA Neil E. Hubbard Department of Cell Biology and Human Anatomy, School of Medicine, University of California, One Shields Ave., Davis, CA 95616-8643, USA Helene Jacques Department of Food Science and Nutrition, Institute of Nutraceuticals and Functional Foods, Laval University, 2425 Agriculture St., Paul-Comtois Building, Quebec, QC, G1V 0A6 Canada, [email protected]

Contributors

xxiii

Gerhard Jahreis Department of Nutritional Physiology, Institute of Nutrition, Friedrich Schiller University, Dornburger Str. 24, D-07743 Jena, Germany, [email protected] Esbelle M. Jowers Exercise and Sport Psychology Laboratory, Department of Kinesiology and Health Education, The University of Texas, 1 University Station, D3700, Austin, TX 78712-1204, USA, [email protected] Vijaya Juturu UnitedBio-Med Inc, 102 Hunters Run, DobbsFerry, NY 10522, USA F. Karadas Department of Animal Science, Faculty of Agriculture, University of Yuzuncu Yil, Van, Turkey Nesrin Kartal-Özer Department of Biocemistry, Faculty of Medicine, Marmara University, 34668, Istanbul, Turkey Jose Katz Department of medicine, Columbia University, New York 10033, USA Darshan S. Kelley Department of Nutrition, Western Human Nutrition Research Center, ARS, USDA, University of California, Davis, CA 95616, USA, [email protected] Nirvair S. Kelley Department of Cell Biology and Human Anatomy, School of Medicine, University of California, One Shields Ave., Davis, CA 95616-8643, USA ´ Łukasz Łapinski Psychological Center PARTNER, Wieczorka 22 Str, Gliwice, Poland, [email protected] Douglas F. Larson College of Medicine, Sarver Heart Center, The University of Arizona, Tucson, AZ 85724, USA Nadine Leblanc Department of Food Science and Nutrition, Institute of Nutraceuticals and Functional Foods, Laval University, 2425 Agriculture St., Paul-Comtois Building, Quebec, QC, G1V 0A6 Canada C. Lehane Institute of Brain Chemistry and Human Nutrition, London Metropolitan University, London, England M. Mezes Szent István University, Gödöll˝o, Hungary Robert J. Moffatt Department of Exercise Science, Nutrition and Food, Florida State University, Tallahassee, FL 32306 Lily O’Hara Public Health in the School of Health and Sport Sciences, University of the Sunshine Coast, Sippy Downs, QLD, Australia, [email protected]. T.T. Papazyan Alltech Russia, Moscow, Russia A.C. Pappas Laboratory of Nutritional Physiology and Feeding, Faculty of Animal Science and Aquaculture, Agricultural University of Athens, Athens, Greece Daniel Pella PJ Safaric University, Kosice, Slovakia

xxiv

Contributors

Basant K. Puri MRI Unit, Hammersmith Hospital, Du Cane Road, London, W12 0HS, UK, [email protected] S.S. Rastogi Halberg Hospital and Research Institute, Moradabad, UP 244001, India Uffe Ravnskov Magle Stora Kyrkogata 9, 22350 Lund, Sweden, [email protected] Arash Sabetisoofyani College of Medicine, Sarver Heart Center, The University of Arizona, Tucson, AZ 85724, USA Rakesh Sharma Department of medicine, Columbia University, New York 10033, USA; Center of Nanomagnetics and Biotechnology, Florida State University, Tallahassee, FL 32304, USA, [email protected] Ram B. Singh Helberg Research Institute, Moradabad, Uttar Pradesh, India Isabelle Sioen Department of Public Health, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium, [email protected] Cassandra Stanton Transdisciplinary Research Group, Department of Psychiatry and Human Behavior, Butler Hospital, The Warren Alpert Medical School of Brown University, Providence, RI 02906, USA, [email protected] P.F. Surai Avian Science Research Centre, Scottish Agricultural College, Ayr, UK; Division of Environmental and Evolutionary Biology, University of Glasgow, Glasgow, UK; Szent István University, Gödöll˝o, Hungary; Sumy National Agrarian University, Sumy, Ukraine; Trakia University, Stara Zagora, Bulgaria, [email protected] Stefano Togni DVM—Indena SpA, Viale Ortles, 12, Milano, 20139 MI, Italy, [email protected] Simin B. Vaghefi Department of Nutrition and Dietetics, College of Health, University of North Florida, Jacksonville, FL, USA S. Vajpayee Government Medical College, MS University of Baroda, Surat, Gujarat, India Johan Van Camp Department of Food Safety and Food Quality, Faculty of Bioscience Engineering, Ghent University, Ghent, Belgium, [email protected] Hannah R. Vasanthi Cardiovascular Research Center, University of Connecticut School of Medicine, Farmington, CT, USA; Department of Biochemistry, Sri Ramachandra Medical College and Research Institute, Sri Ramachandra University, Chennai, India Madhuri Vemuri Department of Nutrition, Western Human Nutrition Research Center, ARS, USDA, University of California, Davis, CA 95616, USA Y. Wang Institute of Brain Chemistry and Human Nutrition, London Metropolitan University, London, England Julia Watkins Department of Nutrition and Dietetics, College of Health, University of North Florida, Jacksonville, FL, USA

Contributors

xxv

Ronald Ross Watson College of Medicine, Sarver Heart Center, The University of Arizona, Tucson, AZ 85724, USA; College of Public Health, The University of Arizona, Tucson, AZ 85724, USA ´ Agnieszka Wilczynska-Kwiatek Institute of Psychology, University of Silesia, ul. ˙ Grazy´nskiego 53, 40-126 Katowice, Poland, [email protected]; [email protected] Sherma Zibadi College of Medicine, Sarver Heart Center, The University of Arizona, Tucson, AZ 85724, USA; College of Public Health, The University of Arizona, Tucson, AZ 85724, USA

Part I

Behavioral Aspects of Eating

Chapter 1

Western Diet and Behavior: The Columbus Concept ´ Agnieszka Wilczynska-Kwiatek, Fabien De Meester, Ram B. Singh, ´ and Łukasz Łapinski

Key Points • Increased intake of refined grains and fast foods is associated with a lower intake of ω-3 fatty acids, vitamins, and antioxidants, and associated with a sequence in the emergence of chronic diseases of affluence. • Increased consumption of refined carbohydrates may also increase the risk of mental disorders: not only depression, anxiety, stress, personality, and behavioral disorders but also general cognitive impairment in older people. • Dietary intake of ω-3 fatty acids, antioxidant vitamins A, E, C, and beta-carotene is inversely associated with these psychological disorders. • There is some evidence that increased intake of linoleic acid, saturated fat, and trans fat as well as refined carbohydrates is proinflammatory, leading to increased plasma levels of transcription factors of proinflammatory cytokines. • As cytokines may be positively associated with affective and anxiety-related disorders and type A behavior, available clinical trials indicate that treatment with ω-3 fatty acids can modulate depression and behavioral disorders. Keywords Diets · Food · Nutrients · Fatty acids · Depression · Anxiety · Psychological disorders · Cognitive impairment

1 Introduction Research has indicated that brain function is highly sensitive to variations in diet. Probably the best known example is the consumption of caffeine, which is present in tea, coffee, chocolate, and other foods. Caffeine is a stimulant that improves mental alertness and performance. It has become clear that many other dietary components—from vitamins to macro-elements— influence brain function. For some, biochemical effects, and for others, behavioral and functional

A. Wilczy´nska-Kwiatek () Institute of Psychology, University of Silesia, ul. Graz˙ y´nskiego 53, 40-126 Katowice, Poland e-mails: [email protected]; [email protected] F. De Meester et al. (eds.), Modern Dietary Fat Intakes in Disease Promotion, Nutrition and Health, DOI 10.1007/978-1-60327-571-2_1, © Springer Science+Business Media, LLC 2010

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effects have been reported. As the study of nutrition, behavior, and brain function is relatively new, it is not surprising that huge gaps exist in the biochemical, physiological, psychological, and behavioral aspects of our knowledge of how diet affects brain function. However, some accurate and relevant data are available. Clear functional effects seem evident although underlying mechanisms are still inadequately understood. The aim of this chapter is to identify the effects of dietary constituents and functional food components (particularly ω-3 fatty acids) on psychological function and mental health.

2 Changing Patterns of Food Consumption in Western Societies As with all organisms, people are dependent on food in order to live and function, yet the nature of this relationship has gone through continual change. Hunter–gatherer cultures were forced to cope with the limited amount of food available in their surroundings. On the other hand, life in most Western civilizations allows for consumption of a considerably higher quantity of calories than what the human body actually requires [1], and the food eaten may come from the furthest reaches of the planet. Barry M. Popkin [2, 1] emphasized that the underlying shifts in demographic, economic, cultural, and related forces that affect fertility, mortality, and disease patterns also affect the structure of diet, physical activity, and body-composition trends. Popkin claimed that nutrition transition has followed five general patterns (see Table 1.1), which are not necessarily restricted to particular periods of human history: (1) hunting and gathering, (2) famine, (3) receding famine, (4) degenerative disease, and (5) behavioral change. The first pattern is found in hunter–gatherer societies, whose diets might be acknowledged to be very healthy. Those societies are nonetheless generally characterized by a very low life expectancy, usually as a result of infectious diseases and other natural causes. As new techniques for gathering food developed, hunter–gatherer societies moved away from a diet based on game, fruits, and vegetables and became more dependent on farming; therefore, grains and cereals became predominant features of their diets. The second pattern is found in simple farming cultures that experience alternating periods of famine and harvest. The Industrial Revolution brought with it colossal dietary changes, and the influx of an enormous labor force into cities required a large amount of inexpensive food to feed them. These requirements were met in part by dramatic changes in the manner of processing and preserving food, for example, canning, freezing, increasingly cheap methods of grinding grains (removing many of their nutrients), and the production of sugar and vegetable oil. Finally, the twentieth century increased the pace of change in food processing in hitherto unimaginable ways. One of the effects, besides increased health and shifting lifestyles, is the fact that current widespread diets differ considerably from those of our ancestors in both quantity and quality. The three consecutive patterns described by Popkin concern the contemporary world to a great degree. In pattern 3, famine begins to recede as income rises. In pattern 4, changes in nutrition as a result of quick economic and industrial development are connected with different diseases such as CVD, depression, and cancer. This pattern may be considered typical of most Western societies. Western diets are becoming increasingly energy dense and sweet. In addition, high-fiber foods are being replaced by processed versions of the same foods [2, 1]. The increased intake of refined grains and fast foods is associated with a lower intake of ω-3 fatty acids, leading to a sequence in the emergence of chronic diseases of affluence: obesity, diabetes, metabolic syndrome, heart attack, and bone and joint diseases. Such dietary changes

Robust, lean population; few nutritional deficiencies

Hunter–gatherers

Primitive, onset of fire

Subsistence, primitive stone tools

Economy

Household production

Income and assets

Plants, low-fat wild animals, varied diet

Nutritional status

Nutrition profile Diet

Labor intensive, primitive technology begins (clay cooking vessels) Subsistence, few tools

Children and women suffer most from low fat intake, nutritional deficiency diseases emerge, stature declines Agriculture, animal husbandry, homemaking begin; shift to monocultures

Cereals predominant, diet less varied

Table 1.1 Characteristics of the five patterns of the nutrition transition by Popkin Transition profile (1) Collecting food (2) Famine

Increases in income disparity and agricultural tool industrialization

Fewer starchy staples; more fruit, vegetables, animal protein; low variety continues Continued MCH1 nutrition problems, many deficiencies disappear, weaning diseases emerge, stature grows Second agricultural revolution (crop rotation, fertilizer), Industrial Revolution, women join labor force Primitive water systems, clay stoves, cooking technology advances

(3) Receding famine

Rapid growth in income and income disparities, technology proliferation

Fewer jobs with heavy physical activity, service sector and mechanization, household technology revolution Household technology mechanizes and proliferates

More fat (especially from animal products), sugar, processed foods; less fiber Obesity, problems for elderly (bone health, etc.), many disabling conditions

(4) Degenerative disease

Service sector mechanization and industrial robotization dominate, increase in leisure exercise offsets sedentary jobs Significant reduction in food preparation costs as a result of technologic change Decrease in income growth, increase in home, and leisure technologies

Higher quality fats, reduced refined carbohydrates, more whole grains, fruit, vegetables Reduction in body fat and obesity, improvement in bone health

(5) Behavioral change

1 Western Diet and Behavior: The Columbus Concept 5

Much infectious disease, no epidemics

Young population

Rural, low density

Nonexistent

Age structure

Residency patterns

Food processing

Low fertility, high mortality, low life expectancy

(1) Collecting food

Morbidity

Demographic profile Mortality and fertility

Table 1.1 (continued) Transition profile

Food storage begins

Rural, a few small, crowded cities

Young, very few elderly

Epidemics, endemic disease (plague, smallpox, polio, tuberculosis), deficiency disease begins, starving common

Age of Malthus; high natural fertility, short life expectancy, high infant and maternal mortality

(2) Famine

Chiefly rural, move to cities increases, international migration begins, megacities develop Storage processes (drying, salting) begin, canning and processing technologies emerge, increases in food refining and milling

Chiefly young, shift to older population begins

Mortality declines slowly, then rapidly; fertility static, then declines; small, cumulative population growth, which later explodes Tuberculosis, smallpox infection, parasitic disease, polio, weaning disease (diarrhea, retarded growth) expand, later decline

(3) Receding famine

Numerous food-transforming technologies

Lower density cities rejuvenate, increase in urbanization of rural areas encircling cities Technologies create foods and food constituent substitutes (e.g., macronutrient substitutes)

Increases in health promotion (preventive and therapeutic), rapid decline in cardiovascular disease, slower change in age-specific cancer profile Increases in the proportion of elderly >75 years of age Chronic disease related to diet and pollution (heart disease, cancer), decline in infectious disease

Rapid decline in fertility, rapid increase in proportion of elderly person Dispersal of urban population decreases in rural green space

Life expectancy extends to ages 70 and 80 years, disability-free period increases

(5) Behavioral change

Life expectancy hits unique levels (ages 60–70), huge decline and fluctuations in fertility (e.g., postwar baby boom)

(4) Degenerative disease

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may also increase the risk of mental disorders and dysfunctions, like depression, stress, anxiety, and personality and behavioral disorders—in addition to general cognitive impairment in the aged [3–5]. Recent studies (ibid. [6, 7–29]) contain advanced research on the influence of foods on individuals’ mental conditions. A crucial role has been ascribed to ω-3 fatty acids, which are particularly important for the normal functioning of most human organs. A deficiency in essential fatty acids can cause intensification of cardio-, cerebro-, and retinal–vascular diseases; brain and autoimmune diseases; cancers; obesity; diabetes; bone loss; and so forth. The researchers also emphasize the role of fatty acids in treating mental disorders such as depression, bipolar disorders, and schizophrenia, as well as aggression prevention and support in the treatment of Alzheimer’s disease (ibid. [30]). With further research the cycle of civilization-based nutritional changes can be viewed optimistically. The fifth and final pattern indicated by Popkin represents another change in thinking and behavior. However, Western societies must take precise action to promote healthy lifestyles. Pattern 5 is a positive model based on rejecting negative trends characteristic of earlier patterns. It is a conscious step toward healthy lifestyles and nutrition, with all modern knowledge and technology available as a basis for healthier choices. Such an approach is promoted by the recently developed Columbus Concept, which refers to a return of modern dietary patterns to their Paleolithic standards, with particular attention to essential fatty acids (www.columbusconcept.com).

3 A Healthful Change in Behavior A healthful change in behavior is associated with human developmental change and increased human consciousness and intentional behaviors [31]. Ajzen and Fishbein [32] explain the undertaking of health-oriented decisions by rational action theory. A change expected in the area of dietary behavior may occur when an individual has proper motivation and intention, which mark the beginning of change implementation. Changes in behavior are preconditioned by the knowledge and awareness of the direction and scale of necessity. A change in dietary behavior is equivalent to adopting a new attitude toward one’s own diet. Being complex in nature, a change in attitude must concern all of its aspects: cognitive (acquisition of knowledge and identification of benefits), emotional (positive approach, satisfaction, etc.), and behavioral (taking specific actions). Obstacles to diet-related human behavioral change are determined by dietary habits originating in socializing processes, cultural influences, and, to a significant extent, tradition. A major enemy of health is Western societies’ demands for fast and easily available food (e.g., sweets, French fries) to satisfy cravings. As a rule, the internally motivated modification of improper dietary habits and the adoption of healthful dietary behavior are determined by one’s individually perceived susceptibility to a given disease or the gravity of an already developed illness. External stimuli that favor undertaking healthful actions include health-promoting campaigns organized by mass media, other people’s advice, physicians’ indications, friends’ or family members’ diseases, and news articles [33]. According to a study conducted in 1981 by Mark Condiotte and Edward Lichtenstein [34], it is the sense of self-efficacy that plays a major role in maintaining healthful habits. It should be emphasized that everyday human functioning (including nutritional) is in a dynamic state of fragile balance [35, 36].

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Even if consumers aim to modify their nutritional and dietary habits and make them more health-oriented, the Western diet offers foods that are difficult to recognize as healthful. Maintaining a balance in human health requires returning to traditional dietary solutions by means of modern science and available technologies. This optimal approach seems well supported by the Columbus Concept as a market initiative.

4 The Columbus Concept The Columbus Concept surmises that humans evolved on a diet that was low in saturated fat with equal amounts of ω6 and ω-3 fatty acids. In nature, lipid and fatty-acid fractions are grossly balanced (polyunsaturated:saturated or P:S = ω6:ω-3 = 1:1) and rich in monounsaturated fatty acids (P:M:S=1:6:1). These ratios represent the overall distribution of fats in a natural, untamed environment (www.columbus-concept.com). The Columbus foods include eggs, milk, meat, oil, and bread, all rich in ω-3 fatty acids, similar to wild foods consumed before the agricultural revolution. Blood-lipid composition reflects one’s health status: (a) circulating serum lipoproteins and their ratio provide information on their atherogenicity to blood vessels and (b) circulating plasma fatty acids, such as the ω6:ω-3 fatty-acid ratio, indicate the proinflammatory status of blood vessels. Both (a) and (b) are phenotype related and depend on genetic, environmental, and developmental factors. As such, they appear as universal markers for holistic health. Blood cholesterol is central to this approach; blood lipoproteins affect blood-vessel integrity when circulating throughout the body. Of major importance to a healthy dietary regimen appear to be both the essential dietary nutrients (essential amino acids, fatty acids, antioxidant vitamins, and minerals) and the functional components (diet, sport, spiritualism, etc.). Dietary patterns rich in the preceding nutrients protect against chronic diseases of affluence such as CVD, diabetes, and cancer, as well as mental diseases such as depression, type-A behavior, anxiety, and stress.

5 Omega-3 and Omega-6 Polyunsaturated Fatty Acids (PUFAs) The ω6 and ω-3 PUFAs linoleic and linolenic acid are essential fatty acids in humans (and many other mammals), as they cannot be synthesized by organisms but instead have to be obtained from one’s diet. PUFAs are composed of hydrocarbon chains of variable length with a methyl group at one end (omega), a carboxyl group at the other, and several double bonds. The position of the first double bond differentiates ω-3 fatty acids (such as α-linolenic acid or C18:3ω-3) and ω6 (like linoleic acid or C18:2ω6) [37]; ω-3 PUFAs have a double bond at the third carbon, while ω6 PUFAs have one at the sixth. The chemical structures of linoleic acid (LA), α-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) are shown in Figs. 1.1, 1.2, 1.3, and 1.4, respectively. ALA, which is often called a short-chain ω-3 PUFA (C18:3ω-3), can be metabolized to longer chain PUFAs such as EPA (C20:5ω-3) and DHA (C22:6ω-3). LA can be converted to arachidonic acid or AA (C20:4ω6). The metabolism of essential fatty acids is shown in Fig. 1.5.

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Western Diet and Behavior: The Columbus Concept

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Fig. 1.1 Chemical structure of LA

Fig. 1.2 Chemical structure of ALA

Fig. 1.3 Chemical structure of EPA

Fig. 1.4 Chemical structure of DHA

n-6 Series 18:2 n-6 Linolenic Acid Δ-6 Desaturation ↓ 18:3 n-6 γ-Linolenic Acid Elongation ↓ 20:3 n-6 Dihomogammalinolenic Acid Δ-5 Desaturation ↓ 20:4 n-6 Arachidonic Acid Elongation ↓ 22:4 n-6Adrenic Acid Δ-4 Desaturation ↓ 22:5 n-6 Docosapentaenoic Acid (n-6)

n-3 Series α-Linolenic Acid ↓ Stearidonic Acid ↓ Eicosatetraenoic Acid (n-3) ↓ Eicosapentaenoic Acid ↓ Docosapentaenoic Acid (n-3) ↓ Docosahexaenoic Acid

18:3 n-3 18:4 n-3 20:4 n-3 20:5 n-3 22:5 n-3 22:6 n-3

Fig. 1.5 The metabolism of essential fatty acids

Omega-3 PUFAs are present in linseed oil, walnuts, wheat, soybeans, and particularly in game, river and coldwater algae, and sea fish (tuna, salmon, herring, etc); omega-6 PUFAs are primarily found in maize, sunflower, sesame oils, modern meat, and eggs. Some biochemical data suggest that ω-3 PUFAs play an important role in neural structure and function. The brain and the central nervous system (CNS) contain high concentrations of ω-3

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PUFAs, and several studies suggest a role for ω-3 PUFAs in neurotransmitter synthesis, degradation, release, reuptake, and binding [38–40]. Fatty acids constitute part of all phospholipids and consequently of all biological membranes. Membrane fluidity, of crucial importance for healthy membrane functioning, depends on lipidic components. In addition, membrane fluidity is determined by the phospholipids to free cholesterol ratio, as cholesterol increases membrane viscosity [41]. DHA deficit is associated with dysfunctions in neuronal membrane stability and the transmission of serotonin, norepinephrine, and dopamine, which might relate to the etiology of mood and the cognitive dysfunction of depression. A diet rich in essential polyunsaturated fatty acids allows for a higher incorporation of cholesterol in the membranes to balance their fluidity, which, in turn, contributes to lower blood-cholesterol levels [37]. The significant factor in fatty-acid efficacy does not seem to be its absolute level but instead the ratio between various groups of fatty acids. It is known, for instance, that the relative amounts of ω6 and ω-3 PUFAs in the cell membrane are responsible for affecting cellular function [42, 43]. The types of fatty acids that are available to the composition of cell membranes depend upon diet. The retina and the brain, particularly the cerebral cortex, are rich in ω-3 fatty acids [44, 45], and the role of ω-3 PUFAs in visual and cognitive development has been widely examined [46–49]. Any dietary deficits of essential PUFAs have consequences on cerebral development, modifying the activity of enzymes in the cerebral membranes. In addition, it has been ascertained that maternal intake of ω-3 PUFAs during pregnancy and lactation may positively influence the later visual and mental development of children [49, 50]. The essential PUFAs are precursors of eicosanoids—prostaglandins and leukotrienes—which are involved in inflammation and immune response, and a diet rich in fish oil reduces the production of PGE2. Furthermore, an increase in EPA intake leads to a reduction in the production of inflammatory cytokines. Therefore, it might be important to use ω-3 PUFAs in the treatment of chronic inflammatory diseases like rheumatoid arthritis. Finally, it was reported that ω-3 PUFAs might prevent the onset of hormone-dependent tumors (i.e., prostatic cancer) [51]. To sum up, DHA and EPA play roles in numerous cellular functions, including membrane fluidity, membrane enzyme activities, and eicosanoid synthesis, all of which are essential for brain development in infants and required for maintaining normal brain function in all humans [52]. On the other hand, large multi-gram amounts of ω-3 PUFAs may cause excessively prolonged bleeding, possibly resulting in hemorrhagic strokes and oxidative damage to various tissues [3]. For this reason it is often suggested to accompany ω-3 PUFA supplementation with various antioxidants such as vitamins E and C, flavonoids, and polyphenols. In fact, much evidence indicates that antioxidants are also essential in maintaining neurophysiologic conditions [53].

6 Nutrients and Brain Function Polyunsaturated fatty acids (PUFAs) constitute key structural components of the phospholipid membranes in body tissues, being especially rich in the human brain and the central nervous system (CNS) [54]. They are known to play a role in nervous system activity, neuroplasticity of nerve membranes [55], synaptogenesis [56], synaptic transmission [44], and neurotransmitter uptake. Most neurotransmitters, catecholamines, acetylcholines, serotonin, and dopamine can also affect the function of the cardiovascular system, in addition to their effects on neuropsychiatric

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systems and behaviors [57–60]. The synthesis of these neurotransmitters has been shown to depend on dietary precursors such as tryptophan, choline, tyrosine, and arginine [57, 58]. Some evidence suggests that total and saturated fat, linoleic acid, trans fat, sugar, salt, alcohol, and obesity may have adverse effects on brain and heart function as well as mental function. In contrast, ω-3 fatty acids, monounsaturated fatty acids, antioxidant vitamins, flavonoids, coenzyme Q10, potassium, magnesium, calcium, and moderate alcohol consumption may have beneficial effects. There is evidence that ω-3 fatty acids and other nutrients can affect cognitive function, mood, behavior, personality disorders, and depression (see below). Table 1.2 shows nutrients having possible effects on brain and psychological function, and Fig. 1.6 presents nutrient-related psychological disorders. Figure 1.7 illustrates the effects of lifestyle factors on biomarkers leading to cardiovascular disease and psychological problems. Table 1.2 Nutrients having possible effects on brain and psychological function

Beneficial effects

Adverse effects

Omega-3 fatty acids Monounsaturated fatty acids Vegetable proteins Soluble fiber Vitamins: A, E, C, beta-carotenes B vitamins and folic acid Coenzyme Q10 Flavonoids Potassium Magnesium Calcium Zinc Copper Selenium Chromium

Excess of total fat Excess of saturated fat trans fat Excess of linoleic acid Excess of sodium

The brain is responsible for approximately one-fifth of the body’s basal metabolism, which is provided by glucose and oxygen. Nitrogenous and lipid materials are essential to the growth and regeneration of myelin sheaths and axis cylinders as well as for enzyme systems needed for cellular metabolism and neuroprotection. Vitamins, minerals, electrolytes, ω-3 fatty acids, and coenzyme Q10 in the neurons may influence the excitability of nerve centers. These vitamins, minerals, antioxidants, flavonoids, and ω-3 fatty acids should be adequately available, as dietary deficiencies in them are associated with psychological disorders [53, 61, 62]. Epidemiological studies indicate that diets rich in antioxidants and anti-inflammatory compounds (i.e., polyphenols), such as those found in fruits and vegetables, may lower the risk of developing age-related, neurodegenerative diseases such as Alzheimer’s or Parkinson’s disease [53].

7 Nutrients and Affective Function A lack of ω-3 long-chain polyunsaturated fatty acids is implicated in the development of several human conditions and diseases, including dementia, schizophrenia, and depression [4, 5, 61]; however, ω-3 treatment of these diseases often shows positive results [63–67]. Descriptions of

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•

Affective disorders i.e. major depressive disorder, bipolar disorder, postpartum depression

•

Anxiety disorders i.e. obsessive compulsive disorder, substance abuse

• • • • • •

Stress-related disorders Schizophrenia Personality disorders Behavioral disorders and dysfunctions Attention deficit hyperactivity disorder Cognitive impairment in aging, dementia, Alzheimer’s Disease

Fig. 1.6 Psychological disorders related to nutrients

ω-3-related effects on depression, although they might be considered controversial, have led to the conclusion that ω-3 PUFAs can affect both cognitive and affective function, and may even act as “mood stabilizers.” Several lines of evidence suggest a relationship between dietary intake of ω-3 PUFAs and depressed moods in humans. In this section we aim to list the findings of published randomized controlled trials investigating the effects of dietary supplementation with ω-3 PUFAs on affective function, mainly in the treatment of mental disorders. A summary and comparison of a number of investigations in this area allows us to evaluate whether or not available data support the hypothesis that ω-3 PUFAs play a role in alleviating depression and/or anxiety. In an exhaustive search of databases (among them PubMed and EBSCO) through February 2009, we have found several clinical trials of ω-3 PUFAs in relation to affective functions1 [6, 7–29] (see Table 1.3). As can be seen in Table 1.3, the list of available clinical trials in this area makes it difficult to unambiguously affirm or reject the hypothesis about the influence of ω-3 PUFAs on emotional function. The trials vary widely, not only in terms of approach or quality of design but also in terms of groups tested, sample size, composition and quantity of PUFAs taken, length of supplementation period, and psychometric instruments used. The results of particular investigations are also ambiguous. Early studies of the relationships between ω-3 PUFAs and affective function in doubleblind, placebo-controlled trials were published by researchers at the Department of Neurology,

1 The search terms for n–3 PUFAs (n–3, omega-3, α-linolenic, eicosapentaenoic, docosahexaenoic, EPA, DHA, ALA, fish, etc.) were combined with terms for mental disorders and psychological function (depression, depressed mood, depressive disorder, affective, cognitive, anxiety, bipolar, personality, etc.).

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Fig. 1.7 Effect of lifestyle factors on biomarkers leading to cardiovascular disease and psychological problems

Keck et al.

Nemets et al.

Peet and Horrobin

Llorente et al. Marangell et al.

Su et al.

Zanarini and Frankenburg

4

5

6

7 8

9

10

2003

2003

2003 2003

2002

2002

2002

1999

Borderline personality disorder

Major depression

Postpartum depression Major depression

Unipolar depressive disorder Major depression

Bipolar disorder 2.0 g e-EPA

6.0 g e-EPA

30: 20/10

28: 14/14

4.4 g EPA 2.2 g DHA 1.0 g E-EPA

70: 17→1 g/day 1, 2, 4 g EPA 18→2 g/day 17→4 g/day 99: 44/45 Ok. 0.2 g DHA 36: 18/18 2.0 g DHA

20: 10/10

116: 59/57

30: 14/16

56

56

120 42

84

28

120

112

90

MADRS MOAS

HDRS MADRS BDI BDI MADRS HDRS HDRS

HDRS YMRS CGI GAS IDS YMRS HDRS

BDI

Yes

Yes

No No

Yes

Yes

No

Yes

No

Stoll et al.

50: 24/26

Likert scale

3

1999

90

Warren et al.

0.14 g EPA 0.09 g DHA 0.14 g EPA 0.09 g DHA 6.2 g EPA 3.4 g DHA

2

63: 39/24

Yes

Chronic fatigue syndrome Chronic fatigue syndrome Bipolar disorder

Behan et al.

1

1990

Statistical significant difference

Table 1.3 Chronological list of clinical trials investigating effects of omega-3 PUFA on depressed mood and other affective manifestations Intervention No. of subjects, total: treatDuration Outcome No. Study Year Group ment/placebo Daily dose (d) measures

14 ´ A. Wilczynska-Kwiatek et al.

Study

Post et al. Fux et al.

Hirashima et al.

Silvers et al.

Fontani et al.

Osher et al. Freeman et al.

Frangou et al.

Nemets et al.

Hallahan et al.

No.

11 12

13

14

15

16 17

18

19

20

Table 1.3 (continued)

Year

2007

2006

2006

2005 2005

2005

2005

2004

2003 2004

49: 33/16

77: 40/37

21: 12/9

121 11

Patients with recurrent self-harm

49: 22/27

12 16: 6→0.5 g EPA + DHA 3→1.4 g EPA + DHA 7→2.8 g EPA + DHA Bipolar disorder 75: 24→1 g/d 25→2 g/d 26→placebo (Children) [6–12 years] 28: 13/15 Major depression

Bipolar disorder Postpartum depression

Healthy subjects

Major depression

Bipolar disorder Obsessive–compulsive disorder Bipolar disorder

Group

No. of subjects, total: treatment/placebo

HDRS-SF BD POMS

– HDRS YBOCS T2 time HDRS

Outcome measures

112

84

HDRS CGI YMRS CDRS CDI CGI BDI HDRS MOAS IMT/DMT PSS

Up to 168 HDRS 56 EPDS CGI HRSD

35

84

28

112 42

Duration (d)

1.2 g EPA + 0.9 g DHA 84

0.38–0.4 g EPA 0.18–0.2 g DHA

1, 2 g/day e-EPA

5.0–5.2 g EPA 3.0–3.4 DHA or 1.3 g EPA 0.7 g DHA 0.6 g EPA 2.4 g DHA 1.6 g EPA 0.8 g DHA 0.4 g other n – 3 PUFAs 1.5–2 g EPA 0.5 g EPA + DHA 1.4 g EPA + DHA 2.8 g EPA + DHA Ratio EPA:DHA→1.5:1

6 g EPA 2.0 g E-EPA

Daily dose

Intervention

Yes

Yes

Yes

Yes Lack of placebo control group

Yes

No

Yes

No No

Statistical significant difference

1 Western Diet and Behavior: The Columbus Concept 15

van de Rest et al.

Buydens-Branchey et al. 2008

Lucas et al.

22

23

24

Year

Rogers et al.

21

22: 11/11

302

190: 96/94

120: 59/61 Middle-aged women with moderate-to severe psychological distress (with and without MDE diagnosis) Middle-aged women 91: 46/45 with moderate-to-severe psychological distress (without MDE diagnosis)

Substance abusers

Older subjects (≥65 years) independently living

Mild-to-moderate depressive disorder

Group

No. of subjects, total: treatment/placebo

1.05 g E-EPA 0.15 g E-DHA

2.25 g EPA + 0.5 g DHA + 0.25 other PUFAs 1.05 g E-EPA 0.15 g E-DHA

1.8 g EPA + DHA or 0.4 g EPA + DHA

0.63 g EPA 0.85 g DHA

Daily dose

Intervention

56

56

84

182

84

Duration (d)

PGWB HSCL-D-20 HDRS

PGWB HSCL-D-20 HDRS

DASS BDI GHQ STAI CES-D MADRS GDS-15 HADS-A POMS

Outcome measures

Yes

No

Yes

No

No

Statistical significant difference

EPA Eicosapentaenoic acid; e-EPA, ethyl eicosapentaenoate; DHA, docosahexaenoic acid; MDE. major depressive episode; BDI, Beck Depression Inventory; HDRS, Hamilton Depression Rating Scale; HDRS-SF, HDRS Short Form; YMRS, Young Mania Rating Scale; CGI, Clinical Global Impression; GAS, Global Assessment Scale; IDS, Inventory of Depressive Symptomatology; MADRS, Montgomery-Asberg Depression Rating Scale; MOAS, Modified Overt Aggression Scale; YBOCS, Yale-Brown Obsessive–Compulsive Scale; POMS, Profile of Mood States; EPDS, Edinburgh Postnatal Depression Scale; CDRS; Children’s Depression Rating Scale; CDI, Children Depression Inventory, IMT/DMT, Immediate and Delayed Memory Tasks; PSS, Perceived Stress Scale; DASS, Depression Anxiety and Stress Scales; GHQ, General Health Questionnaire; STAI, State-Trait Anger Inventory; CES-D, Center for Epidemiologic Studies Depression Scale; GDS-15, Geriatric Depression Scale; HADS-A, Hospital Anxiety and Depression Scale; PGWB, Psychological General Well-Being Schedule; HSCL-D-20, 20-item Hopkins Symptom Checklist Depression Scale.

2009

2008

2008

Study

No.

Table 1.3 (continued)

16 ´ A. Wilczynska-Kwiatek et al.

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University of Glasgow [7]. In 1990, a group of 63 adults with the diagnosis of post-viral fatigue syndrome were enrolled in a clinical trial of essential fatty-acid therapy involving daily administration of small doses of ω-3 PUFAs over a 3-month period. In consultation with the patients and using a Likert scale, doctors assessed overall condition, fatigue, depression, myalgia, dizziness, and poor concentration. At 1 month, 74% of patients on active treatment and 23% of those on placebos assessed themselves as improved over the baseline. At 3 months the corresponding figures were 85 and 17% (P <0.01), which shows that the placebo group had reverted toward the baseline state, while those in the ω-3 PUFA group demonstrated continued improvement. The positive therapeutic results obtained by Behan and colleagues became an inspiration for scientists and opened the field for further research. Warren et al. [8] attempted to replicate the study by Behan et al. (with similar composition, doses, and duration), using a more reliable and objective measure, namely the Beck Depression Inventory (BDI). Although some slight improvement was noted in the participants’ conditions, no significant differences were observed between the treatment and placebo groups. Therefore, it was not possible to repeat the results of Behan et al. using the current research criteria for chronic fatigue syndrome. No such powerful effects could be confirmed. Since about 2002 we have observed increased interest among researchers in the influence of fatty acids on psychological function and mental health. A few studies have reported improvements in depressive symptoms associated with bipolar disorder (BD) after supplementation with ω-3 PUFAs compared with a placebo [9, 21, 23]. Stoll and associates [9] observed that, compared to subjects receiving the placebo (olive oil), patients with bipolar disorder who had received fish oils (6.2 g/day EPA and 3.4 g/day DHA) for at least 30 days were significantly less likely to relapse and experienced significantly longer remission times. It has been reported that ω-3 PUFA groups also showed better improvement than did the group given olive oil for both depressive symptoms [using the Hamilton Depression Rating Scale (HDRS)] and overall pathology [using the Clinical Global Impression (CGI) and Global Assessment Scales (GAS)], but not for manic symptoms assessed with the Young Mania Rating Scale (YMRS). Although the sample was small, it was the first study that indicated a potentially beneficial influence of ω-3 PUFAs in BD, particularly in the depressive phase. Similar effects were observed in a later investigation conducted by Frangou et al. [23]. They conducted a high-quality, controlled trial of 75 medicated outpatients with BD who were supplemented with either 1 or 2 g EPA ethyl ester (e-EPA) or a placebo for about 84 days. Although no significant effect from either dose was observed on mania, the authors reported statistically significant effects of EPA on depressive symptoms (regardless of the dose taken). An investigation performed by Osher et al. [21] also—though seriously limited by the open-label design and small sample size—seemed to confirm the beneficial influence of 1.5–2 g/day EPA in the depressive phase of BD. Major depressive disorder is one of most common and serious affective diseases, with a lifetime prevalence estimated in between 5 and 11% of the population [68]. This illness is understood to have a complex biological, psychological, and sociological etiology, and completely effective therapy has not yet been found. Most treatments have a response rate (defined as 50% improvement in symptoms) of about 66%, and around 80–90% of patients eventually respond to some treatment. However, about 10–20% of patients are treatment refractive; in other words, they do not respond at all or respond poorly to treatments. Such statistics show that there is much room for innovation and improvement in the prevention and treatment of depression. Diet has been suggested as playing a role in depression, and it has been widely discussed that the rising rates of

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this disorder are at least partially due to a decreased consumption of ω-3 PUFAs, which are being replaced in the diet by ω6 fatty acids and trans fats. What supports this hypothesis is that studies of subjects with depressive disorder have reported statistically important, consistent deficits in ω-3 PUFAs in their blood plasma/serum and red blood cells, while ω6 PUFA levels seem largely unaffected, and as a result there are higher ω6:ω-3 ratios (i.e. [69–71]). This evidence is leading researchers to undertake further attempts at clinical trials of ω-3 PUFAs on subjects with depressive disorders. Initially, a double-blind, placebo-controlled trial testing the role of ω-3 supplementation in major depressive disorders was carried out by Peet and Horrobin [6]. They supplemented 70 subjects2 with 1, 2, or 4 g/day ethyl ester-EPA (eEPA) or a placebo for 84 days. It was reported that a daily dose of 1 g e-EPA, but not 2 or 4 g/day, was significantly more efficient than the placebo in improving symptoms, as measured by the Hamilton Depression Rating Scale (HDRS), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Beck Depression Inventory (BDI). The first significant effects were observed after 28 days of supplementation. Though the effect is not really impressive (i.e., e-EPA reduced the HDRS score by 3.8 points more than did the placebo), it is significant. Moreover, the authors have reported that a higher proportion of patients receiving 1 g/day obtained about 50% improvement in their symptoms as compared with those in the placebo group. A beneficial effect of ω-3 PUFAs on mood disorders was shown in the work of Nemets et al. [11], as well. Twenty patients with a diagnosis of unipolar disorder were administered a daily dose of 2 g e-EPA for 28 days. The authors reported a significant reduction in depressive symptoms rated by HDRS in the ω-3 group compared to the placebo group after 2, 3, and 4 weeks. Similar to Peet and Horrobin’s trial, Nemets and associates observed that a significantly higher proportion of patients obtained a 50% reduction in symptoms in the ω-3 PUFA group as compared to those in the placebo group. An apparent antidepressant effect of EPA and DHA in the treatment of affective disorders has been reported by Su et al. [14]. Investigators conducted a shorter duration, 8-week, doubleblind, placebo-controlled trial comparing ω-3 PUFAs (440 mg/day EPA + 220 mg/day DHA) with a placebo, in addition to their usual treatment, of 28 patients with major depressive disorder. Interestingly, participants in the EPA + DHA group showed significant differences in HDRS (compared with those in the placebo group) from the 4th week of supplementation, and the differences between placebo and ω-3 groups kept increasing to week 8. It should be noted, however, that the sample was rather small. An investigation by Nemets et al. [24] shows a significant therapeutic influence of small doses of EPA + DHA on depression occurring in children. Childhood depression is less common than that in adults but is still estimated to affect 2–4% of children [24]. The authors administered 0.38–0.4 g/day EPA + 0.18–0.2 g/day DHA or a placebo for 112 days to 28 children who were currently depressed. The ω-3 group showed significant improvement as compared to the placebo group when results were analyzed using both the Children’s Depression Rating Scale (CDRS) and the Clinical Global Impression (CGI) Scale. It is also worth mentioning that participants did not take conventional antidepressant pharmaceutical treatments.

2 Participants with major depressive disorder who had persistent symptoms of depression in spite of conventional antidepressant pharmaceutical treatment.

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Most recently, ω-3 PUFA supplementation has been reported to be beneficial in psychological distress. An investigation published in February 2009 by Lucas et al. [29] concerns the comparison of e-EPA supplementation with a placebo for the treatment of psychological distress (PD) and depressive symptoms in middle-aged women. One hundred and twenty women with moderate-to-severe PD were administrated with either 1.05 g/day e-EPA + 0.15 g/day e-DHA or a placebo for 8 weeks. Researchers at Laval University, Saint Francois d’Assise Hospital, Quebec, observed very curious results. Taking into consideration the entire sample, no significant difference between the ω-3 PUFA group and the placebo group was confirmed. However, when only individuals who did not meet the major depressive disorder criteria of the DSM-IV (n = 91) were analyzed after 8 weeks, a significant reduction in psychological distress was noted, as rated by the Psychological General Well-Being Schedule (PGWB). In addition, a reduction of depressive symptoms as measured with both the 20-item Hopkins Symptom Checklist Depression Scale (HSCL-D-20) and the 21-item Hamilton Depression Rating Scale (HAM-D-21) was observed in the ω-3 PUFAs group (as compared with the placebo group). These results are in line with the investigation made by Hamazaki et al. [30]. These results permit us to suppose that ω-3 PUFAs can positively influence negative emotional states in healthy individuals as well. This hypothesis is not new, as Fontani et al. [20] have already published their investigation concerning ω-3 PUFAs’ effects on mood and cognitive and physiological functioning in healthy humans. This trial, conducted at the University of Siena, was aimed at examining the effects of ω-3 supplementation on healthy volunteers performing a series of attention tests (tests involving different types of attention were used). The tests were accompanied by neurophysiological recordings to evaluate the possible modification of neuroelectrical parameters (EEG and EMG). Each test subject’s mood was diagnosed (using Profile of Mood States, POMS), and the subject’s reaction time was recorded. Subjects were tested at the beginning of the experiment and after 35 days. Blood samples were taken on day 1 and day 35 to analyze specific parameters: AA:EPA ratio, cholesterol, triglycerides, HDL, LDL, and glycemia. Over a period of 35 days, participants were supplemented with ω-3 PUFAs. In addition, a control group was supplemented with a placebo (olive oil). After this 35-day supplementation, blood analyses showed that the AA:EPA ratio was strongly reduced by ω-3 treatment. Supplementation with ω-3 PUFAs was associated with clear variations in the profile of mood state. The POMS analysis showed an increase in vigor and a decrease in such mood states as anger, anxiety, fatigue, depression, and confusion. The reaction time in attention tests also decreased only after ω-3 supplementation. Though the sample was not large, the results strongly suggest the beneficial influence of ω-3 PUFA supplementation on the general psychological state, including mood and cognitive function, non-specific for depressive disorders. Data supplied by Fontani et al. reinforce the hypothesis of the direct action of ω-3 fatty acids on the central nervous system. It may be assumed that the importance of these results is strengthened by the fact that they occurred within subjects in good health and leading physically active lifestyles (i.e., in whom ω-3 PUFAs improved an already good condition of well-being). In spite of the fact that much evidence suggests a significant influence exerted by dietary intake of fatty acids on affective function, the actual effects of ω-3 PUFAs on depressed moods remain unclear. Indeed, a number of studies show a lack of therapeutically important effects of ω-3 PUFA supplementation on mood and psychological states. A study by Hakkarainen et al. [65] examined a total of 29,133 men aging from 50 to 69 years in a population-based trial in Finland and did not find associations between the dietary intake

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of ω-3 PUFAs or fish consumption and depressed mood, major depressive episodes, or suicide. Here, we must take into consideration that general fish consumption is much higher in Finland than in many other European countries, including Poland, and that there might be a dietary intake level above which ω-3 PUFAs are of no further benefit. Marangell et al. [13] reported that a daily dose of 2 g DHA did not improve depressivesymptom scores relative to placebos. However, this trial differed from previous investigations reporting positive findings in that the authors used a composition high in DHA rather than high EPA or e-EPA. Karen M. Silvers et al. [19] conducted a placebo-controlled trial of DHA-rich supplementation in the treatment of depression. Seventy-seven patients received either 2.4 g/day DHA, 0.6 g EPA, or a placebo. The authors used different inclusion criteria than those used in other trials: participants were included in this trial based on their HDRS score rather than through psychiatric interviews (as a consequence, this group of participants might have been more heterogenous). Although significant reduction in depressive symptoms measured by HDRS was observed, no difference was apparent between placebo and ω-3 PUFA groups. Such a large change in both groups could also have been caused by an exceptionally powerful placebo effect or a potential lack of pathology in the subjects at the baseline. It is therefore difficult to draw decisive conclusions from this study. British researchers [26] conducted a large double-blind, randomized controlled trial to evaluate the effects of EPA + DHA supplementation (1.48 g/day) on mood and cognitive function in mildly to moderately depressed individuals (190 participants completed the planned 12-week intervention). Compliance, confirmed by plasma fatty-acid concentrations, was good, but there was no evidence at 12 weeks of a difference between supplemented and placebo groups in the depression subscale of Depression, Anxiety, and Stress Scales (DASS) (adjusted difference in mean: –1.0; 95% CI; P = 0.27). Other measures of mood, mental health, and cognitive function, including a Beck Depression Inventory score and attention bias toward threat words, were similarly minimally affected by the intervention. Substantially increasing EPA + DHA intake for 3 months was found to have neither beneficial nor harmful effects on mood in mild-to-moderate depression. Keck and associates [10] in their investigation focused on two groups of patients with bipolar disorder: those with a current depressive episode and those with rapid-cycling bipolar disorder. The authors observed no beneficial influence of 6 g/day e-EPA treatment as compared with a placebo for either depression or mania measured with the Yound Mania Rating Scale (YMRS) or the Inventory of Depressive Symptomatology (IDS). Finally, Llorente et al. [12] reported no therapeutically significant influence of small doses of DHA (0.2 g/day) on postpartum depression, but it should also be noted that female participants had minimal depressive symptoms at the baseline, and just a few of them became depressed. In order to statistically compile and compare data from available trials—which differ from each other in methodology, research-group selection, dose, size, and so forth—Appleton et al. [72] conducted a study aimed at systematically reviewing published randomized controlled trials investigating the effects of ω-3 PUFAs on depressed moods. Eight medical and health databases were searched through all years on record up to June 2006 for trials that exposed participants to ω-3 PUFAs or fish, measured depressed mood, were conducted on human participants, and included a comparison group. The participants either had diagnoses of various clinical conditions or were healthy volunteers. Twelve of the trials mentioned here have been taken under consideration. The pooled standardized difference in mean outcome (fixed-effect model) was

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0.13 SDs (95% CI: 0.01; 0.25) in those receiving ω-3 PUFAs as compared with the placebo, with strong evidence of heterogeneity (I2 = 79%, P <0.001). A sensitivity analysis that excluded one large trial increased the effect size but did not reduce heterogeneity. Meta-regression provided some evidence that the effect was stronger in trials involving populations with major depression—the difference in the effect size was 0.73 (95% CI: 0.05; 1.41; P = 0.04), but there was still considerable heterogeneity when trials that involved populations with major depression were pooled separately. Appleton and associates’ investigation indicates that trial evidence which examines the effects of ω-3 PUFAs on depressed mood is limited and difficult to summarize and evaluate due to considerable heterogeneity. Most trials available were of rather small scale, short duration, and used different combinations of varying doses of ω-3 in diverse groups of subjects. The evidence considered provided insufficient support for the use of ω-3 PUFAs to improve depressed mood. Larger trials with adequate capability to detect clinically important benefits are still required. Although, up to now, researchers have mainly focused their attention on the role of dietary intake of ω-3 in depression, it is worth remarking that numerous interesting trials have also been conducted involving other disorders and psychological states that include underlying emotionalfunction disorders or dysfunctions. Nonetheless, it must be admitted that few tests have thus far been conducted, and our knowledge of the connection between nutrition and psychological function still suffers from many gaps in potential areas of research. Concerning personality disorders, up until now only investigations of ω-3 PUFAs in borderline personality disorder therapy have been undertaken. Zanarini and Frankenburg [15] supplemented 30 women with the disorder with a daily dose of 1 g e-EPA or a placebo for 56 days. Aggression was measured with the Modified Overt Aggression Scale (MOAS) and depression was measured with the MADRS. The authors reported that participants treated with a ω-3 PUFA compound experienced a significantly greater reduction in overall aggression and depressive symptoms as compared to those treated with the placebo. However, when we looked more carefully at the results obtained, we observed that after the supplementation period, the real difference between the treatment and placebo groups barely registered –1.5 in the MADRS or –0.8 in the MOAS. We can thus recognize that the conclusions drawn by the authors might have been a bit exaggerated. As this is the only available research concerning ω-3 and personality disorders, we acknowledge that the significance of fatty acids in therapy for related disorders remains unclear. Fux, Benjamin, and Nemets [17] in their crossover trial examined the effects of PUFAs in obsessive–compulsive disorder (OCD). Eleven participants with mild OCD were allocated to begin 6 weeks of a placebo followed by 6 weeks of 2 g/day EPA or the other way around, i.e. 6 weeks of 2 g/day EPA followed by 6 weeks of a placebo. The authors concluded that EPA in the treatment of this disorder was not efficacious, as no significant difference compared to the placebo on any of the scales was found. Let us keep in mind, however, that a decidedly small sample was used in the experiment, and the period of supplementation was comparatively short. Despite the fact that the authors did not observe a significant influence of PUFAs, the visible limitations of their experiment force us to acknowledge that the role of ω-3 in treating OCD requires further trials and investigation. The efficacy of ω-3 fatty acids in patients with recurrent self-harm practices was assessed in an investigation conducted by Hallahan and colleagues [25]. Forty-nine patients presenting after

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an act of repeated self-harm were administrated with either 1.2 g/day EPA + 0.9 g/day DHA or a placebo for 12 weeks in addition to standard psychiatric treatment. Depression had been assessed with the BDI and the HDRS, suicidality and aggression with the MOAS, impulsivity with the Immediate and Delayed Memory Tasks (IMT/DMT), and daily stresses with the Perceived Stress Scale (PSS). After supplementation the ω-3 group, compared to the placebo group, reported significantly greater reductions in suicidality, depression, and daily stresses. These data to some extent confirm the results of other investigations. Tanskanen et al. [73, 74], in research on a random sample, found that frequent fish consumption might be coupled with a reduced risk of suicidal ideation. In the Huan et al. study [75], there was a nearly eightfold difference in the number of suicide attempts between the lowest and the highest red blood cell EPA level quartiles. It seems likely that there is some relationship between ω-3 fatty acids and suicidal and self-destructive tendencies. Yet here as well, the available quantity of empirical evidence is insufficient. Further investigations in this field are needed. The associations between dietary intakes of PUFAs and mood state in substance abusers were investigated by Buydens-Branchey and colleagues [28]. Once a day, investigators administered either a placebo or a ω-3 PUFA supplement providing 2.25 g EPA, 0.5 g DHA, and 0.25 g other PUFAs to 22 patients treated for substance abuse. Assignment to ω-3 PUFA treatment was accompanied by significant decreases in anger and anxiety scores after a 3-month treatment as compared to placebo assignment. Over the last few decades, the typical age for the onset of major depression has become younger, and its incidence on the whole has increased 20-fold in the Western world since the 1940s. This growth in depression cannot be fully explained by better diagnostic criteria or changes in the attitudes of health specialists [76]. With the unsatisfactory results achieved by monoamine-based pharmacotherapy and the high co-morbidity of other medical illnesses in depression, the serotonin hypothesis appears to be insufficient in approaching the etiology of depression. Based upon evidence from epidemiological data (among others [77, 78]), case– control studies of phospholipid PUFA levels in human tissues, and antidepressant effects in clinical trials, PUFAs have shed a light which could help to discover the unsolved mystery of depression and connections between the mind and the body. The deficit of ω-3 PUFAs has been reported to be associated with neurological, cardiovascular, cerebrovascular, autoimmune, and metabolic diseases, in addition to cancers and psychological conditions and diseases. For instance, animals fed high AA diets (with concomitantly low tissue EPA and DHA) or treated with PGE2 were observed to present symptoms of anorexia, low activity, and changes in sleep patterns and attention, all of which are similar to somatic symptoms of depression in humans. Thus, the deficit of EPA and DHA in depression could be associated with mood disturbance, cognitive dysfunction, medical co-morbidity, and somatic symptoms in depression. Indeed, the role of ω-3 PUFAs in immunity and mood function supports the promising psychoneuroimmunological hypothesis of depression and provides an excellent interface of body and mind [79]. Still, it has not been precisely determined how ω-3 PUFAs affect psychological function. There are several possible mechanisms by which EPA and DHA could improve mood in affective disorders. EPA and DHA are intrinsic to the molecular structure of cell-membrane phospholipids. The fatty acids are also crucial in their role of modulating protein functions in the membrane. PUFAs lend fluidity to cell membranes and have specific functional interactions with membrane enzymes, receptors, and other proteins. Both EPA and DHA can inhibit the protein kinase C–signal transduction enzyme complex. In addition, EPA and DHA can block calcium influx into

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the cell through the L-type calcium channel, similar to the calcium channel blockers verapamil or nimodipine [80]. Omega-3 fatty acids are often employed in addition to conventional medicine. This is because some psychiatric patients with persistent anxiety or depression are dissatisfied with the apparent ineffectiveness of traditional treatments and seek a more holistic approach with fewer side effects. Nevertheless, the role of ω-3 PUFAs as an adjunct to antipsychotics and melatonin as a treatment or prophylactic agent for side effects remains ambiguous, requiring further trials with sound methodology [81].

8 Nutrients and Cognitive Function It has also been suggested that ω-3 PUFA intake (and consequently high ω-3 PUFA blood concentrations) might be associated with human cognitive function. However, the majority of studies conducted in this field have considered only pathological situations. Many investigations have ascertained that dietary intake of fish and ω-3 PUFAs is associated with a lower risk of cognitive impairment, dementia, Alzheimer’s disease, and stroke [63, 64, 82, 83]. On the other hand, relatively few studies have examined the beneficial role of ω-3 PUFAs in cognitive performance in healthy adults. Assessments of the cognitive benefits to adults are limited mainly because of a lack of information on the characteristics of food-supplement users, subjects’ diets, and the fact that those who seem healthier are also more likely to watch their diets and use supplements. For instance, the relationship between better retention of cognitive function in later life and diet might be explained by better lifelong cognitive function informing health choices in old age. Most studies in this field use observational designs, and relatively few studies of the cognitive benefits of proper diet and food-supplement use have adjusted the results for the possible role of mental ability in earlier life, mainly because this information is usually not available (instead, years of formal education and so forth are often relied on as measures of mental ability). Nevertheless, there is a strong suggestion that ω-3 PUFA intake affects cognitive performance in adults. Lawrence J. Whalley et al. [84, 85] conducted an observational study of 350 mentally healthy subjects born in 1936 whose mental ability was tested in 1947 and who were followed up in 2000/2001, at which point cognition, diet, supplement use, and risk factors for vascular disease were assessed. This investigation showed that the use of food supplements in late adulthood is associated with improved cognitive performance. Furthermore, this association does not depend on differences in cognitive ability present in childhood. Specific cognitive advantages at the age of 64 were found in users of food supplements (including fish oil supplementation), as compared with nonusers. Cognitive advantages were found on the digit-symbol subtest, which is highly sensitive to cognitive aging and Alzheimer’s disease. The blood samples of fish oil users and nonusers were examined; there were significant correlations between childhood IQ and erythrocyte ω-3 PUFAs in 2000/2001. This means that higher childhood IQ is probably associated with higher ω-3 PUFA/fish oil consumption in later adulthood. IQ at the age of 64 years was significantly correlated in the total sample with erythrocyte membrane ω-3 PUFA content and with the ratios of DHA/AA and ω6:ω-3 PUFAs. The Whalley et al. study suggests that greater dietary fish oil consumption is related to higher cognitive function in late adulthood.

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These results coincide with those of the Norwegian investigation conducted by Eha Nurk et al. [86]. A large cross-sectional study of 2,031 healthy subjects over 70 years showed a similar relation between the intake of different amounts of seafood and cognitive performance. Generally, it was found that fish eaters had significantly better results on all cognitive tests (KOLT, TMT-A, m-DST, m-BD, m-MMSE, S-task) than did non-consumers. Participants who declared that their mean daily intake of fish and fish products was ≥10 g/day had significantly better mean cognitive tests and a lower prevalence of poor cognitive performance than did those whose intake was <10 g/day. Furthermore, the associations between total intake of seafood and cognition strongly depended on the dose and the type of fish. The maximum effect was reported at an intake of about 75 g/day and with fatty fish (the richest source of ω-3 PUFAs). The association between plasma ω-3 PUFA proportions and cognitive performance in older adults was shown in the Carla Dullemeijer et al. study [87]. In a longitudinal study, Dutch researchers found that higher plasma proportions of ω-3 PUFAs significantly predicted less decline in such cognitive domains as sensorimotor speed and complex speed over 3 years than did lower proportions of ω-3 PUFAs. Still, it has not been determined whether cognitive decline is pathological or the result of the normal aging process. Nonetheless, current scientific data indicate that fish/ω-3 PUFA consumption may be associated with a slower decline, which seems to be a valuable finding. On the whole, the above results ought to be considered with a dose of skepticism. As in all observational studies, the direction of associations between cognitive scores in later life, selfreported supplement use, and blood ω-3 PUFAs remains uncertain. For example, participants with higher mental ability may be better informed about healthy nutritional habits and therefore follow a diet rich in ω-3 and vitamins, etc. Randomized controlled trials (RCTs) offer much greater opportunity than do observational studies for the control of experimental variables such as the composition and the quantity of PUFA taken. Such designs allow avoidance of many potentially confusing elements that often make it hard to interpret an observational study. The effects of ω-3 supplementation on some cognitive and physiological parameters in healthy subjects (22–51 year) have been examined in controlled trials conducted by Fontani et al. [20] (see above). Different types of attention (Alert, Go/No-Go, Choice, Sustained Attention) were measured in a 35-day ω-3 PUFA supplementation group vs. a placebo group. Supplementation with ω-3 PUFAs has been associated with an effect on reactivity and with a reduction of reaction time in the Go/No-Go and Sustained Attention tests. The latency of EMG activation was concomitantly reduced in the same test with multi-choice options. EEG frequency shifts to the theta and alpha bands were recorded in all the tests after ω-3 PUFA supplementation. These results indicated a beneficial influence of ω-3 PUFAs on cognitive function (attention) in healthy humans. As a matter of fact, one might say that they improve an already good condition of cognitive function. The authors decidedly ascribe changes in the reaction time and psychological parameters to the action of ω-3 on the central nervous system. These results are in line with the above-mentioned effects of ω-3 PUFAs in pathological circumstances.

9 Conclusions In this work we have examined some important evidence that particular nutrients may influence the structure, biochemistry, and function of the central nervous system. Fatty acids of the ω-3

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family can probably have positive effects on both emotional and cognitive functions. Although there is some recent research not confirming a decisive link in this area, previous publications have shed new light on the problem of proper nutrition and opened the field for further research. Data concerning the influence of ω-3 PUFAs on emotional and cognitive functioning are relatively limited and often ambiguous. The results of much epidemiological, clinical, and experimental research confirm the hypothesis of the role of ω-3 PUFAs in pathogenesis and the treatment of depression, as well as their importance in the prevention of mental impairment in old age. Although the available data suggest that ω-3 PUFAs may have an equally beneficial effect on the mental functioning of healthy persons, this area still needs to be researched more extensively. We may assert that the use of foods rich in ω-3 can have a stabilizing effect on mood through a decrease in negative affective states such as fear, anger, and depression. Much evidence indicates that nutrients are short-term acting agents; so in order to maintain positive results, it is necessary to take them with a high degree of regularity. Further research needs to be conducted in this area, in particular using the double-blind test with a placebo control group. Although some data confirm the functional effects of diet on the central nervous system, the biochemical mechanisms that form their basis remain unexplained. Unfortunately, this subject is not an area of intensive research at present. As has already been noted, most research on the psychological correlatives of particular nutrients concern pathological cases; the number of publications concerning their role in emotional and cognitive function in healthy persons is insufficient. The methods of diet control typically used may arouse some reservations: nutrition questionnaires, a blood test for ω-3 levels (which does not reveal much about nutritional habits in earlier life), and recommendations made in intervention tests that subjects increase their intake of fish or supplement capsules. There appears to be a need for research on functional alimentation enriched in precisely defined proportions of nutrients. What is more, the available intervention research typically involves a small sample, and the supplement administration period is often less than 90 days. There are also other issues related to the role of ω-3 fatty acids which have yet to be unsolved. First of all, there is not enough data on unwanted side effects of the prolonged use of ω-3. Why does a dose of 1–2 (g/day) seem more effective than higher doses? What is the optimal proportion of EPA to DHA? And finally, what length of use is necessary to obtain maximal therapeutic results [88]? Omega-3 fatty acids allow us to see many psychological disorders and dysfunctions in a new light. It is exceptionally important that we gradually refine the lens of our current knowledge on this subject. Further investigations are needed.

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Chapter 2

The Social Context of Dietary Behaviors: The Role of Social Relationships and Support on Dietary Fat and Fiber Intake Anish R. Dube and Cassandra A. Stanton

Key Points • Positive role modeling with structured meals in the home, increased fruit and vegetable availability, decreased availability of snacks high in saturated fats, and supportive school policies may be necessary to address the child obesity epidemic. • Mounting evidence suggests that targeting the social support system to encourage more healthful dietary practices is also critical for adults, especially among particular ethnic and economically disadvantaged subgroups. • By providing adequate social support to sustain the desired behavioral changes and addressing broader community level influences to make healthy eating more practical, lifelong dietary changes will result in a decline in poor-diet-associated diseases, a lowered burden on the health-care system, and a significant reduction in health disparities. Keywords Social support · Dietary fats · Dietary fiber

1 Introduction Poor diet, along with physical inactivity, is a modifiable behavioral risk factor that has been identified as the leading cause of mortality in the United States [1] and the major contributor to the current “obesity epidemic” [2]. Moreover, the costs associated with being overweight or obese in the United States present an enormous burden to our society not just in medical expenditures, with one study estimating a staggering $78.5 billion in 1998 or 9.1% of the total annual US medical expenditures of that year [3], but also as lost productivity in the workplace and restrictions to unquantifiable personal opportunities [4]. Diets low in fiber and high in saturated fats

C.A. Stanton () Division of Psychiatry and Human Behavior, The Warren Alpert Medical School of Brown University, Butler Hospital/Transdisciplinary Research Group, 345 Blackstone Blvd., Providence, RI 02906, USA e-mail: [email protected] F. De Meester et al. (eds.), Modern Dietary Fat Intakes in Disease Promotion, Nutrition and Health, DOI 10.1007/978-1-60327-571-2_2, © Springer Science+Business Media, LLC 2010

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have been linked to a wide array of clinical diseases, ranging from diabetes [5–7] to different cancers [8–11] and diminished cardiovascular health [5]. While there has been some evidence that the rise in obesity may be in part attributable to genetic factors [12–14], many scientists have accumulated evidence that the bulk of the increase in obesity can be attributed to social and cultural changes concerning food consumption and health behavior choices [15–18]. In particular, social relationships across the lifespan have been found to have profound influences on the development of health-compromising and health-promoting behaviors [19]. This chapter reviews the literature on food intake as a product and part of the social context, the role of social support in promoting or deterring healthful dietary choices, and the growing availability of interventions targeting social influences on dietary behaviors.

2 The Social Context of Feeding Behavior At a very basic primal level, eating fulfills the body’s needs for replenishing its depleted energy reserves. It is at the act of eating that one’s genes, past sociocultural influences and present environment converge to create the singular behavior of eating, unique to each individual. In this context, genes refer to one’s genetic predispositions toward certain diseases, such as diabetes, and toward certain food preferences. For example, northern European populations are thought to better metabolize lactose due to high levels of lactase activity well into adulthood [20]. Past sociocultural influences include exposure to certain dietary customs related to one’s ethnic background and upbringing, as well as specific familial preferences/choices. It is important to bear in mind that the interaction between the individual and her environment at any given point in time is not static, nor is this a one-way relationship; the individual is being acted upon by the environment at the same time that the individual is acting upon the environment. Baranowski [21] proposed a theory of “family reciprocal determinism” to describe this concept, adapting it from psychologist Albert Bandura’s theory of reciprocal determinism that states that “an individual’s behavior both influences and is influenced by personal factors and the social environment” [22]. This is especially important when designing interventions seeking to promote healthier dietary behaviors, as both the subject and the environment need to be adequately addressed if the intervention is to be successful. For example, as the following section will illustrate, in trying to reduce childhood obesity it is necessary to address not just the child’s food preferences but also the availability and accessibility of low-fat and high-fiber foods in the child’s home and school environments [23–26].

3 Childhood Influences Affecting Eating Behavior In tackling the “obesity epidemic,” children have become a particular locus of intervention efforts in the hopes of preventing, rather than treating, the next wave of Americans with obesity-related health problems. Scientists have confirmed that American children are getting “heavier and fatter,” with a disproportionate amount of the burden falling on Hispanic and African-American children [27] and in the youth of lower SES backgrounds [28].

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A substantial portion of a child’s daily energy consumption is done at home, accounting for the majority of one’s daily caloric intake from childhood, through adolescence, and into young adulthood [29]. As children grow older they begin to make their own food choices outside the home setting, such as at school and at malls with peers, though most of their energy intake is still done within the confines of the home [29]. Even among more independent adolescents, food choices are associated with the food environment at home [30]. There is robust evidence to suggest that parents and caregivers can mold the child’s dietary preferences based on mealtime interactions and the availability of specific foods at home [23–26] despite the growing influences of the media and “peer social norms” with increasing age [23, 30]. By increasing the availability and access to low-fat healthy foods, such as fruits and vegetables [23, 25, 30], parents can help establish healthful dietary habits. Increasing fruit and vegetable consumption is of particular importance in children and adolescents as recent data support the notion that there is a decline in fruit and vegetable intake during the transition from early to middle adolescence (of 0.7 servings) and further reductions again from middle to late adolescence (of 0.6 servings) [31]. Solutions to tackling this problem may be fourfold: increasing the availability of fruits and vegetables in the home setting, reducing overall and saturated fat intake, changing the structure of how a meal is consumed at home with positive role modeling, and a policy shift at schools by the offering of healthier snack options.

3.1 Increasing Availability of Fruits and Vegetables As mentioned, fruit and vegetable availability is one of the key predictors of actual fruit and vegetable intake in children and adolescents. Numerous studies have confirmed that when fruits and vegetables are accessible at home, their actual consumption by the pediatric population increases [23, 25, 30, 32]. While one study found that the only correlate for fruit and vegetable consumption in young adults and across gender was taste preference, adolescents tasting more fruits and vegetables would presumably be more likely to enjoy eating them [33]. Furthermore, despite high taste preference being such a strong indicator of consumption of these items, actual intake of fruits and vegetables is likely to increase, given a high availability, even in the presence of a low taste preference [34]. Fruit and vegetable availability in the home, in a study of middle and high school-aged adolescents, was found to be associated with social support for healthy eating, family meal patterns, family food security, and SES [34]. These social variables are critical to address in interventions aimed at increasing fruit and vegetable availability and higher fiber intakes.

3.2 Dietary Fat Intake and Increasing Consumption of Meals at Fast Food Restaurants Besides the need for increasing fruit and vegetable intake in adolescents, reducing overall dietary fat, and more specifically saturated fats, is a significant public health concern. The decline in fruit and vegetable intake in adolescents is often accompanied by an increase in both overall

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and saturated fat consumption, especially when increasing amounts of one’s daily energy are consumed at fast food restaurants [35]. Skipping traditionally “at-home meals,” like breakfast [36], and eating out at fast food restaurants become more frequent during the transition from late adolescence and into young adulthood [36, 37]. In turn, consumption of fast food restaurant items on a regular basis is associated with higher levels of overall energy intake [35, 37], total fat intake [35, 37], saturated fat intake [37], and increased weight gain [36]. Findings on percentage dietary fat intake as a proportion of total caloric intake in certain population subgroups are particularly alarming, with one study noting that over three quarters of urban African-American youths reported fat as accounting for 40–50% of their total caloric intake [38]. Similarly, in a study of Mexican children along the Mexican–American border, 85% of children reported consuming at least one portion of a high-fat snack daily [39]. Gehling and colleagues [40] in Australia have suggested that simple measures, such as the use of reduced fat milk, reducing number of snacks, the substitution of water for juices and soft drinks, withholding the addition of fat to vegetables, and encouraging consumption of leaner meats, may be effective in moderately reducing total energy and fat intakes [40]. Nutritional labels for food items at fast food restaurants have also been suggested as a benefit to more health-conscious adolescents, even though the data has failed to show a change in food ordering behavior in most adolescents in the presence of nutritional labels [41].

3.3 Parental Influences, Positive Role Modeling, and Family Meals Aside from providing healthy foods in the home and reducing fat consumption, simply being a role model for healthy eating also predicts healthy eating among youth. Both children [42] and adolescents [43] have been shown to eat more fruits and vegetables when eating at the same time as their parents. Multiple studies have found evidence of parent–child dietary concordance [44, 45], with specific evidence from Stanton and colleagues [46] supporting greater concordance in the diets of mother–daughter dyads [46]. Adolescent perceptions of maternal eating behavior have been shown to be even more crucial than actual maternal eating habits in children’s food choices and stress the need for mothers to share their attitudes about healthy foods with their children [47]. Other studies have found that children are more likely to try novel foods if they see an adult also trying the food [48]. Excessive parental control over feeding behavior, however, has been found to be correlated with disordered eating and even childhood obesity [49]. There has also been an added emphasis placed on the importance of family meals after three major studies concluded that children and adolescents eating their evening meals with parent(s) present were more likely to have higher consumption rates of fruits and vegetables, as well as more nutritious eating behavior in general, than those without [34, 42, 50]. In addition to the number of evening meals that were eaten with/in the presence of a parent, the nature of the meal (a positive atmosphere and the priority placed on a structured family meal with rules) was also influential [51]. Children who were allowed to snack while watching television daily were also more likely to have higher BMIs and eat fewer fruits and vegetables [52], reinforcing the need for structured family meals. Further supporting these assertions is the finding in young adults that taking one’s time and eating the evening meal with others, family or otherwise, was correlated with increased fruit and vegetable intake, while “eating on the run” was associated

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with an increased consumption of soft drinks and fast food and decreased intake of nutritious food items [53].

3.4 The Need for a Change in School Policies In conjunction with the changes necessary in the home environment for fostering healthier eating practices in youth, there also needs to be a concerted effort in promoting healthier snack options in the school environment. One study suggested that while parental support did yield a decrease in energy consumption from fat in girls, it did not affect energy consumption from fat in boys and neither did the study find a reduction in soft drink consumption in either gender by parental support alone [54]. By regulating what food items are available for consumption in the cafeteria and in the greater school environment and reducing less healthful options available through vending machines, primary prevention targets of improving dietary behavior in youths may be aided [55]. Additionally, perceived school social norms need to be brought in line with nutritious goals as real consumption of fruits and vegetables during school lunches was found to be correlated with pervading school social norms on eating fruits and vegetables [56].

4 Social Influences on Dietary Practices of Adults Many of the same factors associated with the dietary behaviors of children have also been documented with adults. As with children, among adults the influences of what and how the people around them are eating at multiple levels of context have a significant impact on fat and fiber intakes. For example, familiarity with the audience co-participating in the meal is predictive of one’s own consumption behavior. In fact, unfamiliarity tends to reduce both men and women’s consumptions, although only women have been shown to match food intake [57]. These findings may prove particularly useful in improving healthy food intake in the elderly who tend to suffer from lower absolute levels of nutrients despite no apparent reduction in the functionality of non-physiological factors in determining nutrient intake [58]. It may be possible to target overall consumption in this population in order to increase nutrient levels by controlling the familiarity of the environment, the number of people at the meals, the food tailored to individual taste preferences as well as other factors such as the duration, time, and setting of the meals [58]. The idea that social cues at mealtime can impact dietary intake furthers the notion that though it may be difficult/not possible to alter one’s genetic propensities, it is certainly possible to manipulate surrounding social environments by making adjustments to key components of eating behavior associated with increased/decreased energy intake. For example, several studies have shown an increase in food consumption if the meals were longer in duration, in both males and females, suggesting that by decreasing overall meal durations we may be able to decrease total caloric intake. Pliner and colleagues [59] examined the effects of group size on consumption in which participants who were given 36 min to complete their meal were likely to eat more than participants given 12 min to complete meals [59]. However, Pliner’s study failed to show an effect on energy intake of group size, though they did find that pairs eating together were closer

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in energy intake matching than were groups of four people eating together. Another study found both meal duration and group size interacted to influence food intake [60]. Specifically group size modified (increasing) food intake only if the meal duration was longer but not when meal duration was shorter. Shorter meal durations may allow for greater concentration on the meal itself and more active self-monitoring of total energy intake in addition to increased attention to meal composition. Further research needs to explore the mechanism behind decreased energy intake when meals are constrained by time limits. For instance, eating while simultaneously engaged in other activities, particularly activities that are cognitively engaging, has also been shown to mediate increased energy consumption. Hetherington and colleagues [61] proposed that distraction from eating due to other tasks impaired the ability to self-monitor one’s intake and tested this hypothesis by comparing eating behavior in different settings (eating alone versus eating with others, friends, and strangers versus eating in front of a television set in a counterbalanced order) [61]. Eating with friends and eating while watching television were associated with increases in energy consumption by about 18 and 14%, respectively, as compared to eating alone. Consistent with previous findings [59, 60], the meal duration corresponded with the amount of food consumed and eating with strangers yielded lower levels of food intake than did eating with familiar faces [61]. It is possible that while distraction impairs the self-monitoring behavior of one’s food intake and attention to food, eating in the presence of unfamiliar faces diminishes this distraction and facilitates focus back to the food. The social context, and by extension overall energy intake, should thus be viewed as a complex interaction of multiple different determinants rather than being dictated by singular, isolated, and circumscribed “causal factors.”

5 Social Support Interventions One public health strategy to reduce dietary fat intake is to increase dietary fiber intake, such as fruits and vegetables. Perceived social support has been implicated as an important contributor to the availability of fruits and vegetables and has also been linked to improved health practices in women [62]. While social support is now recognized as being crucial in one’s sustained efforts in subscribing to a novel change in routine behavior, such as amount of fat and fiber intake in one’s diet, an important distinction can be made between actual social support (structural support) and perceived social support (functional support). For example, interactive support (improving one’s structural support) in the form of telephone calls with nutritional coaching and verbal support in addition to supplemental mailings and prepackaged meals (high in soluble fiber) has been shown to be effective and may prove a useful model for dietitians to follow [63]. However, Verheijden and colleagues [64] argue that while the bulk of interventions are focused on increasing structural support in weight management programs, there is a stronger association between functional support and positive health outcomes [64]. They suggest that even in the presence of actual social support, individuals may perceive a lack of a sufficiently motivating environment to sustain any meaningful change in behavior. Also, notably, Verheijden found social support to be unclearly defined in most studies they reviewed. Perhaps due to this lack of clarity, the usefulness of social support itself has not always been unequivocal. A worksite environmental intervention succeeded in increasing perceived

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social support from co-workers in regard to reducing dietary fat intake but failed to produce an actual reduction in fat intake or increase in fruit and vegetable consumption [65]. Likewise, pre-intervention habits, along with perceived social support, have been implicated as being significant predictors of one’s intention to alter fat intake [66] and may prove a more important target in modifying behavior. Further complicating the picture is the finding that social support may vary between genders, with females reporting more encouragement and increased support in healthy dietary behaviors and physical activity from their friends than do males [67]. Studies with youth have also found subgroup differences in perceived social support and its association with dietary intake. In a study of rural adolescents, Stanton and colleagues [68] reported that even after controlling for demographics, the frequency of how often a family member or a friend performed a behavior or said something that was supportive of healthy eating significantly predicted the adolescent’s fat and fiber intake. Interestingly, African-American students in this study reported higher support for healthy eating from friends than did Caucasian students. It may be that adolescents who are more likely to have higher caloric intakes (i.e., more likely to be overweight) also have friends who are overweight and thus there is more mutual attention to and support for dieting behaviors. Alternately, this finding may have resulted from differences in how food and eating behaviors are culturally instilled. Among adults, differences in eating patterns between African-Americans and Caucasians and the social context of where and with whom food is eaten have been found to be at least as important as attitudes about specific foods [69]. Among children, Corwin and colleagues [70] found that African-American children had more exposure to foods higher in fat and sugar than did Caucasian children in that sample and this exposure was positively associated with a social support scale reflecting encouragement from parents, teachers, and peers for eating fruits and vegetables. Although preliminary evidence from these studies suggests that social support from family and friends may have differential influences on subgroups of youth, evidence suggests that across the board, specific encouraging behaviors from family and friends, such as offering low-fat snacks and talking about healthful eating, can be helpful. Identifying and fostering these sources of positive support for healthy eating are critical to developing effective health promotion programs targeting high-risk adolescents. Based on a review by Ammerman and colleagues [71], it was found that people most likely to benefit from a dietary change program were those people who were most “at risk” and were in need of the most help [71]. The review found that most types of interventions (“individual-directed, system/physician-directed, access-enhancing, policy-level/environmental, media campaigns, community-based/social network, and tailored/new technologies”) were successful in decreasing total and saturated fat intake and increasing fruit and vegetable consumption to at least some degree, regardless of where the emphasis was placed [71]. They also found that interventions involving small group interactions, goal setting, and with an appropriate understanding of cultural sensitivities were likely to be helpful. Another study went further and concluded that motivated, “free-living individuals” were able to successfully maintain dietary modifications over a 4-year period when given sufficient support, necessary instructions, and adequate encouragement [72], although a follow-up 8-year study failed to find an “effect of low-fat, high-fiber, high-fruit, and vegetable diet on adenoma recurrence” [73]. Several tailored interventions have also looked to achieve dietary modifications in economically disadvantaged minority populations, such as some African-American, Hispanic, and other low-income communities, and have met with a fair degree of success. Tailored Internet-based interventions were used to encourage healthful eating in African-American girls between the ages of 8 and 10 and were found to not only be effective in increasing fruit, juice, and

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vegetable intake, in addition to increasing physical activity, but also be feasible [74]. Similarly, Block and colleagues [76] utilized modern technologies by having participants from low-income backgrounds have at least one experience with the Little by Little CD-ROM [75] and observed a higher consumption of fruits and vegetables in this group than in controls [76]. These innovative strategies may be used as an adjunct to supportive interventions like the “High 5, Low Fat” programs (directed toward African-American parents through personal visits, newsletters, and group meetings) [77] and “The Rural Physician Cancer Project” (aimed at rural populations through “physician-endorsed self-help using low-literacy nutrition education materials and personalized dietary feedback”) [78] that have also proven useful in promoting dietary change. These findings confirm the need for interventions attuned to high-risk populations and that also address differences in dietary behaviors and norms arising from geographic, educational, cultural, and socioeconomic backgrounds. For example, one study found that African-American women with strong ethnocultural associations tended to consume diets higher in fat content, despite intentions to avoid high-fat foods [79]. Public health efforts may need to effect structural changes in order to reduce health disparities in determinants like price (related to low-fat eating behavior) [80] and convenient access to healthy food options which are known to be inadequate in African-American communities (of all incomes) and in areas of widespread poverty [81]. Native Americans as a group have been identified as being at “highest risk” on a number of health indices (including but not limited to diet and obesity) [82] and may require approaches that are more culturally sensitive.

6 Conclusions and Clinical Implications There are many different social contextual variables that dynamically interact and hold potential for several different algorithms of interventions that may impact more healthful dietary practices. Macro-level influences also need to be addressed in effecting dietary modifications since SES has been correlated with nutritional quality [83] and environmental interventions subsidizing fruits and vegetables [84] have yielded positive results. Likewise, it may be useful to make food items that are low in saturated fat more accessible by increasing easy availability, lowering their prices, and/or providing coupons for them while visibly marketing them [85]. The successes of such varied types of interventions may alternatively be interpreted optimistically as a sign that there may not be any one “designer intervention” amenable to recasting but that perhaps we may look toward many more sustainable “local” solutions that utilize native systems of knowledge and follow ecological models of greater self-empowerment. This can be achieved by paying more attention to the social contexts under which local dietary practices are taking place, providing adequate social support to sustain the desired behavioral changes, and addressing broader community level influences to make healthy eating not just desirable but also practical. Ultimately, lifelong dietary changes that incorporate more fruits and vegetables and reduce intake of unhealthy fats will result in an improved quality of life through a decline in poor-diet-associated diseases, a lowered burden on the health-care system, and a significant reduction in the health disparities presently experienced by disaffected communities.

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Acknowledgments Preparation of this manuscript was supported in part by grant K07-CA95623 from the National Cancer Institute (C. Stanton, PI). We would like to acknowledge Brian Young’s database and literature review support.

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Chapter 3

Social Class, Food Intakes and Risk of Coronary Artery Disease in the Developing World: The Asian Paradox Ram B. Singh, S.S. Rastogi, R.K. Goyal, S. Vajpayee, Jan Fedacko, Daniel Pella, and Fabien De Meester

Key Points • Coronary risk factors, such as hypertension, diabetes mellitus, tobacco consumption, hypercholesterolemia, obesity, and coronary artery disease are major health problems in developing economies of Asia. • It is a paradox that in south Asia, most people are vegetarian (India) but have an increased risk perhaps due to the presence of new risk factors: higher lipoprotein(a) (Lpa), hyperhomocysteinemia, insulin resistance, low high-density lipoprotein cholesterol, and poor nutrition during fetal life, infancy, and childhood. • The prevalence of hypertension, diabetes, and heart disease is significantly higher in high income populations with lipid-related risk factors; increased intake of refined starches and sugar are greater in these populations, requiring modification of existing American and European guidelines. • Refined carbohydrates, trans fatty acids, saturated fat, and ω-6-rich oils in conjunction with low physical activity and consumption of tobacco may be leading factors to deaths and disability due to CVD and diabetes in Asia. Keywords Diet · ω-3 fatty acids · Antioxidants · Heart disease · Refined foods · Hypertension · Diabetes mellitus

1 Introduction Cardiovascular diseases (CVDs) are the leading causes of death in the world, according to WHO 2008 assessment. These are diseases of the heart and blood vessels, atherosclerosis, heart attacks, and stroke. At least 80% of premature deaths from these diseases could be prevented through a healthy diet, regular physical activity, and avoiding the use of tobacco. The risk of CVDs, hypertension, stroke, coronary artery disease (CAD), and diabetes mellitus is changing R.B. Singh () Halberg Hospital and Research Institute, Moradabad, UP 244001, India e-mail: [email protected], [email protected] F. De Meester et al. (eds.), Modern Dietary Fat Intakes in Disease Promotion, Nutrition and Health, DOI 10.1007/978-1-60327-571-2_3, © Springer Science+Business Media, LLC 2010

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dynamically around the world, particularly in the south Asian subcontinent, where type 2 diabetes and CAD are highly prevalent. People of Indian descent around the globe have the highest rates of premature CAD, with clinical manifestations occurring about 10 years earlier than in other populations [1–4]. Numerous studies over the past 50 years, involving several generations, have consistently shown that the incidence and mortality rates of CAD are 50–300% higher among overseas Indians compared with compatriots of other ethnicities in several countries [5–13]. The countries of Asia are in nutritional transition from poverty to affluence. India, China, Indonesia, Thailand, Philippines are rapidly developing countries, whereas Hong Kong, Singapore, Taiwan, Korea, Malaysia are newly industrialized countries showing rapid increase in CVD, diabetes, and metabolic syndrome. Japan, Australia, and New Zealand are developed countries, showing reduction in CVD after initial rise in the prevalence rates between 1950 and 1970. Bangladesh, Nepal, Bhutan, Myanmar, Vietnam, Pakistan, Afghanistan, Sri Lanka are either poor or disturbed countries with little economic development, but there is a rising prevalence of CVD. The implication of changes in social class of CVD is that the factors linking economic position to disease may change. It is logical to mention that as economic development proceeds, CVD appears to increase and when economic development is associated with education and health education, CVD begins to decline. It seems that CVD develops in a society in the form of a wave, affecting first the affluent and subsequently the less affluent, declining first in those better off, due to learning of the methods of prevention, and possibly subsequently in the rest of the population, which may be a dream in the middle- and low-income countries. Economic development is associated with increased wealth and per capita income, resulting in higher education, better housing and air conditioning, use of automobiles, and other consumer durables, better occupation, and increased consumption of refined, ready prepared foods, animal foods, syrups, and alcohol as well as tobacco. There is decreased physical activity and sports activity, resulting in sedentary behavior due to change is occupation and lifestyle. The implications of the ongoing demographic transition, with respect to health and nutrition, appear to be far reaching. All Asian nations are struggling to achieve socioeconomic development, during the last few decades, and have adopted policies for the containment of the growth of their populations. The rise and fall in CAD in both sides of the Atlantic was related to economic development. However, there is a contrast between economic development of Japan and of the Western world. The gross national product (GNP) of Japan was lower than that of the United Kingdom in the 1970 but 50% higher in 1987, which became fourth in the world after Switzerland, the United States, and Norway. The relation is stronger with measures of income distribution than with GNP. Japan has the highest rapid growth but the smallest relative difference in income between the top and the bottom 20% of income group, with highest life expectancy in the world. The consumption of salt and tobacco has decreased but people continue to eat fish and vegetables, resulting in decrease in hypertension and stroke as well as stomach cancer, without much change in CAD, although dietary fat intake showed some increase. In New Zealand and Australia, the trend is similar to that in Western European and North American countries.

2 Social Class and Mortality The total world population in 2007 was 6.6 billion including 1.3 billion southeast Asians, which would increase to 7.9 billion and 1.6 billion, respectively, by the year 2025 (Table 3.1). Adult population aged 20–79 years in the world was 4.1 billion including 770 million southeast Asians

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Table 3.1 Trends in population growth in southeast Asia (in thousands)

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Country

1980

88,164 Bangladesh 1,296 Bhutan 17,892 DPR Korea 684,460 India 148,033 Indonesia 1,669 Mongolia 35,289 Myanmar 14,288 Nepal 14,815 Sri Lanka 47,063 Thailand Source: WHO [51].

2000

2050

148,361 2,030 27,256 960,611 198,687 2,686 55,108 22,493 21,076 68,609

221,750 3,166 37,556 1,233,790 246,855 3,944 81,568 33,604 26,844 90,114

in the year 2007, which would increase to 5.2 billion and 1,083 million, respectively, by the year 2025. The estimated increase in the population would be much more by the year 2050, as given in Table 3.1. Approximately, two-thirds of the population in developed countries, mainly lower social classes, and half of the population in developing world, mainly higher social classes, would be at risk of greater mortality due to CVD and diabetes [2–10]. It has been pointed out that in 1998, non-communicable diseases (NCDs) were responsible for 59.0% of total global mortality and 43% of the global burden of disease [10, 11]. It is interesting that 78% of NCD deaths were borne by low- and middle-income countries, as was the 85% of the NCD burden of disease. Looking at NCD overall, by the late 1990s, nearly 50% of deaths worldwide were due to CVD, diabetes, cancer, and chronic lung disease [2, 10]. The stage at which hypertension, diabetes, CAD, and cancer emerge as significant causes of death corresponds to a life expectancy level between 50 and 60 years and at this level, cardiovascular disease mortality accounts for 15–20% of all deaths. CVDs were on average already becoming a significant cause of death in developing countries between 1970 and 1975, whereas the corresponding period in developed countries was 50 years earlier in the 1920s. Life expectancy in India increased from 41.2 years in the decades 1951–1961 to 61.4 years during the 1991–1996 period and 63 years during the 1996–2006 period, causing great increase in the population at risk from mortality and morbidity due to NCDs [2, 3]. Other experts [2, 10–12] also believe that in the heavily populated countries of China and India, which account for more than one-third of the world’s population, CVD dominates the death toll, with millions of deaths a year attributable to CVD in each country. In Latin America, the Caribbean, and the Middle East Crescent, heart disease also contributes greatly to mortality [12]. Psychosocial factors, diet, tobacco, and sedentary behavior appear to be important causes of death due to circulatory diseases in both developed and developing countries and among migrants in the United States and England and Wales from the Indian subcontinent [12–20]. The immigrant Indians in the United Kingdom and Singapore have 40% greater mortality from circulatory diseases compared to indigenous populations [15–19]. A study in India showed that social class has become an important determinant of mortality in the urban population of north India. Circulatory diseases as the cause of death were significantly more common among social classes 1–3 than in social classes 4 and 5. Infections as the cause of death were significantly more common among social classes 4 and 5, in both sexes, compared to higher social classes 1–3. It is possible that in the light of WHO estimates, there appears to be decline in deaths due to infection and increased death rate due to CVD and diabetes in higher social classes, whereas infections remain the major cause of death in lower social

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classes. This phenomenon may be due to aging of population and economic development causing rapid changes in diet and lifestyle, resulting in nutritional transition from undernutrition to overnutrition [1–5]. We also found that obesity, hypertension, CAD, and tobacco intake were more common among higher social classes, which appear to be the risk factors of death due to circulatory diseases. In developed countries [1] such as the United States, during same period (2001), a mortality ratio of 3.09 and 20.90 were reported among subjects aged 25–64 years, in both sexes, with an education level of 12 years, compared with those having higher educational level. This finding is universal in the developed countries, such as Australia, New Zealand, and Japan, but not in the developing countries of Asia such as India, China, Thailand, Philippines, Pakistan, Bangladesh, Nepal, Sri Lanka because the developing economies have not yet learned the methods of prevention of diseases [1–4]. In Korea, Hong Kong, and Singapore, which are newly industrialized countries, education level is beginning to have inverse association with the burden of CVD and diabetes. In south India, life expectancy has become as great as in developed countries, and there is a marked decrease in undernutrition and deaths due to infections, but morbidity and mortality due to circulatory diseases are increasing [1–5]. Level of education has become a very good indicator of social class in the Western world [1]. There are several factors which may explain the impact of social class on health in developed countries: smoking, behavior, obesity, physical activity, nutrition, psychosocial factors, all favoring the higher social classes. In developing countries, like India, China, Sri Lanka, Thailand, Indonesia, and Brazil, enormous occupational physical activity in lower social classes is protective against morbidity and mortality due to circulatory diseases, while they continue to have more deaths due to infections and poor nutritional status. Unfortunately, the impact of better education due to lack of health education, possibly, has not yet started in these countries, resulting in marked increase in mortality and morbidity due to circulatory diseases and neoplasms, with increase in social class in conjunction with improvement in nutritional status, as observed in our study [5]. These populations need to learn the methods of prevention for which WHO and International College of Cardiology are working hard independently. All-cause mortality showed that circulatory diseases and diabetes were the cause of death in 31.3% (n = 695) of the victims and malignant diseases were the cause of death in 5.8% (n = 181) of victims, while infections remain as the cause of death among 41.1% (n = 915) of victims. We did not find a record indicating AIDS as the cause of death. This is possible because it appears to be diagnosed more often in metro cities than in smaller towns. The relatives also tend to request the doctor to hide the diagnosis. Injury (14.0%, n = 313) and miscellaneous causes of death such as burns and suicide (12.0%, n = 202) were also observed quite commonly. It seems that in our study, NCDs were recorded as the cause of death in 58.9% of victims. Suicides were more common among women than among men, which is similar to the trend in China. Estimated and projected mortality rates per 100,000 population for India by the WHO indicate that in the year 2000, all-cause deaths should be 876 in men and 790 in women, which should decrease to 846 in men and 745 in women by the year 2015. Infections as the cause of death were projected to be 215 in men and 239 in women in the year 2000, which were projected to become 152 in men and 175 in women. However, circulatory diseases were estimated to be 253 in men and 204 in women in the year 2000 and to increase to 295 in men and 239 in women. Similar increase in deaths due to neoplasms was estimated from the year 2000 to 2015: from 88 to 108 in men and from 74 to 91 in women, respectively [1–3, 12]. Non-infectious diseases predominate at ages above 60 years. In the Indian study [5], approximately 693 adult men and

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418 women died in approximately 1 year in this north Indian urban population (6.4 million) in the year 2000. The deaths due to circulatory diseases were 203 in men and 120 in women, whereas deaths due to cancer were 38 in men and 27 in women in the year 2000. According to Registrar General of India [7], in the year 1994–1998, trends indicate that there has been a significant decline in proportionate deaths from infectious diseases from 22 to 16%. However, mortality from cardiovascular disease (CVD) increased from 21 to 25%, which is lower than death rate of 29.1% reported by Singh et al. in 2005 [5]. In Chennai, Gajalakshmi et al. performed verbal autopsy among 48,357 adults aged 25–69 years. Deaths due to vascular diseases were 38.6% (n = 18,680), followed by cancer (8.7%), tuberculosis (5.8%), and respiratory causes (3.5%). In another larger sample consisting of 150,000 subjects, there were 1,354 deaths in the 1st year follow-up and verbal autopsy revealed that circulatory diseases as the cause of death were noted in 34% men and 30% women. Mohan et al. studied the mortality rates due to diabetes in selected urban population from south India [9] among 1399 subjects (respondents 1262). During a median follow-up of 6 years, deaths were significantly greater among diabetics compared to nondiabetics (18.9 vs. 5.3 per 1,000 person years, P = 0.004). Mortality rates due to CVD were 52.9% among diabetics and 24.2 among nondiabetics. It is clear that the burden of CVD and diabetes appears to be quite significant in India, indicating urgency for prevention program [4–11]. The higher risk of CAD mortality is not explained by conventional risk factors common among Indian immigrants to industrialized countries [12–14]. Indian Society of Hypertension and International College of Nutrition and other experts have proposed guidelines for prevention of CVD and diabetes in Indians and Asians, which are being used for public education by the health workers [15–19].

3 Burden of Cardiovascular Disease in Asia According to WHO records, stroke mortality is higher in Asian countries, except Japan and Singapore, than in the Western countries. Recently, Ueshima et al. [20] have done a selected review of the burden of CAD and stroke in Asia. Japan had the highest stroke mortality in the world in 1965, which rapidly decreased by 80% during the period from 1965 to 1990. The present stroke mortality in Japan is similar to rates in the Western world. In China and South Korea, the trends of mortality now show similar characteristics to the Japanese trend observed in the past. The recent age-adjusted stroke mortality rate in China is reported to be decreasing in urban areas, whereas mortality is still increasing or is stable in rural areas [21]. In South Korea, ageadjusted stroke mortality is also decreasing but remains at a higher level. Other countries of Asia, including Middle Eastern countries, central Asian countries, and south Asian countries except Singapore, have higher stroke mortality than do Western countries [6, 21–25]. According to other estimates, during the period of 1965–1990, cardiovascular mortality fell by 50% in Australia and by 60% in Japan [21, 22]. The decline in stroke mortality has been more marked especially in Japan, where there was a non-significant increase in coronary mortality in 1985 in some areas. The discordant trend of rising CVD mortality rates in India, China, and other parts of Asia, however, is in sharp contrast to the decline in the CVD epidemic in developed countries. The rise in CVD in the developing nations of Asia during the past 2–3 decades has attracted least attention and poor public health response even within these countries. It is not widely realized that the developing Asian countries contribute a greater share to the global

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burden of CVD than do the developed countries of the world due to a larger growth in population (Table 3.1). It has been estimated that 5.3 million deaths attributable to CVD occurred in the developed countries in 1990, whereas the corresponding figure for the developing nation of Asia was 6.3 million [21, 22]. It is possible that the cause-specific mortality ascertainment methods currently used in Asia call for cautious interpretations of these estimates. In a recent multinational assessment, stroke ranks the second or the third leading cause of death in Hong Kong, Taiwan, South Korea, and Singapore [20]. Malaysia, Thailand, Philippines, and Indonesia are countries with moderate hospital-based data on stroke. India is the only country among three-country assessment to have some data on stroke prevalence. The conservative assumptions made by the experts suggest that the absolute burden of stroke mortality is indeed likely to be greater in developing Asia. China, Taiwan, and Japan rank highest in terms of stroke mortality in the region. The mortality rates of cerebrovascular diseases in these countries stand close to a hundred or higher per 100,000 population for men and women of all ages. In China, stroke is the leading cause of death, while in Taiwan it currently ranks second, next to cancer, after being the main cause of death for almost 20 years from 1963 to 1982. The major type of stroke in Taiwan is cerebral infarction, while in Japan and China, it is cerebral hemorrhage. In Japan, twice as many men and women die from stroke as from CAD. The incidence of stroke is four times that of acute myocardial infarction in some areas of China. There are about 5 million surviving stroke patients and some 1.3 million new cases occur each year. However, in New Zealand and Australia, stroke-to-CAD mortality ratio was only 0.3 for men and 0.6 for women. In Japan, workers in agriculture, sales, transportation, and service industries have higher rates of stroke than those in business [20–22]. New Zealand, Australia, Singapore, and Hong Kong have a low stroke mortality of between 50 and 100 per 100,000 population. Their stroke mortality rates for men in 1991/1992 ranged from 39 per 100,000 population in Australia to 68 in Singapore [20–22]. The Asian paradox is that CAD, type 2 diabetes, and hypertension are more common among higher social classes, whereas in the Western countries, the burden of these problems is greater among lower social classes [23–31]. The population of southeast Asia is rapidly increasing, whereas the increase is slowed in China and stopped in Australia, New Zealand, and Japan (Table 3.1). In Japan, birth rate has decreased but population appears to be stable because of the ageing of the population. The prevalence of diabetes and pre-diabetes was about 6% each in the year 2007 in southeast Asia, indicating that 46.5 million subjects above 20 years had this problem, which would be doubled by the year 2025. Similar targets have been calculated for CAD. The burden of hypertension would be fourfold greater compared to that of diabetes. The prevalence of CAD is lower in Korea, China, Hong Kong, Taiwan and very low in Japan, whereas in south Asia it is higher compared to industrialized countries. The prevalence of hypertension is significantly higher in Japan, Korea, China, Taiwan, which has started decreasing now with decrease in salt consumption. The prevalence of type 2 diabetes and metabolic syndrome is rapidly increasing in all the countries of Asia.

3.1 Hypertension In various studies, the prevalence of hypertension (>140/90 mmHg) has been reported to be 22–30% in India among urban subjects above 20 years of age. The prevalence of CAD varies

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49

between 8 and 14% in various cities of India. In rural population, the prevalence of diabetes, hypertension, and CAD is two- to threefold lower compared to urban subjects. The prevalence of hypertension, type 2 diabetes mellitus, and CAD is significantly higher among social classes 1–3 compared to social classes 4 and 5 [29–31] (Tables 3.2, 3.3, and 3.4).

Table 3.2 Prevalence of hypertension in rural and urban population of India (>140/90) No. of >140/90 mmHg Authors Year Age State subjects (%) Pre-hypertension Rural Hussain et al. Gupta et al. Singh et al. Singh et al.

1988 1994 1997 1997

Urban Wasir et al. 1995 Gupta et al. 1997 Singh et al. 1997 Singh et al. 1997 Singh et al. 1998 Begum et al. 1998 Singh et al. 1998 Singh et al. 1998 Singh et al. 1998 Source: Singh et al. [44, 23].

20–70 20–80 20–65 25–64

Rajasthan Rajasthan UP UP

5,142 3,148 162 1,702

6.8 21.2 12.9 17.3

20–75 20–65 20–65 25–64 25–64 25–64 25–64 25–64 25–64

Delhi Rajasthan Moradabad Moradabad Moradabad Trivandrum Calcutta Nagpur Mumbai

679 2,212 152 1,806 3,212 1,497

6.2 31 32.8 22.3 25.3 30.7 19.1 24.2 28.0

Table 3.3 Prevalence of type 2 diabetes in India Year Author Place 1971 Tripathi et al. 1972 Ahuja et al. 1979 Gupta et al. 1984 Murthy et al. 1986 Patel 1988 Ramchandran et al. 1989 Kodall et al. 1989 Rao et al. 1991 Ahuja et al. 1992 Ramchandran et al. 1995 Singh et al. 1997 Ramchandran et al. 1998 Singh et al. 2000 Rammurthy et al. 2001 Ramchandran et al. 2001 Iyer et al. 2004 Sadokot et al. 2006 Mohan et al. 2006 Menon et al. 2008 Kumar et al. Source: Modified from Singh et al. [23].

Cuttack (central) New Delhi (north) Multicentre Tenali (south) Bhadran (west) Kudremukh (south) Gangavathi (south) Eluru (south) New Delhi (north) Madras (south) Moradabad Madras (south) Moradabad Kerala (south) National (DESI) Dombivill National Chennai Chennai Kolkata

Urban (%) 1.2 2.3 3.0 4.7 3.8 5.0 – – 6.7 8.2 7.9 11.6 6.0 12.4 12.1 6.2 5.9(4.3) 14.3 19.5 11.5

24.6 24.6 21.3 25.7 30.1

Rural (%) – – 1.9 – – – 2.2 1.6 – 2.4 2.5 – 2.9 2.5 – – 2.7 – – –

50

R.B. Singh et al. Table 3.4 Prevalence percentage of coronary artery disease and coronary risk factors in south Asians and British North Indians South Indians, Sri Lanka, UK South British Rural Urban urban urban Asians native Coronary artery disease 3.0 9.0 13.9 Smoking (men) (%) 30 25.6 44.6 Diabetes (%) 2.3 6.0 12.0 Hypertension (<140/90 mmHg) 10.0 25.0 30.0 (%) Total fat (kcal daily) 14.8 24.7 28.8 Saturated fat (percentage kcal 4.9 9.2 14.4 daily) Cholesterol in diet (mg daily) 53 166 240 Body mass index (kg/m2 ) 21.6 22.9 22.7 Waist–hip ratio (male) 0.86 0.89 0.89 Fasting plasma insulin (male) 4.8 5.1 16.6 (mU/L) 2-h after glucose (mU/L) 11.8 24.2 60.6 Serum cholesterol (mg/dL) 168 190 210 HDL cholesterol (mg/dL) 43.5 44.2 45.1 Angiotensin-converting enzyme 37.5 63.4 72.0 (IU) TNF-α (pg/mL) 4.5 15.6 18.8 IL-6 (pg/mL) 2.8 11.5 14.4 Nitrite (μmol/L) 1.0 0.76 0.67 Values are means. HDL, high-density lipoprotein cholesterol. Source: Modified from Singh et al. [32, 38, 39].

11.5 57.4 5.8 27.2

15.0 22 19.0 28.0

6.0 30 5.0 30.0

28.0 13.6

38.8 13.7

42.2 18.5

210 21.0 – –

200 26 0.98 9.8

405 26 0.94 7.2

– 196 45.2 –

41.0 230 45.0 80.0

19.0 236 46.2 –

– –

– –

– –

In rural population, the prevalence of hypertension was 6.8% in Haryana and 21.2% in Rajasthan. In urban population, the prevalence was significantly greater in Trivandrum in south India compared to Moradabad in north India (Table 3.2). There has been a marked rise in mean blood pressures of the population from 73.2 mmHg diastolic in 1942 to 84.0 mmHg in 1997. Similarly, systolic mean blood pressure was 112.2 mmHg in 1942, which increased to 118 mmHg in 1984 and 122 mmHg in 1997. In the Five City Study, mean systolic blood pressure was 125 mmHg and diastolic pressure was 82 mmHg in an urban women sample of 3,212 subjects aged 25–64 years. The prevalence of hypertension (>140/90 mm Hg) was significantly greater in south India and west India compared to east, central, and north India. The overall prevalence of hypertension in the five cities was 25.6% (n = 823) among women (Table 3.2). Data among men are not yet available. The prevalence of various types of hypertension was as follows: isolated systolic hypertension 2.9% (n = 96), borderline 14.9%, isolated diastolic hypertension 50.5%, definite hypertension 18.6%. Risk factors of hypertension were age [years mean (SD)] 44.2 [15] vs. 36.8 [12], BMI (kg/m2 ) 24.2 (2.7) vs. 22.2 (2.7) as well as sedentary behavior (89.9 vs. 40.9%), salt intake (87.9 vs. 47.8%), and alcohol consumption (20.5 vs. 5.2%). These observations indicate that the hypertension as well as its risk factors has become a public health problem in India as revealed by the Five City Study [23–25]. The prevalence of hypertension among subjects above 20 years varies between 25 and 30% in various countries of Asia [20–25].

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3.2 Blood Pressure Variability There is a great need of conducting population surveys with ambulatory blood pressure monitoring to demonstrate vascular variability disorders (VVDs) as proposed by Franz Halberg, Germaine Cornelissen, and Othild S. from Halberg Chronobiology Center, University of Minnesota Medical School, Minneapolis, USA, and Kuniaki Otsuka, Tokyo Women’s Medical University, Tokyo, Japan, for the diagnosis of circadian-hyperamplitude tension, mesor hypertension, and ecphasia because south Asians living in the United States appear to have significantly greater risk of these problems compared to Caucasians. Collaborators may contact Dr. Germaine Cornelissen (e-mail: [email protected]).

3.3 Type 2 Diabetes Mellitus It is clear from Table 3.3 that the prevalence of type 2 diabetes mellitus was quite low before 1984 among both rural (1.6–2.4%) and urban (3.4–4.5%) populations of India. There has been a marked increase in the prevalence of diabetes in the last two decades. In rural populations it became 1.6% at Eluru in Andhra Pradesh to 2.9% at Moradabad in UP. In urban populations, the prevalence of type 2 diabetes was 5% at Kudremukh as observed by Ramchandran et al. in 1988, which increased to 14.3% in Madras as reported by Mohan and coworkers in 2006 (Table 3.5). Type 2 diabetes, hypertension, and CAD appear to be a manifestation of metabolic syndrome among Indians [36–38]. The prevalence of metabolic syndrome has been estimated to be between 20 and 25% among subjects above 20 years of age in south Asia [23–25]. Table 3.5 Genetic and other specific risk factors common in south Asians for unexplained heart disease Genetic or environmental Other risk factors 1. Insulin resistance and hyperinsulinemia 2. Poor beta-cell function 3. Increased prevalence of type II diabetes 4. Increased lipoprotein(a) 5. Increased angiotensin-converting enzyme 6. High Apo-B

1. Increased plasminogen activator inhibitor-1 2. Decreased tissue plasminogen activator 3. Decreased antioxidant vitamins A, C, β-carotene, E, Se, Zn, flavonoids, other polyphenolic substances 4. Low high-density lipoprotein cholesterol 5. Elevated homocysteines 6. Low Apo A1 7. Increased heart rate and BP variability 8. Increased small dense LDL cholesterol 9. Increased ω-6/ω-3 ratio in the diet. 50:1 due to increased intake of sun flower, corn, and soya bean oils

3.4 Coronary Artery Disease The risk factor-adjusted CAD rates are twofold greater among overseas south Asians compared to Caucasians [1–4, 17–38] (Table 3.4). South Asians develop clinical manifestations such as myocardial infarction (MI) at a young age and often follow a malignant course [39, 40]. Approximately 50% of the first MI among south Asian men occurs before the age of 55 years

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and 25% occurs before 40 years of age. The CAD mortality among south Asians younger than 30 years of age has been described to be threefold higher than that in whites in the United Kingdom and 10-fold higher than that in Chinese in Singapore. The same pattern of CAD is observed among all south Asians—whether living abroad or within Indian subcontinent—which include persons of Indian, Pakistani, Bangladeshi, and Sri Lankan origin. In urban population of south Asia, there has been a 10-fold increase in the prevalence of CAD in the last three decades. CAD appears to be more common in urban areas than in developed countries. Studies from rural areas have reported a threefold lower prevalence of CAD compared to cities; however, a threefold increase has been observed in these populations, in the last few decades, particularly in south India and Punjab. CAD prevalence has been studied in the urban populations of Chandigarh, Haryana, Delhi, UP, Rajasthan, and Kerala. The prevalence was lowest of 4% in Rohtak in the 1970s and highest of 14% in Trivandrum, as reported by Beegom and Singh [35]. The prevalence of CAD and its risk factors is significantly higher in south India compared to north India, in both rural and urban areas. The Five City Study provided most interesting evidence that CAD has become an important concern in India. CAD was threefold more common in the urban north India at Moradabad (9.0%), fourfold more common in urban south India at Trivandrum (13.9%), Mumbai (11.6%) in west India, Nagpur (10.0%) in central India, and Kolkata (8.0%) in east India, compared to rural populations. The risk of CAD, type 2 diabetes, and hypertension is higher in higher social classes 1–3, than among lower social classes in both rural and urban subjects.

4 Social Class, Coronary Risk Factors, and the Asian Paradox Social class has become an important determinant of CVD and diabetes in the industrialized countries. In south Asian countries, such as India, Pakistan, Bangladesh, Nepal, and Sri Lanka, as well as other Asian countries, such as Thailand, Malaysia, Philippines, Indonesia, Myanmar, North Korea, higher social classes 1–3 have greater prevalence of hypertension, CAD, and diabetes compared to lower social classes [20–26]. However, in industrialized countries of Asia, lower social classes have greater burden of CVD and diabetes [20–22]. While tobacco consumption is as common in Asia as in the Western world, other conventional risk factors, such as hypercholesterolemia, hypertriglyceridemia, obesity, central obesity, diabetes mellitus, and hypertension, are not that common and severe as in the industrialized countries. The paradox is that dietary intakes and physical activity explain only a part of differences in prevalence and risk of CVD and diabetes in these population groups (Tables 3.4 and 3.5). However, these risk factors have become a public health problem in these countries and would soon become more common than in Western countries. The Asian paradox is that the risk of risk factors is greater at relatively lower levels of risk factors, resulting in increased susceptibility and severity of atherosclerosis and rapid emergence of CAD at a younger age [20–22, 41–44]. This phenomenon occurs in all developing populations due to nutritional transition from poverty to affluence among populations that are adapted to survive on low nutrient intake and physically demanding occupations, which may be the cause of the Asian paradox [41–45]. It is a paradox in south Asia that serum cholesterol, body fat, dietary fat intake are higher among higher social classes, whereas in the Western populations, these risk factors are greater among lower social classes, causing a greater

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increase in CAD [43–45]. Such observations have also been reported from other countries of Asia [46–51]. In one study [46], the prevalence of risk factors in relation to social class was studied. Body mass index >25 and >27, central obesity, and sedentary lifestyle were significantly more common among higher social classes 1–3 compared to lower social classes (Table 3.6). Salt intake and tobacco consumption showed no social class difference. Table 3.6 Prevalence of risk factors (n, %) of chronic diseases in relation to social class Central BMI BMI obesity Sedentary Salt intake Social classes (>27 kg/m) (>25 kg/m) (WHR>0.85) lifestyle (>6 g/day) Social class 1 209(21.2) (n = 985) Social class 2 130(16.4) (n = 790) Social class 3 60(8.9) (n = 774) Social class 4 18(3.0) (n = 602) Social class 5 8(3.8) (n = 206) Total 425(13.0) (n = 3357) Mantel-Haenzel 7.55 χ2 P-value <0.01 BMI, body mass index. Source: Singh et al. [46].

Tobacco users (>once/week)

612(62.1)

955(96.9)

908(92.2)

496(50.3)

81(8.1)

395(50.0)

452(57.2)

564(71.4)

421(53.3)

47(5.9)

331(19.5)

265(39.3)

285(42.3)

451(66.9)

45(6.7)

39(6.4)

72(11.9)

90(14.9)

398(66.1)

48(7.9)

12(5.8)

18(8.7)

18(8.7)

123(59.7)

18(8.7)

1189(36.5)

1762(54.0)

1865(57.2)

1889(58.0)

241(7.4)

12.17

11.66

12.65

3.14

3.16

<0.001

<0.001

<0.01

<0.09

<0.09

5 Nutritional and Epidemiological Transition in Asia Asia is highly populated among all the continents because Asia has the maximum natural resources for human development. Almost two-thirds of the total world population (4.1 of 6.3 billion) live in Asia, mostly in India and China. According to World Development Reports, in which affluence was measured by evaluation of per capita net domestic product, growth of production and the human development index (in which longevity, income, and knowledge were measured) showed significant increase in almost all the Asian countries from 1960 to 2005 [20–26]. Asia has a rapid economic development causing increased consumption of salt, tobacco, fat, sugar, and energy in the last four decades. There is also an increase in per capita income, gross domestic product, food production, and automobile production in the last four decades. This period from 1970 to 2008 has witnessed marked changes in diet and lifestyle, particularly in the urban populations, which may be the cause of the epidemic of CVD and diabetes among Asians [2–10, 20–26]. These development and changes in diet and lifestyle were associated with a several fold increase in the prevalence of hypertension (>140/90 mmHg), CAD, and diabetes from 1960 to 2007 in different Asian countries. In most societies of the world, economic development is associated with the improvement in food supply, better nutritional status, and an increase in life

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expectancy. There are rapid changes in diet and lifestyle in most Asian countries due to economic development in the last four decades. With these changes have come the problems of diet-related chronic diseases which typically occur in middle and later adult life, and counteract the gains in life expectancy attributable to a better food supply. The life expectancy in most Asian countries was about 40 years in the 1950s, which has risen to >63 years in 2008 due to better food supply. Burkit and Trowell as well as Singh and Niaz, after reviewing descriptive epidemiological studies from many developed and developing countries, concluded that there is usually a sequence in the emergence of chronic diseases as the diet of the developing country becomes more Westernized [20–25]. Overweight, central obesity, and hyperinsulinemia come first, then appendicitis, insulin resistance, diabetes, and hypertension tend to occur early, followed after few decades by CAD, insulin resistance syndrome, and gall stones, then cancer of the gastrointestinal tract and bone and joint diseases and renal diseases. Such changes have occurred more obviously in countries or population groups undergoing rapid transition between different cultural stages. This analysis reflects cross-sectional data from different countries but the pattern has been confirmed by longitudinal studies of the evolving pattern of diseases and life expectancy in many developed and developing countries [41, 42]. The dietary staple in southern China, southern India, and in most Asian countries has been rice for many centuries. In north India and north China, Pakistan, Afghanistan, Iran, Nepal, the main staple is wheat or corn. Traditionally, fat and sugar consumption have been low. The salt consumption in China and Japan was 10–20 g/day and in India it varied between 5 and 20 g/day. However, the diet is rapidly changing in the cities to resemble that of the more affluent countries, which has been associated with marked increase in overweight, hypertension, diabetes, and CAD [42–46]. Such trend have been reported in most of the countries of Asia [20–23]. The global availability of inexpensive vegetable fat has resulted in greatly increased fat consumption among low- and middle-income countries such as India, China, Thailand, Philippines as well as Taiwan, Hong Kong, Singapore, and Korea. The transition has occurred at lower levels of gross national product than previously and is further accelerated by rapid urbanization and industrialization. In China the proportion of higher income persons who were consuming a relatively high-fat diet (>30% en/day) rose from 22.8 to 66.6% between 1989 and 2003. The lower and middle-income classes also showed a rise from 19 to 36.4% in the former and from 19.1 to 51.0% in the latter. In Japan, there is a threefold increase in dietary fat from 1955 when Japanese were supposed to have undernutrition. Undernutrition was fully controlled by 1965 in Japan, without any increase in CAD, although dietary fat intake doubled from 1955 (Table 3.7).

Table 3.7 Percentage of nutrient intake per day by Japanese between 1955 and 1994

Year

Protein

Fat

Carbohydrate

Energy

1955 13.3 8.7 78 – 1965 13.1 14.8 72.1 – 1975 14.5 22.3 63.1 2,226 1980 14.9 23.6 61.5 2,119 1985 15.1 24.5 60.4 2,088 1989 15.6 25.7 58.7 – 1990 15.5 25.3 59.2 2,026 1994 15.8 25.8 58.4 2,023 Source: Health and Welfare Statistics Association. Data of National Nutrition Survey (Kohsci-no-Shiyyo) 1970–1997, vol. 17–44.

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In India, in a recent study, the intake of fruits and vegetable showed no significant difference in higher and lower social classes but the consumption of visible fat was threefold greater in social classes 1 and 2 than social classes 3–5 [46]. Higher social classes also had higher risk of CAD (Table 3.8). Table 3.8 Social class and food intakes and coronary disease in Indian women Total fruits and Coronary vegetables (g/day) Total visible Social classes disease (%) mean + SD fat (g/day) Social classes 1–2 10.1 (n = 1776) Social classes 3–5 3.5 (n = 1482) Source: Singh et al. [32].

FV/visible fat ratio

186 + 65

40.1 + 16

4.63 +1.5

189 + 61

16.1 + 5

11.73 + 3.2

5.1 The South Asian Paradox The increased susceptibility of people of south Asian origin living anywhere in the world may be due to decreased beta cell functions, insulin resistance, and hyperinsulinemia, increased prevalence of type 2 diabetes, increased Lp(a), increased plasminogen activator inhibitor-1 and Apo B lipoprotein, and low HDL cholesterol [27–33] (Table 3.5). Recently, proinflammatory markers, such as tumor necrosis factor-α, interleukin-6, interleukin-18 and highly sensitive C-reactive proteins, genetic factors, angiotensin-converting enzyme activity (39.5 + 4.6 vs. 65.5 + 7.8 IU in rural and urban subjects, respectively, P < 0.03), have been proposed to be important new risk factors of CVD and diabetes [3, 15, 16, 21–41, 47–53]. An increased concentration of ACE in south Asian urban population poses the possibility that ACE-I could be important in the prevention of CVD and diabetes in these populations (Tables 3.4 and 3.5). Despite more than half of the Asian Indians being lifelong vegetarians, CAD rates are similar among both vegetarians and nonvegetarians in India. This is in sharp contrast to Western vegetarians who tend to have very low rates of CAD. The consistently higher rates of CAD among people of south Asian origin in several countries, compared to people of other ethnic origin, who shares the same environment may indicate a possible molecular susceptibility which could be genetic [2–12]. However, Western vegetarian diet is rich in fruits and vegetables, whereas Indian vegetarian diet is grain based but exploited by refined bread, biscuits, candies, syrups, sweets, milk products, such as butter (saturated fat), clarified butter (Cholesterol oxide), and vegetable ghee, which is trans fatty acids, as well as ω-6 rich oils, sunflower, soya bean, and corn oil, which may have adverse effect on the risk of CVD and diabetes due to their proinflammatory effects. The south Asian paradox is that despite low total serum cholesterol (150–200 mg/dL), low body mass index (21–23 kg/m2 ), low fat intake (21–30% en/day), lower prevalence of hypertension, lower prevalence of obesity (5– 7%), and moderate smoking among south Asians (compared to Caucasians), there is a greater risk and prevalence of atherogenesis, case fatality in acute coronary syndrome, and mortality due to coronary artery disease [11–16]. Epidemiological transition from poverty to affluence indicates that populations adapted to survive on low fat intake and physically demanding occupations may develop conservatory mechanisms [42–44]. However, low intake of micronutrients, particularly

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low ω-3 fatty acids, antioxidant vitamins, and phytochemicals, may predispose these subjects to CAD and diabetes at modest increase in the conventional risk factors, at a younger age below 45 years. Recent studies [52, 53] indicate that genetic and proinflammatory factors may also enhance the susceptibility of Asians to CAD. Although behavioral precedents including diet and cigarette smoking play an important role, CAD exhibits significant heritability, a part of which can be attributable to genetic variants affecting known biochemical and metabolic risk factors. In the last 2 years, impressive progress has been made in understanding the genetic basis of several of these factors using both candidate gene and genome-wide association study (GWAS) approaches. Candidate genes, coding for proteins of known biological significance in a disease process, provide a logical first step in understanding the genetics of common disease states. Populations of affected and unaffected individuals can be studied by genotyping common single-nucleotide polymorphisms (SNPs) within a gene and its regulatory sequences. Although economically attractive, this approach is acknowledged to have a number of limitations. By definition, studies are limited to genes with a known or suspected role in defining a given phenotype and do not provide new insight into biological pathways leading to disease. Furthermore, candidate gene associations often fail to replicate for multiple reasons. Sample sizes have often been inadequate to provide the statistical power required when multiple variants of small effect are tested. The original observation may have been false positive, emphasizing the need for stringent statistical thresholds. Other issues include heterogeneity of causality. For example, genetic variants affecting plasma lipid traits may have significant effects on CAD risk, but these may be less important than or interact with other risk factors including diabetes and smoking. Finally, appropriate measures must be taken. Sonia et al. studied 8,795 individuals of European, south Asian, Arab, Iranian, and Nepalese origin from the INTERHEART case–control study that genotyped 1,536 single-nucleotide polymorphisms (SNPs) from 103 genes [52]. One hundred and two SNPs were nominally associated with CAD, but the statistical significance did not remain after adjustment for multiple testing. A subset of 940 SNPs from 69 genes were tested against CAD risk factors. One hundred and sixty-three SNPs were nominally associated with a CAD risk factor and 13 remained significant after adjusting for multiple testing. Of these 13, 11 were associated with apolipoprotein (Apo) B/A1 levels: eight SNPs from three genes were associated with Apo B and three cholesteryl ester transfer protein SNPs were associated with Apo A1. Seven of the eight SNPs associated with Apo B levels were nominally associated with CAD (P < 0.05), whereas none of the three cholesteryl ester transfer protein SNPs was associated with CAD (P ≥ 0.17). Of the three SNPs most significantly associated with CAD, rs7412, which defines the Apo E2 isoform, was associated with both a lower Apo B/A1 ratio (P = 1.0 × 10–7 ) and a lower CAD risk (P = 0.0004). Two low-density lipoprotein receptor variants one intronic (rs6511720) and one in the 3 untranslated region (rs1433099) were associated with both a lower Apo B/A1 ratio (P < 1.0 × 10–5 ) and a lower risk of CAD (P = 0.004 and 0.003, respectively). In brief, 13 common SNPs were associated with coronary risk factors. Importantly, SNPs associated with Apo B levels were associated with CAD, whereas SNPs associated with Apo A1 levels were not. The Apo E isoform and two common low-density lipoprotein receptor variants (rs1433099 and rs6511720) influence CAD risk in this multiethnic sample. In one study [53], Dhingra et al. included 595 nonhypertensive Framingham Offspring Study participants (mean age 55 years; 360 women) without prior heart failure or myocardial infarction who underwent routine measurements of plasma tissue inhibitor of metalloproteinase-1 (TIMP-1), metalloproteinase-9 (MMP-9), and procollagen III N-terminal peptide. The authors

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correlated plasma TIMP-1, procollagen III N-terminal peptide, and MMP-9 to the incidence of hypertension and progression of BP by ≥1 category (defined on the basis of the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure). On follow-up (4 years), 81 participants (51 women) developed hypertension and 198 (114 women) progressed to a higher BP category. In multivariable models, a 1-SD increment of log-TIMP-1 was associated with a 50% higher incidence of hypertension (95% CI 1.08–2.08) and a 21% (95% CI 1.00–1.47) higher risk of BP progression. Individuals in the top TIMP-1 tertile had a 2.15-fold increased risk of hypertension (95% CI 0.99–4.68) and 1.68-fold (95% CI 1.05–2.70) increased risk of BP progression relative to the lowest tertile. Individuals with detectable MMP-9 had a 1.97-fold higher risk of BP progression (95% CI 1.06–3.64) than those with undetectable levels. Plasma procollagen III N-terminal peptide was not associated with hypertension incidence or BP progression. It is clear that proinflammatory biomarkers are important in the development and progression of hypertension.

6 Food Consumption Patterns and Trends The agriculture and food sector figures prominently in this enterprise and must be given due importance in any consideration of the promotion of healthy diets for individuals and population groups according to WHO experts 2003 [51]. Food strategies must not merely be directed at ensuring food security for all but must also achieve the consumption of adequate quantities of sale and good quality foods that together make up a healthy diet. Any recommendation to that effect will have implications for all components in the consumption patterns worldwide and deliberate on the potential of the food and agriculture sector to meet the demands and challenges posed by this report. In fact, the number of people ≥60 years of age is expected to double by 2025 and to triple by 2050 globally. The proportion of this aged population is likely to increase more in the AsianPacific region, because more than half of the world’s population lives in Asia. Thus, more than half of the world’s cardiovascular burden is predicted to occur in this area. Therefore, CVD prevention in Asia is an important issue for world health. The Seven Countries Study conducted in 1957 found that Japanese populations had lower fat intake, lower serum total cholesterol, and lower CAD than did populations in the United States and Scandinavia, in spite of higher smoking rates. The serum total cholesterol level in Japan has increased rapidly since World War II in accordance with an increase in dietary fat intake from 10 to 25% of total energy intake per capita per day. Despite this increase, the specific characteristic of lower CAD incidence and mortality than that in Western countries has persisted. Whether Japanese people and certain other Asian populations have different risk factors for CAD than do Western populations or have some protective factors has been a subject of discussion for quite some time [51, 54–56]. Diets evolve over time and are under the influence of several factors and complex interactions. Individual preferences, income, food prices, beliefs, cultural traditions, as well as environmental, geographical, social, and economic factors all interact in a complex manner to shape dietary consumption pattern. FAO produces food balance sheets for all countries, which give a complete picture of production, imports, stock changes and exports, as well as utilization, including final demand in the form of food use and industrial demand [51]. National average apparent food

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consumption is shown in the Table 3.11. These data indicate that dietary energy measured in kilocalories per capita per day has been steadily increasing on a worldwide basis from 1960 to 2000. The per capita supply of energy has risen dramatically in east Asia, which is expected to increase in all countries of the world. The growth in food consumption has been accompanied by significant structural changes and a shift in diet away from staples, such as roots and tubers toward more livestock products and vegetable oils [54–56]. The share of dietary energy from cereals has fallen in developing countries from 60 to 54% in a period of only 10 years. According to FAO projections, there would be a two to threefold increase in the consumption of meat, sugar, and vegetable oil from 1964 to 1997 and to 2030 with a decrease in the intake of pulses.

6.1 Fats and Oil Consumption Trends in supply of fat are given in Table 3.12. These dietary changes are greater in the higher social classes 1–3 in Asia, compared to lower social classes 4 and 5 who may continue to have undernutrition. The national diets of most countries of Asia indicate an increase in the quantity and change in the quality of fats consumed in these countries as well as in other countries of the world [54–56]. The per capita supply of fat from animal foods has increased by 14 and 4 g/capita in developing and industrialized countries, respectively, while there has been a decrease of 9 g/capita in transition countries (Table 3.12). The average global supply of fat has increased by 20 g/capita/day since 1967–1969. In 1961–1963, a diet providing 20% of energy from fat was associated only with countries having at least a per capita gross national product (GNP) of US $1475. By 1990, however, even poor countries having a GNP of only US $750 per capita had access to a similar diet comprising 20% energy from fat [51]. This change was mainly the result of an increase in the consumption of vegetable fats by poor countries of Asia with smaller increases occurring in middle-income and high-income countries. By 2005, vegetable fats accounted for greater proportion of dietary energy than did animal fats for most countries of the world including Asia. The proportion of energy from added sugars and refined starches in the diets of low- and middle-income countries was also a feature of nutrition transition [54–56] (Tables 3.9, 3.10, 3.11, and 3.12). Examination of the purchasing habits of people in India and China also indicates the enhancing fat intake of the poor, more than that of rich [46, 54–56]. These dietary changes have resulted in a decrease in undernutrition in association with increased consumption of saturated fat, trans fat, ω-6-rich oils as well as refined starches and sugars, particularly among higher social classes in Asia. In most countries of Asia, dietary energy contributed by saturated fatty acids is lower, ranging from 5% among social classes 3–5 to 10% among social classes 1 and 2. National dietary surveys conducted in some countries of Asia confirm these data [45, 46, 54–56] (Tables 3.9, 3.10, 3.11, and 3.12). Foods from animal sources such as meat, milk, clarified butter used in south Asia are rich in saturated fat, whereas vegetable oils used in all countries of Asia are rich in ω-6 fatty acids. Trans fats due to their taste and stability are preferred by the food industry for manufacturing ready-made foods in most countries of the world. There is a change in types of edible oils in developing countries, with the increasing use of hardened margarines rich in trans fatty acids. Palm oil is not commonly used but it is becoming increasingly important in the diets of much of southeast Asia and is likely to be a major source of fat in the diet in the next few years. All

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Table 3.9 Food consumption pattern and body mass index of women in five cities Moradabad Trivandrum Calcutta Nagpur Foods (g/day) (n = 902) (n = 760) (n = 410) (n = 405) Body mass index Wheat, rice, millets (kg/m2 ) Roots and tubers Nuts and oil seeds Pulses (legumes) Vegetables Fruits Milk and milk products Sugar and confectionery Total visible fat Indian ghee Butter Vegetable ghee Refined oils Oils Meat and eggs Fish Total foods Total fruits, vegetables, and pulses Social class 1–3 (%) Staple oil

Bombay (n = 780)

22.5 ± 4 245 ± 25

22.6 ± 4 328 ± 22

22.3 ± 4 268 ± 25

22.6 ± 4 213 ± 41

23.1 ± 4 354 ± 35

74 ± 10 44 ± 1

108 ± 12 116 ± 13

94 ± 10 2.6 ± 0.5

112 ± 27 5±1

67 ± 12 4±1

38 ± 6 70 ± 6 76 ± 10 232 ± 16

30 ± 5 102 ± 10 40 ± 7 120 ± 16

28.01 148 ± 26 109 ± 18 189 ± 32

56 ± 21 80 ± 23 80 ± 5 151 ± 41

56 ± 17 128 ± 25 103 ± 18 152 ± 50

34 ± 5

56 ± 6

24 ± 6

43 ± 21

30 ± 8

22.8 ± 14 7.8 ± 1 2.6 ± 0.1 9.4 ± 1.8 2.0 ± 0.6 1.8 ± 0.3 3.8 ± 1 – 800 ± 132 184 ± 16

27.6 ± 14 – 2.2 ± 0.4 – 2.8 ± 0.6 22.6 ± 13 7.2 ± 2 202 ± 15 1191 ± 202 172 ± 18

35 ± 18 0.6 ± 0.2 0.6 ± 0.2 0.2 ± 0.01 – 30 ± 15 1.6 ± 0.5 56 ± 12 955 ± 156 285 ± 35

51 ± 16 3.1 ± 0.4 1.9 ± 0.3 2.0 ± 0.4 44.0 ± 10 – 1.5 ± 0.3 – 792 ± 190 215 ± 25

36.0 ± 17 2.4 ± 0.6 1.9 ± 0.7 3.1 ± 0.4 28.6 ± 8.6 – 38 ± 11 29 ± 9 1194 ± 185 287 ± 37

70.6

79.9

73.9

73.1

77.3

Mustard oil + Coconut oil Mustard oil Ground nut Veg. ghee vegetable oil ghee Vegetable ghee, trans fatty acid; Indian ghee, clarified butter (figures were rounded); –, indicate no data. All data entries are given as mean ± SD.

stages of the oil production process, from plant breeding to processing methods, including the blending of oils aimed at producing edible oils that have a healthy fatty acid ratio, need potential development in the light of health effects of fatty acids. Olive oil is consumed in Mediterranean region and deaths due to CVD are less common. There is a need to prepare blends with olive oil and flax seed oil to provide adequate MUFA, flavonoids, and ω-3 fatty acids.

6.2 Livestock Products Table 3.13 shows the consumption of livestock products in various countries and regions of the world. In east Asia, the consumption of meat per capita was 8.7 kg/year in 1964–1966, showing about fourfold increase in 1999 which is projected by sevenfold in the year 2030. Similarly the

∗P

< 0.05;

∗∗ P

Social class 1 (n = 985) Social class 2 (n = 790) Social class 3 (n = 774) Social class 4 (n = 602) Social class 5 (n = 206) Total (n = 3357) Kendall’s t

36 ± 10

76 ± 20

96 ± 22

121± 25

124± 26

80 ± 18

104± 21

0.018

298 ± 47

325 ± 58

356 ± 48

252 ± 41

302 ± 56

0.041∗ 0.22

181 ± 28

114 ± 25

162 ± 36

205 ± 42

182 ± 35

189 ± 40

Vegetables and fruits

2.1 2.0 1.5 1.0 – 1.84 0.028∗

Butter

0.025

222 ± 30

140 ± 26

210 ± 32

256 ± 38

222 ± 51

225 ± 50

Total FVL

3.1 2.1 1.8 2.4 2.2 2.94 0.19

Veg. ghee

< 0.01; FVL, fruit, vegetable, legume; BMI, body mass index (figures were rounded).

0.019

41 ± 11

26 ± 8

48 ± 16

51 ± 15

40 ± 12

Pulses, legumes

3.8 2.7 1.6 – – 2.8 0.039∗

Root and tubers

Social class

52 ± 71 42 ± 12 32 ± 15 25 ± 8 13 ± 3 38 ± 18 0.041∗

Wheat, rice millets (g/day) 267 ± 36

196 ± 71 183 ± 62 170 ± 52 162 ± 55 35 ± 12 171 ± 62 0.071∗∗

Social class 1 Social class 2 Social class 3 Social class 4 Social class 5 Total Kendall’s t

Table 3.10 Food intakes (g/day) in relation to social class Pro-atherogenic Milk and Sugar and foods milk products confectionery Indian ghee

0.022

34 ± 6.3

32 ± 5.4

41 ± 7.1

40 ± 6.8

31 ± 5.5

23 ± 4.1

Nuts and oil seeds

36 ± 6 29 ± 4 24 ± 19 ± 5.2 26.4 0.052∗∗

Veg. oils

0.018

57 ±16

42 ±10

61 ±13

64 ±15

52 ±12

45 ± 7

Fish

45 ± 18 34 ± 15 27 ± 12 22 ± 9 8±4 32 ± 21 0.068∗∗

Total visible fat

0.028

986 ± 205

922 ± 176

1052 ±212

995 ± 183

981 ± 175

988 ± 182

Total foods

5.0 ± 2 6.5 ± 2 9.4 ± 3 9.5 ± 4 17.5 ± 5 7.9 ± 1.8 0.048

0.066∗∗

22.7±2.8

19.4±3.5

21.2±3.8

22.0±4.0

23.8±4.4

24.1±4.7

BMI (kg/m2 )

16 ± 6 14 ± 5 10 ± 4 8±4 3±1 12 ± 4 0.038∗

FVL foods fat Meat and ratio eggs

60 R.B. Singh et al.

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Table 3.11 Global and regional per capita food consumption (kcal/capita/day) Region 1964–1966 1974–1976 1984–1986 1997–1999 World Developing countries Near East and north Africa Sub-Saharan Africaa Latin America and the Caribbean East Asia South Asia Industrialized countries Transition countries a Excludes South Africa. Source: WHO [51].

2015

2030

2,358 2,054 2,290 2,058 2,393

2,435 2,152 2,591 2,079 2,546

2,655 2,450 2,953 2,057 2,689

2,803 2,681 3,006 2,195 2,824

2,940 2,850 3,090 2,360 2,980

3,050 2,980 3,170 2,540 3,140

1,957 2,017 2,947 3,222

2,105 1,986 3,065 3,385

2,559 2,205 3,206 3,379

2,921 2,403 3,380 2,906

3,060 2,700 3,440 3,060

3,190 2,900 3,500 3,180

Table 3.12 Trends in the dietary supply of fat Supply of fat (g/capita/day)

Region

1967–1969

1977–1979

1987–1989

1997–1999

Change between 1967–1969 and 1997–1999

World North Africa Sub-Saharan Africaa North America Latin America and the Caribbean China East and southeast Asia South Asia European Community Eastern Europe Near East Oceania a Excludes South Africa. Source: FAO STAT [51].

53 44 41 117 54

57 58 43 125 65

67 65 41 138 73

73 64 45 143 79

20 20 4 26 25

24 28 29 117 90 51 102

27 32 32 128 111 62 102

48 44 39 143 116 73 113

79 52 45 148 104 70 113

55 24 16 31 14 19 11

consumption of milk became 2.5-fold greater in 1999, which is projected to increase by fivefold by 2030 in east Asia. In south Asia, the consumption of meat in 1964–1966 was half than that in east Asia, which showed some increase in 1999 and is projected to increase fourfold greater by the year 2030. The consumption of milk was 10-fold greater in south Asia compared to east Asia in 1964–1966, which doubled in 1999 and is projected to increase fourfold more by the year 2030. The projected rise in the consumption of meat and milk in the industrialized countries and transition countries would be much greater (Table 3.13). The world’s livestock sector is growing at an unprecedented rate and the driving force behind this unprecedented surge is a combination of population growth, rising incomes, and urbanization [51, 54–56]. There is a need to plan food production to supply adequate slowly absorbed designer foods rich in protein, ω-3 fatty acids, MUFA, antioxidants, vitamins, and minerals, which are beneficial in the prevention of CVD [51–65]. Annual meat production is projected to increase from 218 million tons in 1997–1999 to 376 million tons by 2030 (Table 3.13). There is a strong positive relationship between the level

62

R.B. Singh et al. Table 3.13 Per capita consumption of livestock products Meat (kg/year) Region

1964–1966

World 24.2 Developing 10.2 countries Near East and north 11.9 Africa Sub-Saharan Africaa 9.9 Latin America and 31.7 the Caribbean East Asia 8.7 South Asia 3.9 Industrialized 61.5 countries Transition countries 42.5 a Excludes South Africa. Source: WHO [51].

1997–1999

2030

1964–1966

1997–1999

2030

36.4 25.5

45.3 36.7

73.9 28

78.1 44.6

89.5 65.8

21.2

35

68.6

72.3

89.9

9.4 53.8

13.4 76.6

28.5 80.1

29.1 110.2

33.8 139.8

37.7 5.3 88.2

58.5 11.7 100.1

3.6 37 185.5

10 67.5 212.2

17.8 106.9 221

46.2

60.7

156.6

159.1

178.7

of income and the consumption of animal proteins, such as eggs, meat, and milk, with greater consumption in the higher social classes compared to lower social classes (Tables 3.8, 3.9, and 3.10). The city dwellers consume high animal protein and fat diets characterized by higher intake of meat, poultry, milk, and other dairy products compared to rural subjects and these foods are and would be substituted for staple foods; rice and potato (for in place of by). It has been estimated that the number of people fed in a year per hectare ranges from 22 for potatoes and 19 for rice to 1 and 2 for beef and lamb, respectively. Thus, the future of livestock production has to be shifted from farm to manufacturing of designer foods, which may require less land and less environmental impact. The total food fish supply and hence consumption have been growing at a rate of 3.6% per year since 1961, while the total world population has been expanding at 1.8% per year [51]. The average per capita consumption of sea foods increased from 9 kg/year in the early 1960s to 16 kg/year in 1997. The per capita availability of fish and fishery products has therefore nearly doubled in 40 years, outpacing population growth. Fish provides about 20–30 kcal/capita/day, except in Japan where the intake is 180 kcal/capita/day. Recommending the increased consumption of fish for prevention of CVD is the area where the feasibility of dietary recommendations needs to be balanced against concerns for sustainability of marine stocks and potential depletion of this source.

6.3 Fruit and Vegetable Availability and Consumption A low consumption of fruits and vegetables in many regions of the developing world has been confirmed by the findings of food consumption surveys [51, 54–56]. In India, fruit and vegetable intake is 120–140 g/capita/day, with about 100 g/capita/day from roots and tubers and 40 g/capita from pulses. In urban populations, the consumption of fruits, vegetables, and pulses are about 222 g/capita/day as revealed by the Five City Study (Tables 3.9, 3.10, and 3.11). In contrast, in China, the intake of fruits and vegetables increased to 369 g/capita/day by 1992. The

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Table 3.14 Supply of vegetable per capita, by region 1979 and 2000 (kg/capita/year)

63

Region

1979

2000

World Developed countries Developing countries Africa North and Central America South America Asia Europe Oceania Source: Reproduced from WHO [51].

66.1 107.4 51.1 45.4 88.7 43.2 56.6 110.9 71.8

101.9 112.8 98.8 52.1 98.3 47.8 116.2 112.5 98.7

supply of vegetables per capita per day in various regions is given in Table 3.14. In Asia and other developing countries, the supply of vegetable has doubled from 1979 to 2000. In 1998, only 6 of the 14 WHO regions had an availability of fruits and vegetables equal to or greater than the earlier recommended intake of 400 g/capita/day. The availability of vegetables increased from 1990 to 1998, whereas the availability of fruits declined from 1990 to 1998. In 2000, the global annual average vegetable supply per capita was 102 kg, with the highest level in Asia (116 kg) and lowest in South America (48 kg) (Table 3.14).

7 Recommendations for Dietary Consumption The world scientific community has been reading the diet and lifestyle guidelines recommended by the Americans for the prevention of coronary artery disease (CAD) with great interest for the last few decades. Recommendations of the American Heart Association have been reformed for better understanding, based on new scientific evidence which has emerged after publication of guidelines in 2000. However, most of these guidelines ignore the role of diet in patients with acute myocardial infarction (AMI) and stroke. These patients due to their serious condition are highly motivated to follow what is being advised by the physician. It is easy to change health behaviors of the victims when they are admitted in the intensive cardiac care unit to follow the same diet when they go back home. Singh and coworkers used 400 g/day of fruits, vegetables, and legumes in conjunction with mustard oil to decrease the risk of hypertension, diabetes, and CAD in the 1990s [57–59]. This diet was re-examined by DASH investigators to decrease the risk of hypertension in the United States [60–62]. Most American experts very diligently advise dietary patterns, including grains, vegetables, fruits, nuts, seeds and legumes, fats and oils, based on various cohort studies and intervention trials [60–84]. There is no recommendation for refined starches, which is the most wise step in the prevention of endothelial dysfunction [63–66]. However, there is no guideline about the type of oil and type of nuts depending upon the ω-3 fat and monounsaturated fatty acid (MUFA) content of these foods. While foods and beverages with added sugars and refined starches as well as excess of ω-6, total and saturated fat and trans fatty acids may be proinflammatory, increased intake of ω-3 fatty acid and MUFA may be protective against surge of TNF-α, IL-6, IL-18, and adhesion molecules like VCAM-1 (vascular cell adhesion molecule-1) and IVAM-1 caused by high glycemic, rapidly absorbed

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proinflammatory foods [63–69]. These foods are known to initiate a proinflammatory milieu in the body which may further increase complications among patients of CVD. An AHA advisory [70] was undertaken to summarize the current evidence on the consumption of ω-6 PUFAs, particularly linoleic acid, and CAD risk. According to this advisory, aggregate data from randomized trials, case–control and cohort studies, and long-term animal feeding experiments indicate that the consumption of at least 5–10% of energy from ω-6 PUFAs reduces the risk of CAD relative to lower intakes. The advisory also indicated that higher intakes appear to be safe and may be even more beneficial (as part of a low-saturated-fat, low-cholesterol diet). The advisory completely ignored the proinflammatory and HDL cholesterol lowering effects of linoleic acid in the diet and earlier cohort studies and randomized controlled trials showing adverse effects of high P:S ratio, linoleic acid-rich diets on total cardiac events and mortality [68–75]. There is a need to be cautious and investigate the causes of such intentional as well as motivated views of AHA because CVD, diabetes mellitus, cancer, autoimmune diseases, rheumatoid arthritis, asthma, and depression are associated with increased production of thromboxane A2, leukotrienes, interleukins-1 and -6, tumor necrosis factor-α, and C-reactive proteins. Increased dietary intake of ω-6 fatty acids without consideration for ω-3 fat is known to enhance all these risk factors as well as atherogenicity of cholesterol and oxidized LDL cholesterol which have adverse proinflammatory effects and may result in thrombosis and acute coronary syndrome (ACS), cancer, diabetes mellitus, and metabolic syndrome [63–75]. A low ω-6/ω-3 ratio and a polyunsaturated/saturated fatty acid ratio of 1:1 in the diet have been proposed by the Columbus Paradigm Institute (www.columbus-concept.com) for prevention of dyslipidemia and CAD [67, 68]. It seems that this weakness in the guideline may be due to missing related work [63–78]. In fact one of the greatest weaknesses of the American advisory is that there is no discussion on proinflammatory foods, so there is an opportunity for the ω-6 fatty acid-rich oil industry (corn, soy bean, sun flower oils) to influence the consumers without consideration for their health. The increased servings of grains, vegetables, fruits, nuts, and fish are good for prevention of weight gain, hyperlipidemia, and hypertension as well as for prevention of dyslipidemia and metabolic syndrome and CAD by inhibiting the rise in FFA and maintaining good endothelial function [63–78]. There is overemphasis on dietary cholesterol in the earlier recommendations, although it is well known that dietary cholesterol has only little influence on atherothrombogenicity of serum LDL, which can be further decreased by substituting Columbus foods. Columbus foods are natural wild foods or wild-type designer foods rich in phytochemicals which are slowly absorbed without causing any abnormal increase in R blood glucose, insulin, proinflammatory cytokines, and free fatty acids [67–69]. The Columbus Concept stands for a return of α-linolenic acid (ALA, C18:3ω-3)—herein referred to as wild- or game-type land-based fatty acid—into the feed ration of land-based bred animals to such an extent that their fat depots (white adipose tissue) exhibit a balanced ratio of essential fatty acids, i.e., ω6:ω-3 = 1:1, characteristic of fat depots in wild animals or game. This return to the wild standard translates into a substantial reduction in long-chain ω-6 fatty acids and a moderate species-specific increase in long-chain ω-3 fatty acids in organs and peripheral tissues of these domesticated animals or livestock. The ω6:ω-3 = 1:1 ratio is also taken as reference for the design of composite plant-derived table oils and fats as these represent other primary sources of energy in the modern human diet. Provided particular attention is drawn to the antioxidant content of such foods, the twofold end results are a return to animal and plant food supplies in better compliance with human genetic heritage and a possible rehabilitation of dietary cholesterol and saturated fats (former CSI, C: cholesterol, S: saturated fats, I: index). Taken within a

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Table 3.15 Dietary Factors guidelines and desirable level of risk factors for developing Energy (kcal/day) Total carbohydrate (kcal/day) populations Complex carbohydrate (kcal/day) Total fat (kcal/day) Saturated fatty acids (kcal/day) Polyunsaturated fatty acids (kcal/day) Polyunsaturated/saturated fat ratio n–6/n–3 Fatty acid ratio Dietary cholesterol (mg/day) Whole grains (wheat, rice, grams, beans) (g/day) Fruit, vegetables, and nuts (g/day) Salt (g/day) Staple oils, canola, mustard oil, olive oil or blends Brisk walking (km/day) Meditation/pranayam (min/day)

Desirable values 1900–2300 65.0 55.0 21.0 7.0 7.0 1.0 <5.0, ideal 1:1 100 400–500 400–500 <6.0 25–50 g/day 30.0

Body mass index (kg/m2 ) Range Average

19.0–23.0 21.0

Waist–hip girth ratio Male Female

<0.88 <0.85

Serum total cholesterol (mg/dL) (4.42 mmol/L) Mild hypercholesterolemia (mg/dL) (4.42–5.20 mmol/L) Hypercholesterolemia (mg/dL) (>5.20 mmol/L) Low-density lipoprotein cholesterol (mg/dL) (2.32 mmol/L) Borderline high (mg/dL) (2.32–2.84 mmol/L) High (mg/dL) (2.84 mmol/L) Triglycerides (mg/dL) (1.7 mmol/L) High-density lipoprotein cholesterol (mg/dL) (0.9 mmol/L) Blood pressure (mmHg) Drug therapy in view of high risk of diabetes and CAD

<170 170–200 >200 <90

90–110 >110 <150 >40 men, >50 women

<135/88 Amlodipine, ACE-I, receptor blockers and new beta-blockers Fish oil, aspirin, statins Source: Modified from Indian Consensus Group [15].

R larger context, the Columbus Concept stands for the return of a specific healthy cholesterol into men’s food supply and bloodstream, the so-called wild or game cholesterol that is associated with a dietary balanced essential fatty acid ratio (ω6:ω-3 = 1:1) [54–58]. As observed from the overall distribution of fats in a natural untamed environment, nature recommends

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the consumption of a balanced ratio of saturated and polyunsaturated fatty acids as part of a dietary lipid pattern rich in monounsaturated fatty acids (P:M:S = 1:6:1). The value of such diet has also been proven in long-term clinical trials [73–75]. In randomized controlled intervention trials, Singh et al. [76] administered 400 g/day of fruits, vegetables, and nuts (almonds and walnuts) and another 400 g/day of whole grains including legumes in conjunction with 25–50 g/day of mustard oil in 1,001 patients with high risk of vascular disease, which showed significant benefit. Other workers also found a beneficial effect of fruit, vegetables, nuts, and ω-3 fatty acid-rich foods, Mediterranean diet, or DASH diet on the risk of CVD [57–66, 77, 78]. Increased intake of monounsaturated fatty acid and ω-3 fatty acids has been suggested to be protective against diabetes and metabolic syndrome [63–78], whereas increased consumption of trans fatty acids, saturated fat, and refined starches can predispose CVD and diabetes.

8 Conclusions In conclusion, it is possible that eating 400 g/day of fruits, vegetables, and nuts (almonds and walnuts 50 g/day), another 400 g/day of whole grains including legumes in conjunction with 25–50 g/day of canola oil or Columbus oil (olive oil + linseed oil) for prevention of type 2 diabetes, hypertension and CAD (Table 3.15). The role of 1,000 g/day of designer foods with similar content of nutrients on the risk of CVD would need further study on which the European Union and the government of India are spending 9.00 million euro in the year 2009. However, the future of such advice would be served by designer foods because of the higher cost and availability of natural wild foods in the urban lifestyle. It is important to do regular spot running and meditation (each 30 min) and cessation of tobacco intake for prevention of these problems. Moderate alcohol intake, particularly red wine rich in flavonoids, appears to be more beneficial as proposed in the French paradox by Serge Renaud. These changes in diet and lifestyle could be protective against premetabolic syndrome and vascular variability disorders [79, 80]. The value of such advice has also been confirmed in the recent cohort studies [81–84].

References 1. World Health Organization. Preventing chronic disease: a vital investment. Geneva: World Health Organization, 2005. 2. Indrayan A. Forecasting vascular disease cases and associated mortality in India 2007; http://www.whoindia.org/LinkFiles/Commission on Macroeconomic and Health Bg P2 Forecasting vascular disease cases and associated mortality in India.pdf: Accessed November 6, 2008. 3. Pella D, Thomas N, Tomlinson B, Singh RB. Prevention of coronary artery diseases: the South Asian paradox. Lancet 2003; 361: 79. 4. American Heart Association Heart and Stroke Statistical Update. http://www.americanheart.org/ downloadable/heart/ 1200078608862HS Stats%202008.final.pdf. 2008. 5. Singh RB, Singh V, Kulshrestha SK, Singh S, Gupta P, Kumar R, Krishna A, Srivastav SSL, Gupta SB, Pella D, Cornelissen G. Social class and all cause mortality in the urban population of north India. Acta Cardiol 2005; 60: 611–617. 6. Gupta R, Mishra A, Pais R et al. Correlation of regional cardiovascular mortality in India with lifestyle and nutritional factors. Int J Cardiol 2006; 108: 291–300.

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7. Gazalakshmi K, Peto R, Kanaka S et al. Verbal autopsy of 48,000 adult deaths attributable to medical causes in Chennai, India. BMC Public Health 2002; 2: 7. 8. Joshi R, Cardona M, Iyengar S et al. Chronic diseases now a leading cause of death in rural India: mortality data from Andhra Pradesh rural initiative. Int J Epidemiol 2006; 35: 1522–1529. 9. Mohan V, Shanthirani CS, Deepa M, Deepa R, Unnikrishnan RI, Datta M. Mortality rates due to diabetes in a selected urban south Indian population—the Chennai urban population study (CUPS-16). JAPI 2006; 54: 113–117. 10. Goyal A, Yusuf F. The burden of cardiovascular disease in the Indian subcontinent. Ind J Med Res 2006; 124: 235–244. 11. Chaturvedi N, Fuller JH. Ethnic differences in mortality from cardiovascular disease in the UK: do they persist in people with diabetes? J Epidemiol Commun Health 1996; 50: 137–139. 12. Chaturvedi N, Jarrett J, Morrish N, Keen H, Fuller JH. Differences in mortality and morbidity in African Caribbean and European people with non-insulin dependent diabetes mellitus: results of 20 year follow up of a London cohort of a multinational study. Br Med J 1996; 313: 848–852. 13. Forouhi NG, Sattar N, Tillin T, McKeigue PM, Chaturvedi N. Do known risk factors explain the higher coronary heart disease mortality in South Asian compared with European men? Prospective follow-up of the Southall and Brent studies, UK. Diabetologia 2006; 49: 2580–2588. 14. Enas EA, Singh V, Munjal YP et al. Reducing the burden of coronary artery disease in India. Ind Heart J 2008; 60: 161–175. 15. Indian Consensus Group. Indian consensus for prevention of hypertension and coronary artery diseases: a joint scientific statement of Indian Society of Hypertension and International College of Nutrition. J Nutr Environ Med 1996; 6: 309–318. 16. Singh RB, Mori H, Chen J, Mendis S, Moshiri M, Shoumin Z, Kim SH, Faruqui AMA. Recommendations for the prevention of coronary artery disease in Asians: a scientific statement of the International College of Nutrition. J Cardiovasc Risk 1996; 3: 489–494. 17. Bhalodkar NC, Blum S, Rana T, Bhalodkar A, Kitchappa R, Enas EA. Effect of leisure time exercise on high-density lipoprotein cholesterol, its subclasses, and size in Asian Indians. Am J Cardiol 2005; 96: 98–100. 18. Dodani S, Kaur R, Reddy S, Reed GL, Mohammad N. Can dysfunctional HDL explain high coronary artery disease risk in South Asians? Int J Cardiol 2008; 129(1): 125–132. 19. Beaglehole R, Ebrahim S, Reddy S, Voute J, Leeder S. Prevention of chronic diseases: a call to action. Lancet 2008; 370: 2152–2157. 20. Ueshima H, Sekikawa A, Miura K, Turin TC et al. Cardiovascular disease and risk factors in Asia. A selected review. Circulation 2008; 118: 2702–2709. 21. Zhang XH, Guan T, Mao J, Liu L. Disparity and its time trends in stroke mortality between rural and urban population in China 1987–2001: changing patterns, and its implications for public health policy. Stroke 2007; 38: 3139–3144. 22. Singh RB, Suh IL, Singh VP et al. Hypertension and stroke in Asia: prevalence, control and strategies in developing countries for prevention. J Hum Hyper 2000; 14: 749–763. 23. Singh RB, Singh NK, Vajpayee S et al. Prevalence and prevention of hypertension, diabetes mellitus and coronary artery disease in India. A scientific statement of the International College of Nutrition. In: Singh NK (ed.), Current Trends in Hypertension, Diabetes and Coronary Artery Disease. Varanasi, India: IMS, BHU, 2008, 186–199. 24. Singh RB and the Five City Study Group. Prevalence and risk factors of hypertension and age-specific blood pressures in five cities: a study of Indian women. Int J Cardiol 1998: 63; 165–173. 25. Pella D, Singh RB, Tomlinson B, Kong CW. Coronary artery disease in developing and newly industrialized countries: a scientific statement of the International College of Cardiology. In: Dhalla NS, Chocklingham A, Berkowitz HJ, Singal PK (eds.), Frontiers of Cardiovascular Health. Boston: Kluwer Academic Publishers, 2003, 473–483. 26. Mendis S, Lindholm LH, Mancia G, Whitworth J, Alderman M, Lim S, Heagerty T. World Health Organization (WHO) and International Society of Hypertension (ISH) risk prediction charts: assessment of cardiovascular risk for prevention and control of cardiovascular disease in low and middle income countries. J Hypertens 2007; 28: 1578–1582. 27. Kesteloot H. Social class, all cause and cardiovascular mortality. Acta Cardiol 2004; 59: 117. 28. Kesteloot H. Social class, all-cause, cardiovascular and cancer mortality: the importance of cigarette smoking. Acta Cardiol 2003; 58: 285–287.

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29. Singh RB, Beegom R, Mehta AS, Niaz MA, De AK, Mitra RK, Haque M, Verma SP, Dube GK, Siddiqui HM, Wander GS, Janus ED, Postigione A, Hague MS. Social class, coronary risk factors and undernutrition, a double burden of diseases in women during transition in five Indian cities. Int J Cardiol 1999; 69: 139–147. 30. Singh RB, Sharma JP, Rasogi V, Niaz MA, Ghosh S, Beegom R, Janus ED. Social class and coronary disease in a rural population of north India: The Indian Social Class and Heart Survey. Eur Heart J 1997; 18: 588–595. 31. Singh RB, Ghosh S, Niaz MA, Rastogi V. Validation of physical activity and socioeconomic questionnaire in relation to food intakes for the five city study and a proposed classification for Indians. J Assoc Phys India 1997; 45: 603–607. 32. Singh RB, Verma SP, Niaz MA. Social class and coronary artery disease in India. Lancet 1999; 353: 154–155. 33. Gupta R, Gupta VP. Meta-analysis of coronary heart disease prevalence in India. Indian Heart J 1996; 48: 241–245. 34. Singh RB, Pella D, Kartikey K, DeMeester F and the Five City Study Group. Prevalence of obesity, physical inactivity and undernutrition, a triple burden of diseases, during transition in a middle income country. Acta Cardiol 1997; 62: 119–127. 35. Beegom R, Singh R. Prevalence of coronary heart disease and its risk factors in the urban population of South India. Acta Cardiol 1995; 50: 227–240. 36. Singh RB, Ghosh S, Niaz MA, Gupta S, Bishnoi I, Sharma JP, Agarwal P, Rastogi SS, Beegom R, Chibo H, Shoumin Z. Epidemiologic study of diet and coronary risk factors in relation to central obesity and insulin levels in the urban population of north India. Int J Cardiol 1995; 47: 245–255. 37. Singh RB, Rastogi SS, Rastogi V, Niaz MA, Madhu SV, Chen M, Shoumin Z. Blood pressure trends, plasma insulin levels and risk factors, in rural and urban elderly populations of north India. Coron Artery Dis 1997; 8: 463–468. 38. Singh RB, Otsuka K, Chiang CE, Joshi SR. Nutritional predictors and modulators of metabolic syndrome. J Nutr Environ Med 2004; 14: 3–16. 39. Singh RB, Pella D, Neki NS, Rastogi S, Mori H, Otsuka K. Mechanism of acute myocardial infarction study (MAMI study). Biomed Pharmacol J 2004; 38(Suppl): 111–115. 40. Singh RB, Pella D, Sharma JP, Rastogi S, Kartikey K, Goel VK, Sharma R, Neki NS, Kumar A, Otsuka K. Increased concentrations of lipoprotein(a), circadian rhythms and metabolic reactions, evoked by acute myocardial infarctions, in relation to large breakfast. Biomed Pharmacother 2004; 58(Suppl): 116–122. 41. Singal A, Fewtrel M, Cole TJ, Lucas A. Low nutrient intake and early growth for later insulin resistance in adolescents born preterm. Lancet 2003; 361: 1089–1097. 42. Gillum RF. Editorial, The epidemiology of cardiovascular disease in black Americans. N Engl J Med 1996; 335: 1597–1599. 43. Singh RB, Niaz MA, Beegom R, Wander GS, Thakur AS, Rissam HS. Body fat percent by bioelectrical impedance analysis and risk of coronary artery disease among urban men, with low rates of obesity: the Indian paradox. J Am Coll Nutr 1999; 18: 268–273. 44. Singh RB, Rastogi V, Niaz MA, Ghosh S, Sy RG, Janus ED. Serum cholesterol and coronary artery disease in populations with low cholesterol levels: the Indian paradox. Int J Cardiol 1998; 65: 81–90. 45. Singh RB, Niaz MA, Ghosh S, Beegom R, Rastogi V, Sharma JP, Dube GK. Association of trans fatty acids (vegetable ghee), and clarified butter (Indian ghee) intake with higher risk of coronary artery disease, in rural and urban populations with low fat consumption: the Indian Paradox. Int J Cardiol 1996; 56: 289–298. 46. Singh RB, Beegom R, Verma SP, Haque M, Singh R, Mehta AS, De AK, Kundu S, Roy S, Krishnan A, Simhadri H, Paranjpe NB, Agarwal N. Association of dietary factors and other coronary risk factors with social class in women in five Indian cities. Asia Pac J Clin Nutr 2000; 9: 298–302. 47. Singh RB, Niaz MA. Genetic variation and nutrition, in relation to coronary artery disease. J Assoc Phys India 1999; 47: 1185–1190. 48. Kumar S, Mukherjee S, Mukhopadhya P, Pandit K et al. Prevalence of diabetes and impaired glucose intolerance in a selected population with special reference to influence of family history and anthropometric measurements—the Kolkata Policeman study. JAPI 2008; 56: 841–844. 49. Reddy KS, Yusuf S. Emerging epidemic of cardiovascular diseases in developing countries. Circulation 1998; 97: 596–601. 50. Sachs J and Commission on Macroeconomics and Health. A Race Against Time: The Challenge of Cardiovascular disease in Developing Economies. New York: The Earth Institute, Columbia University, 2004. 51. Joint WHO/FAO Expert Consultation. Diet, Nutrition and the Prevention of Chronic Diseases. Geneva: WHO, 2003, WHO Technical Report Series, 916.

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Chapter 4

Social, Cultural, Economical, and Practical Factors Simin B. Vaghefi, Julia Watkins, and Karri Brown

Key Points • Throughout the centuries, people from different parts of the world have developed eating habits that by experience have proven beneficial for the type of foods available and health and well-being of that culture. • Economic developments and progress of technology as well as availability of conveniences and luxurious living in the Western countries have resulted in dramatic changes in the foods available to consumers and information technologies have helped spread the food eating habits of the West through the entire world. • Fast foods, processed, and prepared foods which are widely available and consumed in the West for the last several decades due to their availability, low cost, and time saved for the families have cost the health of the individuals due to high fat content and low nutritional quality. • Social, cultural, economic, and practical factors influence the modern fat intake by the populations and the contribution to promotion of diseases. Keywords Population food habits · Economics of food choices · High fat content of fast foods · Fat intake and disease

1 Introduction: Social and Cultural Factors 1.1 Cultural Factors Culture plays an important role in every aspect of life, especially in eating habits of people. Habits ingrained in the culture usually have a long history of when and where these habits started. Food and eating are an integral part of living which provide enjoyment and nourishing the body

S.B. Vaghefi () Department of Nutrition and Dietetics, College of Health, University of North Florida, Jacksonville, FL, USA e-mail: [email protected] F. De Meester et al. (eds.), Modern Dietary Fat Intakes in Disease Promotion, Nutrition and Health, DOI 10.1007/978-1-60327-571-2_4, © Springer Science+Business Media, LLC 2010

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three or more times a day is a routine that is ingrained in us from the day we are born. In every culture, feeding the family has become an art which has evolved with different flavor depending on the geographic, climatic other factors throughout the centuries. Food plays a significant role in the family, groups, and society as evidenced in every occasion; when people get together, food plays an important role. People celebrate any cause of happiness (weddings, graduations, birthdays, new friendships, new babies, new home, etc.), sadness, business, holidays, and others with serving foods. Serving foods symbolized sharing with friends, family, people at your work, and those with whom you associate. In joyous occasions it is celebration of happiness and success that is shared together. In sadness, sharing food brings people together and comforts those who have been affected. All cultures in the world share foods in celebrations but the type of foods served and shared is different in different cultures. In the Western societies, these occasions’ foods that have a high fat and calorie content, usually called the comfort foods, dominate the celebration. While the Eastern and Mediterranean cultures prefer low-calorie fruits, vegetables, and high-fiber breads along with some sweets.

1.2 Social Factors With globalization trends and spread of information, communication, lifestyle and food eating habits are becoming similar. As different cultures adopt each other’s lifestyles and eating habits, the uniqueness of each culture is eventually disappearing. Eastern cultures whose food consumption is grain and vegetable based are becoming more omnivores and many of Eastern and Mid-Eastern people change to the Western way of using a high–energy, high-fat-content foods. Western cultures also pick up habits once considered exotic to them. As the result of these changes, world population seems to share the same trends in lifestyle and consequently show similar trends in health and diseases. Breaking bread and serving vine are an ancient tradition that is still practiced. However, modern times have brought modern practices of cutting cake, eating candy, and drinking coffee, carbonated high-sugar drinks in addition or alcoholic beverages for celebrations. Still there are subtle differences that are identifying cultural differences. The east Asian population uses rice as the staple of the diet and consumes other grains and pulses, with a high-vegetable and low-fat diet. Mediterranean people’s diet is high on olives and olive oil, vine, dairy, and meat (saturated fat), while they consume sea food as good portion of their diets (omega-3). People of the Middle East differ in dietary practices in different regions. Arab population eats high-meat/high-fat diets but most of Persian-speaking regions including Iran, Afghanistan, Tajikistan, and others have high whole grains and pulses, plenty of fruits, and vegetables including fresh greens, and meat and dairy intake is rather limited in the diet of these people. South Asian countries where the climate is tropical, people consume a diet similar to the Persian-speaking countries but use a great deal of hot spices in their culinary practices. Western Europeans and the people of the American continents have changed to a predominantly meat and dairy (highly saturated fat) foods with high intakes of purified carbohydrates that make the consumers of this diet highly susceptible to degenerative diseases. Regardless of the globalization of dietary practices, still the Western populations on the average consume more caloric dense foods heavily loaded with fat and sugar and are heavier in weight than the populations of the other parts of the world.

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1.3 Educational Factors People are educated in the art of eating and the knowledge of nutrition in many ways and through many venues. From the dawn of history, children learned the eating habits practiced by their parents and what practiced was repeated through the generation with very little change. As the knowledge of nutrition evolved from sciences through biochemistry, biology, and physiology, many of the old practices that were results of centuries of trials and errors were confirmed scientifically by nutritionist and some were negated. Knowledge of the importance of macro- and micronutrients and their ratios in everyday diet at different ages and for different conditions created a new profession of dietetics. Dieticians became the resource professionals for educating the public about the correct eating practices, as healthy individuals, or for nourishment during ill-health or treating diseases. As the knowledge in this field advanced the principles of energy balance, whole and refined foods, processed foods, saturated, mono-, polyunsaturated, and essential fats including omega-6 and omega-3 (biologically active oils) were elucidated. All these information could have been confusing for lay public, thus nutrition education became a must for the areas of medicine, nursing, and other health-related fields. At the same time, commercial enterprises started pushing highly processed foods, ready-toeat meals and fat- and sugar-loaded snacks, manufactured vitamins, minerals, and any other nutrients that scientists determined, through research, beneficial to peoples’ health. Many of these supplements that are present in natural foods were presented to the consumers as miracle substances not obtainable from natural foods. As it is the nature of free enterprise, these for-profit firms pushed their products encouraging large groups of people to believe that the pure nutrients sold in pills and capsule forms are better than the natural foods containing them. Eventually the deleterious effects of consuming manufactured products become evident as large amounts were consumed by consumers. Interestingly enough, educators, researchers, governmental agencies, and naturalists were able to balance the misinformation with facts and now many people have turned to natural unprocessed foods. In the meantime, researchers are showing that there are some disadvantages in overconsumption of purified nutrients. Nutritionists and dieticians have also been informing people of healthy eating and lifestyle practices while avoiding misrepresented facts promoted by advertisements and manufacturers of supplements of all kinds. As a result of the effort of the educators the rates of degenerating diseases have been declining in the Western world.

1.4 Social Class Factors Unfortunately not everyone is well informed about healthy lifestyle and healthy eating in the developed and developing nations. Thus many of underprivileged populations suffer the consequences of practicing poor eating habits that promote disease. Obesity and cardiovascular diseases and type 2 diabetes even in children are the consequence of overeating high-fat, highenergy, low-nutrient foods that are consumed globally as a result of the transfer of habits without transfer of knowledge. As the level of education varies in population, the social and economic factors also play an important part in their lifestyle and health status. In the society children, young adults and grown-ups are influenced by what is vogue and this factor usually comes into play in the form of peer pressure in young adults in schools and society. As the high-fat

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foods and snacks are easily obtained from vending machines and in the cafeterias, young school children indulge to copy each other in consuming those foods and snacks. In the work-related or social luncheons, high-fat foods are served to please the consumers. As the nutrient composition of meals served in the restaurants changed over the past 50 years, the fat intake has increased through the above-mentioned situations. Institutional meals served to the patrons are also usually high in fat content. All these factors have contributed to increased overweight and obesity and related degenerative diseases.

2 Economic Development, the Western Diet, and Obesity Western diets are being adopted worldwide, and they are creating an “obesogenic diet,” largely due to an excess of fat and calories, as well as contributing to increasing cases of type 2 diabetes and cardiovascular disease [1]. Diets of many different ethnicities have been researched and it has been shown that the Western diet is deteriorating the health of these different groups. Native Alaskans traditionally have had a high-fat diet rich in EPA and DHA, mostly due to the marine animals they eat and the blubber those animals contain. However, currently they are eating a more Westernized diet, and this diet is having a negative health impact on their population. When comparing the traditional Alaskan diet to the Western diet, the Alaskans had an increase in total calories, mostly from fat and protein, when eating a Westernized diet [1]. The type of fat is also important, because when consuming a Western diet, healthy monounsaturated and polyunsaturated fats are minimal and saturated fats are high. This type of diet increases the risk of cardiovascular disease and obesity. Another population the Hmong (southeast Asian) migrants to the United States have experienced an increase in the prevalence of chronic diseases and obesity as they eat a more Western, or American, diet. The traditional Hmong diet is three meals a day, the staple being rice, and is considered very bland with most of the vegetables and fish boiled. Desserts are rarely eaten. The second and third generations of Hmong migrants prefer to eat McDonald’s rather than traditional Hmong foods, or they want the typically bland Hmong diet to be stir-fried, which includes adding oil. They also have a new penchant for sweets and desserts after meals. The Hmong participants in the study admitted to eating more food once in the United States, merely because of the availability, and they believe the American foods have more fat and sugar, making them more appealing. They also notice that the more they eat, the larger they get, and the sicker they feel. The Hmong population is now experiencing increasing BMIs toward obesity and the co-morbidities related to this chronic disease [2]. Fast foods are known for their large portion sizes, the fat content, and being affordable. Research has been conducted to test the postprandial difference between an American Heart Association-approved breakfast and a fast-food breakfast, which is high in fat, sodium, calories, and cholesterol. There is more oxidative stress after the consumption of the fast-food meal, which contributes to heart diseases, specifically atherosclerosis [3]. Therefore, fast-food consumption has a direct link to not only obesity but heart disease as well. Furthermore, childhood obesity is on the rise and one contributing factor is fast-food consumption. Between the 1970s and the 1990s, fast-food consumption of children and adolescents has tripled, and the number is still rising. This is alarming, not only because fast-food consumption equates to greater calorie and fat consumption but also because it has a negative impact on the consumption of fruits, vegetables,

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and milk [4]. Therefore, children and adolescents are consuming sometime all of their necessary calories and sometime [5] excess calories from fast foods and this practice prevents them from eating all the food groups necessary for growth and health as deemed necessary by My Pyramid. Fast-food consumption is known to contribute to obesity in adults, and starting this trend at an early age could lead to obesity and other chronic diseases earlier in life as well. Introducing children to fast foods also ingrains in them the wrong habit of eating unhealthy throughout their life. Comfort foods are foods that can be stress relieving, satisfying, but most of all they have a mental association with pleasure [6]. The comfort foods are usually sweet, high in fat, and just make people feel better, mentally. High-fat foods, especially sweets, are seen as comfort foods because they are usually found at celebrations. Birthday cakes and expensive, indulgent meals are for special occasions and related to happy times. Therefore, high-fat foods are comforting to many people in times of stress, and in our society they are easily attainable and inexpensive all the time. According to a study on Sensitivity to Reward (STR), the brain registers food in the same pathway as addictive drugs, which stimulates a dopamine release. Therefore, a high sensitivity increases the pleasure you obtain from food, thus increasing the desire to eat more of it. Especially high-fat foods and sweets are thought to be the most satisfying in times of stress and sadness [7]. A research study was performed using a survey method with female college students to determine how stress impacts their eating habits. Sixty-three percent of the participants admitted an increase in appetite due to stress or anxiety, and many women reported eating unhealthy snacks, such as chocolate, pizza, ice cream, and other desserts, all of which are high in fat. These snacks were stated to comfort the subjects while they were consuming these foods. However, the subjects also indicated that eating these foods leads to a feeling of guilt, stomach aches, and can even lead to obesity, especially as the need for comfort foods persists [8]. Economic development in the West has caused the availability of high-fat foods in the market for consumption. It is this availability along with relatively low cost of foods and taste of high-fat foods which becomes a leading indicator of dietary fat consumption in the economically well-developed West. Globalization of markets has increased availability and consumption of hydrogenated vegetable oil and fast food at reduced cost. In addition, the global penchant for fast food has been linked to convenience due to the reduced cost and the time invested in acquiring food [9]. Resulting economic development and increase in income of population have been positively associated with dietary fat intake. These changes in the economic environment including urbanization impact the relationship between cost and buying behaviors [10]. It has been shown that the process of urbanization increases household income within a region [11]. Urbanization in combination with the food marketing is a significant determinant of dietary patterns which include higher fat intake [12]. Advances in food production, supply, and marketing technology provide more cost-efficient distribution of foods and economic factors control the availability, cost, and marketing of higher caloric and high-fat food products [13]. The most prevalent sources of high-fat foods are “fast foods.” Economic development includes the integration of fast food and is associated with higher levels of total, saturated, and trans fat in the diet [14]. Globally the effect of nutrition transition is elucidated by the differences in dietary patterns and population health indicators as found in countries at varied phases of economic development [15, 16]. At the same time that developed regions experience increases in fast-food availability and frequency of consumption, emerging countries are encountering a nutrition transition in association with new economic development. Ezzati et al. note that this transition is the result of

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“obesogenic social and economic transformations” which are advancing at rates that are significantly faster than those found in currently developed countries [17]. The effect of these changes in dietary patterns within developing countries is approximately 4–5% more of total percentage of energy intake is comprised of fat than prior to globalization [18]. As less costly and more convenient food sources are introduced into a country, the regular traditional foods of that country are replaced. Fast food supplants diets rich in complex carbohydrates and fiber according to Drewnowski and Popkin [15]. Increases in consumption of fast food alter the nutrient composition of food intake to include increased total saturated and trans fats. Further, fast foods are relatively low in cost and are more convenient for some portions of the population such as working and single-parent families with children [19]. The transition of dietary composition within a region is followed by a subsequent change in population health indicators. Higher intake of saturated fats such as hydrogenated vegetable oil and a trans-unsaturated fat in populations is followed by an increase in risk factors known to be etiological progression of cardiovascular disease. Factors such as hypertension, hypercholesterolemia, particularly elevation of LDL cholesterol, and obesity are health indicators negatively influenced by consumption of high-fat diets. Over time epidemiological findings indicate a shift in morbidity- and mortality-related factors [20, 21], from causes related to infectious to chronic diseases. In summary, the leading causes for the etiology and incidence of cardiovascular disease and dietary patterns which include increased caloric, salt, and fat intake are the result of an economic and nutrition transition within a region [22]. Ford and Mokda [23] report findings from data collected by the International Obesity Task Force identifying those countries which have experienced significant increases in obesity prevalence. These countries include the Bahamas, Barbados, Canada, Chile, Guyana, Mexico, Panama, Paraguay, Peru, St. Lucia, Trinidad and Tobago, Venezuela, Brazil, Canada, Mexico, and the United States. As shown in Fig. 4.1, analysis of data from the Food and Agriculture Organization

Fig. 4.1 The relationship between the availability and the intake of high-fat foods (FAOSTAT|© FAO Statistics Division 2008|02 December 2008)

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(FAO) of the United Nations shows that total fat consumed from all sources (in grams per capita per day) has increased from 1970 to 2003 for these same countries [24]. Since the early 1970s, significant increases in fast-food production have resulted in the optimization of food availability, in frequency, amount, and caloric density [25]. In the United States, the fast-food industry has effectively marketed and made available fast foods such that the American diet has been powerfully altered. Current economic data indicate that 25% of the population consumes fast food most of the time. A 2001 study found that the frequency of consuming fast food was significantly associated with increased total fat intake [26]. Data from the United Nations’ Food and Agriculture Organization indicate that fat from all sources consumed by Americans rose from 119 g/capita/day to 155 g/capita/day during the last decade of the last century and the last few years of this century. Further, recent findings report that the US dietary patterns have changed to include more saturated fats as a result of the availability of fast foods [27]. A US Department of Agriculture report “Nutrient Content of the US Food Supply 2005” found that the availability of total fat per capita per day basis was 190 g. Analysis of types of fat intake indicated that monounsaturated fatty acids increased to 85 g per capita and per day, the highest level over the decade. The report further elucidated that overnutrition in the United States is primarily attributed to a 28% increase in the amount of fat contributing to caloric levels. Overall, between 1995 and 2005 the percentage of fat to total calories rose 6% [28]. Epidemiological findings are indicating that almost one-third of children consume fast food daily [28]. Availability of fast foods in the home has been linked to higher consumption of dietary fat intake in children [29] and lower quality of the diet overall. Outside the home a recent cross-sectional study suggested that local area prices of fast foods and fruits and vegetables may influence healthy eating behaviors among adolescents. That is, when prices of fast foods increase, families tend to prepare meals at home, which will be more conducive to healthier eating behavior [30]. Economic researchers examining the association between food price and dietary intake have found that the rising prices of fast food results in lower consumption of fast foods and overall increase in diet quality. Comparing the intakes of fast foods by income groups, it was determined that as the price of fast foods increased, the consumption of fast foods decreased and the quality of the diet improved. Findings of the study determined that lower income is more strongly associated a higher consumption of fast foods and a reduction in high-fat fast foods when prices are increased, indicating that the lower price of high-fat fast foods is the cause of higher consumption in the lower income families [31]. Research by Eyler et al. determined that lower education and income were risk factors for the adoption of high-fat dietary patterns including an increase in amount and frequency of fast-food consumption [32]. Food prices can also influence food choices. Changing the relative prices of certain types of foods has marked consequences on quality of the diet, a pattern hypothesized to be more salient among the poor segment of the population. In addition, studies have shown that lower income was associated with poorer dietary quality [33]. Within adolescent school and work environments the Changing Individuals’ Purchases of Snacks (CHIPS) study found that reducing the price of low-fat vending machine snacks significantly increased the purchase of low-fat snacks and that a positive association was found between price reductions in vending machines (of 10, 25, and 50%) and increased low-fat snack sales by 9, 39, and 93%, respectively [34].

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3 Practical Factors Eating habits of Western world have changed dramatically from a high-fiber/whole-grain and vegetable-dominant plan in the early twentieth century that was not too different from early agricultural society of distant ancestors’ diet who survived a very physically active, high-fiber, low-energy, low-fat diets where their genetic makeup was conditioned [35]. That type of diet and lifestyle has been shown to be health promoting and disease preventing [36]. Conversely, a meatand fat-dominant diet and highly refined carbohydrates that eventually evolved from middle of the twentieth century have changed the health and lifestyle. The invention and accessibility of convenience appliances that were embraced by homemakers reduced the physical activity, combined with the above eating habits causing a high rate of degenerative disease [37, 38]. Result of a high-fat, high-energy diet and low levels of physical activity has promoted many degenerative diseases. In spite of vast improvements in health and hygiene and ability to fight infectious diseases, mortality from degenerative diseases including cardiovascular, cancer, obesity, and diabetes has increased exponentially. It is suggested that obesity resulting from unbalanced energy in diets high in both fat and carbohydrates and low levels of physical activity predisposes overweight and obese individuals to degenerative disease and has a multi-factorial cause that requires a general and urgent public health strategy for its control [39]. This phenomenon and its effects on the health of the people are extensively covered by Cordain et al. in a well-documented review discussing the rapid change of environment (food and activity) and the “evolutionary discordance” that has presented itself as the rampant increase in the degenerative diseases in the past century [40]. Change in lifestyle also eventually coincided with the economic boom that increased the necessity to engage in outside of home work to earn the needed income. As the affluence increased in the Western Societies, desire for the elevated luxurious living followed. In many households it translated to both parents working outside of home. This changed the old culture of home-prepared meals that gathered the family around the dinner table every evening. These changes altered not only the family culture but also the need to forego home-cooked meals and preference for enjoying restaurant foods. Not very many people could afford the expensive restaurants meals, therefore the fast-food industry flourished. Competition between different types of fast-food vendors and mass production of foods caused this industry to bring the prices and the nutritious quality of meals down to much less than similar foods made at home. The low price of fast foods and having them readily available attract the families in the low socioeconomic bracket to purchase and use fast foods to feed their families. Fast-food industry plays a significant role in the consumption of high-fat diets by the population, especially the low socioeconomic class. Other social factors including urbanization and decreased security outside of the homes keep children from playing outside of home after school and adults from exercising after work such as walking and jogging and increase sedentary recreations such as television viewing and similar pastimes. Obesity being the result of the combination of these changes is prevalent in the United States and the Western world. Unfortunately, due to export of Western culture, especially introduction of fast foods to the underdeveloped and developing countries, and globalization, obesity is fast becoming rampant throughout the globe. Consequently the degenerative diseases have become a global problem. Studies show that obesity as indicated by body mass index (BMI) is inversely proportional to the social and economic standing of the family. Laitinen, Power, and Jarvelin show that obesity in a person can be

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predicted by a low social class of the family, a high maternal BMI prior to pregnancy, and high BMI during adolescence plus early menarche [41]. Due to the economic factors causing both parents to work outside of the home, the culture of home-prepared meals has basically disappeared and is being replaced by consumption of fast foods and restaurant meals. Fast foods are popular for three reasons [1]: fast foods are readily available in every corner of the towns and cities [2]; fast foods are reasonable in price and even cheaper than the foods prepared at home [3]; and very little time is spent at home for preparation, thus saving time for the family. Although these types of food are not as nutritious as carefully prepared home-cooked meals, they are most of the time unhealthy due to a high-fat content and a lack of adequate fruits and vegetables that balance the meals nutritionally. Fast foods are unhealthy also due to the type and amount of fat used in their preparation. Fast-food establishments are not rigidly controlled, thus some unhealthy practices may occur. As the nation becomes more health conscious and competition is increased, the variety of meals is increased and more vegetables and fruits are included in the menu at fast-food restaurants. The establishments claim to use more healthy fats but quantity of fat used in the preparation of fast foods as well as non-fast-food restaurants is excessive due to the fact that most flavors are fat soluble, making the meals more palatable. Also the quality of fats used may not be what they are claimed to be. Restaurant meals as well as fast foods come with fried food components adding to the fat consumed in each meal. It has been shown that each meal consumed outside of home provides a total calorie and fat content that is equal or often more than a whole day’s requirements for both. Deserts and snacks are high-fat/high-carbohydrate food items and are popular with both children and adults, adding extra fat and calories to the day’s meals. It has been shown that carbohydrate foods are contributing to the obesity as much as fatty foods do [42]. In fact some researchers believe that in today’s dietary habits in which high-fat foods are discouraged by the nutrition scientists, high-carbohydrate intake, especially the refined kind, has contributed more to the obesity and consequent increased degenerative disease [43]. These types of foods are also heavily promoted by restaurants. Although more fruits and vegetables are promoted by health organizations and nutrition experts, the palates of the Western population are still not used to these natural foods and crave sweets. Processed foods are another carrier of high fat that is highly promoted and consumed by people. Again time constraint on the part of family as well as enticingly advertised processed and prepared meals forces the home maker to opt for the highly processed foods that require minimum or even no preparation. The processed, ready-to-eat meals are not only expensive but also highly fatty and unhealthy foods.

4 Conclusions Eating habits picked up at schools from the meals offered usually have lasting effects in students. Little attention is paid to this important fact by the school food program and the system administering it does not help to leave a positive influence on the students. School meals are usually highly subsidized by the Federal Government using the commodity foods that are highly fatty foods (commodity butter, sugar, and refined flour) [44], highly processed foods, carbonated beverages etc. The program does not employ enough dieticians to cover schools and

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implementation is contracted out to vendors. Individual schools do not have initiative or the budget to use locally produced ingredients that may be fresh and more nutritious. They depend on the vendors who are more interested at the bottom price and their profit, thus students are fed a kind of fast foods lacking taste and appeal needed to inspire them to lean and copy the menus at home. In conclusion, due to lifestyle, economic, and environmental conditions prevailing in the society that are brought on by changing times, desire for unnecessary luxuries, lack of information on relationship that lifestyle has with health, and low priority for healthy living, the families are sacrificing their health. Dietary habits have changed to high-fat consumption by majority and in spite of repeated warning by experts, people continue to follow that eating pattern. With all the fats and oils that are consumed, majority of people are deficient in the essential fatty acid omega-3, which is found in fish oil, walnut, and other tree nuts. To make sure that people get enough, even FDA has approved supplements of omega-3 in capsules [45].

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18. Guo X, Mroz TA, Popkin BM, Zhai F. Structural changes in the impact of income on food consumption in China, 1989–93. Econ Dev Cult Change 2000; 48: 737–760. 19. Harris-Davis E, Stallmann-Jorgensen I. Addressing overweight in children: a public health perspective. In: Edelstein S (ed.), Nutrition in Public Health: A handbook for developing programs and services. 2nd edn. Sudbury, Mass: Jones and Bartlett Publishers, 2006. 20. Habib SH, Saha S. Burden of non-communicable disease: global overview. Diab Met Syndr Clin Res Rev 2008, doi:10.1016/j.dsx.2008.04.005. 21. Bowman SA, Gortmaker SL, Cara B, Ebbeling CB, Pereira MA, Ludwig DS. Effects of Fast-Food Consumption on Energy Intake and Diet Quality Among Children in a National Household Survey. Pediatrics January, 2004; 113(1): 112–118. 22. Ezzati M, Vander Hoorn S, Lawes CM, Leach R, James WP, Lopez AD, Rodgers A, Murray CJ. Rethinking the “diseases of affluence” paradigm: global patterns of nutritional risks in relation to economic development. PLoS Med 2005; 2(5): e133. 23. Ford ES, Mokdad AH. Epidemiology of Obesity in the Western Hemisphere. J Clin Endocrinol Metab 2008; 93(11): S1–S8. 24. Food and Agricultural Organization of the United Nations. FAOSTAT. (2008). Website: http://faostat.fao. org/default.aspx. 25. Paeratakul S, Ferdinand D, Champagne C, Ryan D, Bray G. Fast-food consumption among US adults and children: dietary and nutrient intake profile. JADA 2003; 103(10): 1332–1338. 26. French SA, Jeffery RW, Story MS, Breitlow KK, Baxter JS, Hannan P, Snyder MP. Pricing and promotion effects on low-fat vending snack purchases: the CHIPS study. Am J Public Health 2001; 91: 112–117. 27. Haddad L. Redirecting the diet transition: what can food policy do?. Dev Policy Rev 2003; 21: 599–614. 28. Hiza HAB, Bente L, Fungwe T. Nutrient Content of the US Food Supply, 2005. (Home Economics Research Report No. 58). Center for Nutrition Policy and Promotion: US Department of Agriculture, 2008. 29. Raynor HA, Polley BA, Wing RR, Jeffery RW. Is dietary fat intake related to liking or household availability of high- and low-fat foods?. Obesity Res 2004; 12: 816–823. 30. Powell LM, Auld C, Chaloupka FJ, O‘Malley PM, Johnston LD. Associations between access to food stores and adolescent body mass index. Am J Prev Med 2007; 33(4): S301–S307. 31. Beydoun MA, Powell LM, Youfa W. The association of fast food, fruit and vegetable prices with dietary intakes among US adults: is there modification by family income?. Soc Sci Med 2008; 66: 2218–2229. 32. Eyler AA, Haire-Joshu D, Brownson RC, Nanney SM. Correlates of fat intake among urban, low income African Americans. Am J Health Behav 2004; 28(5): 410–417. 33. Darmon N, Ferguson EL, Briend A. A cost constraint alone has adverse effects on food selection and nutrient density: an analysis of human diets by linear programming. J. Nutr 2002; 132: 3764–3771. 34. French SA, Jeffery RW, Story MS, Breitlow KK, Baxter JS, Hannan P, Snyder MP. Pricing and promotion effects on low-fat vending snack purchases: the CHIPS study. Am J Public Health 2001; 91: 112–117. 35. Gould SJ. The Structure of Evolutionary Theory. Cambridge, MA: Harvard University Press, 2002. 36. Boaz NT. Evolving Health: The Origins of Illness and How the Modern World is Making Us Sick. New York: Wiley & Sons, Inc, 2002. 37. Blair SN. The evolution of physical activity recommendations: how much is enough. Am J Clin Nutr 2004; 79(suppl): 913S–920S. 38. Brooks GA, Butte NF, Rand WM, Flatt JP, Caballero B. Chronicle of the Institute of Medicine and physical activity recommendation: how a physical activity recommendation came to be among dietary recommendations. Am J Clin Nutr 2004; 79(suppl): 921S–930S. 39. Grundy SM. Multifactorial causation of obesity: implications for prevention. Am J Clin Nutr 1998; 67(suppl): 563S–572S. 40. Cordain L, Eaton BS, Sebastian A, Mann N, Lindeberg S, Watkins BA, O’Keefe JH, Brand-Miller J. Origins and evolution of the Western diet: health implications for the 21st century. Am J Clin Nutr 2005; 81: 341–354. 41. Laitinen J, Power C, Jarvelin MR. Family social class, maternal body mass index, childhood body mass index, and age at menarche as predictors of adult obesity. Am J Clin Nutr 2001; 74: 287–294. 42. Hirsch J, Hudgins LC, Leibel RL, Rosenbaum M. Diet composition and energy balance in humans. Am J Clin Nutr 1998; 67(suppl): 551S–555S. 43. Willett WC. Is dietary fat a major component of body fat?. Am J Clin Nutr 1998; 67(suppl): 556S–562S. 44. USDA Food Distribution Program http://dpi.wi.gov/fns/fooddist.html.kb 45. Healy B. From fish Oil to Medicine. US News and World Report. www.usnews.com August 18/ August 25, 2008.

Part II

Dietary Fats

Chapter 5

Partially Hydrogenated Fats in the US Diet and Their Role in Disease James J. Gormley and Vijaya Juturu

Key Points • To formulators, hydrogenated vegetable oils provide distinctive flavor, crispness, creaminess, plasticity, and oxidation stability. Refinement of the industrial technology of partial hydrogenation and appropriate food labeling may lead to a considerable decrease of human exposure to trans-fatty acids. • Some authorities recommend a broad-based, dietary paradigmatic shift in the United States as a long-term, sustainable solution to the cascade of health problems caused by the consumption of trans-fatty acids in the American diet. Over 80% of coronary heart disease, 70% of stroke, and 90% of type 2 diabetes can be avoided by more healthy food choices that are in accord with elements of the Mediterranean diets. Keywords Trans-fatty acids · Hydrogenated fats · Metabolic complications · Chronic disease · Dietary recommendations After refinement of Sabatier’s early work on hydrogenation by German chemist, Wilhelm Normann, in the early 1900s along with a 1903 British patent [1, 2], Procter & Gamble, later acquired the US rights to the Normann patent in 1909 and began selling Crisco in 1909. US courts soon opened the way to the entire fats and oils industry and, by the 1930s, an all-hydrogenated vegetable shortening and an oleomargarine were widely available. After 1948, traditional stick margarine began to be mass produced for not only the United States but a global market.

V. Juturu () UnitedBio-Med Inc, 102 Hunters Run, DobbsFerry, NY 10522, USA e-mail: [email protected] Disclosures Vijaya Juturu has no relevant conflicts of interest to disclose. James Gormley has no relevant conflicts of interest to disclose. Mr. Gormley is a pro bono board member of the Natural Health Research Institute (www.naturalhealthresearch.org) and president of Gormley NPI Consulting (gormleyconsulting.blogspot.com). F. De Meester et al. (eds.), Modern Dietary Fat Intakes in Disease Promotion, Nutrition and Health, DOI 10.1007/978-1-60327-571-2_5, © Springer Science+Business Media, LLC 2010

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According to Allen in 1978 [3], the entire oil seed industry resulted from the “ability to hydrogenate the by-product oil produced by extraction of the seed” and the growth of the soybean industry paralleled the expansion of hydrogenation of food oils. To formulators, hydrogenated vegetable oils provide distinctive flavor, crispness, creaminess, plasticity, and oxidation stability.

1 The Process of Hydrogenation At its simplest, hydrogenation of oils involves saturation of double bonds in an unsaturated fat with hydrogen utilizing a catalyst, such as nickel, in order to yield fat products that have longer shelf life, can withstand higher temperatures and offer food-production flexibilities that have been attractive to food manufacturers since the early 1950s. That being said, the hydrogenation reaction is not a simple saturation of double bonds with hydrogen but is, according to Allen, “an extremely complex series of reactions that result in a myriad of products” [2, 3]. Hydrogenation causes several chemical changes (Fig. 5.1), one of which is the creation of trans fats (a solid or semi-solid oil product) (Fig. 5.2). The major dietary sources of transfatty acids are partially hydrogenated vegetable oils (Table 5.1). Margarines and shortenings, for example, are “hardened” to solid or semi-solids during hydrogenation. Vegetable oils which have been partially hydrogenated are now partially saturated so the melting point increases to the point where it becomes solid at room temperature or low temperatures. H 2C=CH 2 +H 2 --- > CH3 CH3 alkene plus hydrogen yields an alkane

Fig. 5.1 Hydrogenation reaction

H C

C

H Fig. 5.2 Structure of trans-fatty acid

The composition of saturated fatty acids and trans-fatty acids varies in industrial partially hydrogenated oils. Use of fried oils in restaurants may increase the saturated and trans-fatty acids. Antioxidants decrease in the frying oil which leads to oxidation, and the effectiveness of antioxidant decreases with high frying temperatures.

2 Sources of Trans Fats Trans-fatty acids are unsaturated fatty acids with at least a double trans configuration, resulting in a more rigid molecule close to a saturated fatty acid. These appear in dairy fat because of ruminal activity—TFAs comprise about 5% of dairy and beef fat [4]—and in hydrogenated

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Table 5.1 Partially hydrogenated oils

Partially hydrogenated oils

Total lipid (fat)

Fatty acids, total saturated

Fatty acids, total monounsaturated

Fatty acids, total Fatty polyunsat- acids, urated total trans

Fatty acids, total transmonoenoic

Margarine, industrial, nondairy, 80.20 20.442 46.692 9.265 24.747 21.554 cottonseed, soy oil (partially hydrogenated), for flaky pastries Margarine, industrial, soy and 80.00 16.321 37.460 22.422 20.578 18.970 partially hydrogenated soy oil, use for baking, sauces, and candy 70.22 13.631 33.468 20.248 14.786 14.007 Margarine, margarine-type vegetable oil spread, 70% fat, soybean and partially hydrogenated soybean, stick Oil, industrial, soy (partially 100.00 25.883 59.133 10.305 30.809 27.285 hydrogenated) and cottonseed, principal use as a tortilla shortening Oil, vegetable, industrial, soy 100.00 17.683 41.929 35.638 13.555 10.013 (partially hydrogenated), principal uses: popcorn and flavoring vegetables Oil, vegetable, industrial, soy 100.00 18.101 40.262 36.847 12.927 9.603 (partially hydrogenated), multiuse for nondairy butter flavor Oil, vegetable, industrial, soy 100.00 15.341 34.630 45.228 10.755 8.308 (partially hydrogenated ) and soy (winterized), pourable clear fry 100.00 28.421 59.715 7.095 31.228 28.343 Oil, vegetable, industrial, soy (partially hydrogenated ), palm, principal uses: icings and fillings 100.00 24.750 61.248 9.295 34.162 29.638 Oil, vegetable, industrial, soy (partially hydrogenated), all purpose Oil, soybean, salad, or cooking 100.00 14.900 43.000 37.600 – – (partially hydrogenated) 100.00 10.117 71.075 14.038 27.017 22.789 Oil, vegetable, industrial, canola (partially hydrogenated) oil for deep fat frying USDA National Nutrient Database for Standard Reference, Release 21 (2008) accessed on January 28, 2009

oils; margarines, shortenings, and baked goods contain relatively high levels of trans-fatty acids. Examples of processed foods that are high in partially hydrogenated fats include (but are not limited to) margarine; shortening; donuts; crackers; cookies; cake, cake icing, and pie; microwave popcorn; and movie popcorn “butter” (Table 5.2). Some dietary supplements contain ingredients that also include partially hydrogenated vegetable oil or trans fat as well as saturated fat and cholesterol. FDA’s recently implemented labeling requirements state that if a dietary supplement contains a reportable amount of trans fat,

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Table 5.2 Dietary sources of trans-fatty acidsa (TFA)

Product

Common serving size

Total fat (g)

Trans fat (g)

Combined sat. and trans fat (g)

Medium (147 g) 27 8 15 French-fried potatoese (fast food) Butterb 1 tbsp 11 0 7 Margarine, stickc 1 tbsp 11 3 5 Margarine, tubc 1 tbsp 7 0.5 1.5 Mayonnaised 1 tbsp 11 0 1.5 (soybean oil) 1 tbsp 13 4 7.5 Shorteninge Potato chipse Small bag (42.5 g) 11 3 5 Milk, whole± 1 cup 7 0 4.5 1 cup 0 0 0 Milk, skimc Doughnute 1 18 5 9.5 Cookiese 3 (30 g) 6 2 3 (cream-filled) 1 (40 g) 10 3 7 Candy bare Cake, pounde 1 slice (80 g) 16 4.5 8 a Nutrient values rounded based on FDA’s nutrition labeling regulations. b Butter values from FDA Table of Trans Values, January 30, 1995. c Values derived from 2002 USDA National Nutrient Database for Standard Reference, Release 15. d Prerelease values derived from 2003 USDA National Nutrient Database for Standard Reference, Release 16. e 1995 USDA Composition Data.

which is 0.5 g or more, the product manufacturers must list the amounts on the Supplement Facts panel. Examples of dietary supplements that may contain saturated fat, trans fat, and cholesterol include energy and nutrition bars. Partially hydrogenated vegetable oils provide about three-fourths of the trans-fatty acids (TFAs) in the US diet [5]. As noted, Table 5.2 provides different partially hydrogenated oils and sources of fatty acids.

3 Health Effects Industrially produced trans-fatty acids (IP-TFA) from fast fried foods have powerful biological effects and may contribute to increased weight gain, abdominal obesity, type 2 diabetes, and coronary artery disease. Consumption of hydrogenated oils may cause diabetes, coronary heart disease, cancer, and other chronic conditions. Trans-fatty acids (Fig. 5.2) may decrease the fluidity of membranes and binding of insulin to its receptor, leading to impaired insulin action, insulin resistance, hyperinsulinemia, hyperlipidemia, and increase the risk of cardiovascular disease (CVD) and metabolic disorders. Some reports suggest that TFAs raise total blood cholesterol more so than do saturated fats [5]. Trans fats also tend to increase levels of low-density lipoprotein (LDL) cholesterol and increase levels of high-density lipoprotein (HDL) cholesterol [5].

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Almendingen et al. [6] noted that partially hydrogenated soybean oil (PHSO) has unfavorable antifibrinolytic effects relative to partially hydrogenated fish oil (PHFO) and butter and that butter may be procoagulative relative to PHFO. The PHSO diet resulted in higher levels of plasminogen activator inhibitor type 1 antigen (PAI-1) and PAI-1 activity than did the two other test diets. Fibrinogen increased on the butter diet compared with the PHFO diet. No significant differences in the levels of factor VII (a vitamin K-dependent serine protease glycoprotein, also known as stable factor or proconvertin), plasma fibrinopeptide A (FPA), D-dimer, tissue plasminogen activator (tPA), or β-thromboglobulin (β-TG) were observed among the three test diets. Pedersen et al. [7] compared the effects of three different margarines, palm oil (PALMmargarine), partially hydrogenated soybean oil (TRANS-margarine), and a high content of polyunsaturated fatty acids (PUFA-margarine) on serum lipids in 27 young women. The diurnal, postprandial-state level of t-PA activity was significantly decreased on the TRANS-diet compared to the PALM-diet. Also, t-PA activity was decreased on the PUFA-diet compared to PALM-diet although not significantly (p = 0.07). Thus, palmitic acid from palm oil may be a reasonable alternative to trans-fatty acids from partially hydrogenated soybean oil in margarine [8, 9]. The dietary trans-fatty acids from partially hydrogenated soybean oil (PHSO, TRANS-diet) have an unfavorable effect on postprandial t-PA activity and thus possibly on the fibrinolytic system compared with palm oil [10].

4 Intake of Partially Hydrogenated Fats On average, people in the United States consume 5.8 g of trans fats per day (g/day) or 2.6% of calories per day compared with 2.4 g/day in the EU. On average, Americans consume approximately four to five times more saturated fat than they do trans fat in the diet [11, 12]. The relative risk of cardiovascular heart disease (CHD) associated with an absolute increase of 2% in the intake of TFA was 1.36 in the Health Professionals Follow-up Study [13], 1.14 in the AlphaTocopherol, Beta-Carotene Cancer Prevention Study [14], and 1.93 in the Nurses’ Health Study [15].

5 Partially Hydrogenated Fats in Health and Disease 5.1 Metabolic and Cardiovascular Health In prospective observational studies, a higher intake of trans-fatty acids could increase CHD risk in women by adversely affecting endothelial function and increasing expression or levels of inflammatory markers such as C-reactive protein (CRP), interleukin-6 (IL-6), soluble TNF receptor 2 (sTNFR-2), E-selectin (or CD62E), and soluble cell adhesion molecules, sICAM-1 and sVCAM-1 [16]. In moderately hyperlipidemic subjects, palm and partially hydrogenated soybean oils, compared with soybean and canola oils, adversely altered the lipoprotein profile without significantly affecting HDL intravascular processing markers [8]. In Iranian women, a significant association

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between consumption of hydrogenated vegetable oils and risk of insulin resistance and metabolic syndrome was observed [17]. Earlier metabolic research compared the effects of diets with different fatty acid profiles on serum lipoprotein cholesterol levels; Lichtenstein and colleagues [18] found that the consumption of products that are low in TFAs and saturated fat offers beneficial effects on HDL and LDL levels; the researchers recently confirmed these results, finding that consumption of soybean oils yielded better lipoprotein profiles than did the partially hydrogenated form [19]. In reference to experimental metabolic research relating to markers of obesity, a 2009 study [20] found that in Wistar rats, prolonged intake of partially hydrogenated fats impacts the expression of genes in retroperitoneal adipose tissue when compared to diets with omega-6 and omega-3 PUFAs. Hypertension. Consuming 6 g/day of additional TFAs—less than the amount found in a typical large order of french fries—would increase systolic blood pressure (SBP) by 1.4 mmHg and diastolic by 1 mmHg [21]. A greater intake of TFAs was associated with increased levels of several markers of endothelial dysfunction, including soluble intercellular adhesion molecule 1, soluble vascular cell adhesion molecule 1, and E-selectin [22].

5.2 Maternal Health The alterations of lipid components at the maternal site during pregnancy and/or lactation may have negative long-term consequences in the offspring. Trans unsaturated fats may increase the risk of ovulatory infertility [23]. TFAs enhance inflammatory markers and insulin resistance, cross the placenta, and interfere in the conversion of essential fatty acids into their long-chain derivatives, which are critical in perinatal development [24]. Morrison et al. [25] reported that for each 1-unit increase in the squared term of percent calories from TFAs, the odds of having fetal loss versus no fetal loss increased 1.106 times (odds ratio = 1.106; 95% confidence interval 1.026–1.192). Maternal milk composition precisely reflects the daily dietary intake of trans-fatty acids from 2 to 5% of the total fatty acids in human milk. A 2005 study of lactating women found that consumption of regular margarine decreased milk fat in lean women, a change that could pose serious consequences for infant growth and development [26]. The level of linoleic acid in human milk is increased by a high trans diet, but long-chain polyunsaturated fatty acids remain mostly unaffected. Likewise, infant tissues incorporate transfatty acids from maternal milk, raising the level of linoleic acid and relatively decreasing arachidonic and docosahexaenoic acids. This suggests an inhibitory effect of trans-fatty acid on liver delta-6 fatty-acid desaturase activity.

5.3 Cognitive Health Evidence from prospective epidemiological studies and animal models suggests that intakes of dietary TFA may be associated with neurodegenerative diseases such as cognitive decline [27]. TFA intake modulated brain fatty acid profiles [28]. Morris et al. observed that higher intakes of saturated fat and trans unsaturated fat were positively associated with risk of Alzheimer’s

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disease, whereas intakes of omega-6 polyunsaturated fat and monounsaturated fat were inversely associated.

5.4 Cancer Human ecological, case–control, and prospective studies with TFA exposure observed a weak and inconsistent evidence for a relationship between TFAs and breast cancer by 75% or colorectal cancer [29, 30]. Evidence for an association between TFAs and prostate cancer is limited, but a recent large case–control study has shown a strong interaction between risk and trans-FA intake for the RNASEL QQ/RQ genotype that is present in about 35% of the population [31].

5.5 Obesity Treatment with dietary trans-10cis-12-conjugated linoleic acid causes isomer-specific insulin resistance in men with abdominal obesity [32]. Further studies are required to clarify and elucidate the effects of partially hydrogenated oils or fats on obesity and insulin resistance. Partially hydrogenated vegetable oils have long been suspected to pose adverse health effects in metabolic health but evidence had been lacking, although that is no longer the case.

6 United States and International Dietary Recommendations On January 1, 2006, the US Food and Drug Administration (FDA) began to require that trans fat be listed on food labels [11, 12]; this ruling not only includes foods but also dietary supplements. The FDA’s regulatory chemical definition for fatty acids is all unsaturated fatty acids that contain one or more isolated (i.e., nonconjugated) double bonds in a trans configuration. Under the FDA’s definition, conjugated linoleic acid would be excluded from the definition of trans fat. Dietary supplement manufacturers must also list trans fat on the Supplement Facts panel when their products contain reportable amounts (0.5 g) of trans fat. Examples of dietary supplements with trans fat are energy and nutrition bars/beverages [11]. In 2006, the American Heart Association’s Nutrition Committee [33] recommended that trans fats be reduced to less than 1% of energy. Internationally, food scientists and researchers recognize that consumption of trans fat is associated with CVD risk, in particular, and, thus, to comply with public health policies and regulatory requirements, trans fat should be replaced in food products [34]. Analyses of human milk in Canada in the late 1990s found high levels of TFAs from partially hydrogenated oils. In 2003, Canada introduced mandatory labeling of TFAs on retail foods. Comparing TFA levels from 1998 and late 2005, studies by Friesen and Innis [35] show that FTA levels have decreased in human milk in Canada, which “suggests a concomitant decrease in trans-fatty acid intake among lactating women and breast-fed infants.” In terms of related efforts by other countries, in 2004 Denmark outlawed the sale of oils and fats containing more than 2% industrially processed TFAs [36]. In Costa Rica,

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dietary improvements have been noted but a trend toward high TFA intake, among urban adolescents, has gotten the attention of the country’s health ministry [37] while, in Norway, TFA consumption is so low that it is longer considered a public health concern [38]. In Sweden, public health authorities await more definitive findings [39].

7 Conclusion Refinement of the industrial technology of partial hydrogenation and appropriate food labeling may lead to a considerable decrease of human exposure to trans-fatty acids [40]. Some recognized authorities recommend a broad-based, dietary paradigmatic shift in the United States as a long-term, sustainable solution to the cascade of health problems caused by the consumption of TFAs in the American diet. In fact, Harvard’s Walter Willet [41] observed that over 80% of coronary heart disease, 70% of stroke, and 90% of type 2 diabetes can be avoided by more healthy food choices that are in accordance with elements of the Mediterranean diets. Acknowledgments The authors are grateful to Dr. Ronald Watson for giving an opportunity to share the research on trans-fatty acids in health and disease.

References 1. Normann W. In discussion: Allen RR (2007). Principles and catalysts for hydrogenation of fats and oils. JAOCS 1903; 55(11): 792–795. 2. Allen RR Hydrogenation. Presented at the AOCS World Conference on Soya Processing, March 1981. 3. Allen RR Principles and catalysts for hydrogenation of fats and oils. Presented at the AOCS World Conference on Soya Processing, September 1978. 4. Ascherio Al, Hennekens CH, Buring JE et al. Trans-fatty acids intake and risk of myocardial infarction. Circulation 1994; 89: 94–101. 5. American Heart Association. Know your fats. Available at: http://www.americanheart.org/presenter.jhtml? identifier=532. Accessed May 31, 2009. 2008. 6. Almendingen K, Seljeflot I, Sandstad B, Pedersen JI. Effects of partially hydrogenated fish oil, partially hydrogenated soybean oil, and butter on hemostatic variables in men. Arterioscler Thromb Vasc Biol 1996; 16: 375–380. 7. Pedersen JI, Muller H, Seljeflot I, Kirkhus B. Palm oil versus hydrogenated soybean oil: effects on serum lipids and plasma haemostatic variables. Asia Pac J Clin Nutr 2005; 14(4): 348–357. 8. Vega-López S, Ausman LM, Jalbert SM et al. Palm and partially hydrogenated soybean oils adversely alter liporotein profiles compared with soybean and canola oils in moderately hyperlipidemic subjects. Am J Clin Nutr 2006; 84(1): 54–62. 9. Sundram K, Karupalah T, Hayes KC. Stearic-acid-rich interesterified fat and trans-rich fat raise the LDl/HDL ratio and plasma glucose relative to palm olein in humans. Nutr Metab (Lond) 2007; 15(4): 3. 10. Müller H, Seljeflot I, Solvoll K, Pedersen JI. Partially hydrogenated soybean oil reduces postprandial t-PA activity compared with palm oil. Atherosclerosis 2001; 155(2): 467–476. 11. US Food and Drug Administration. Food Labeling; Trans Fatty Acids in Nutrition Labeling; Consumer Research to Consider Nutrient Content and Health Claims and Possible Footnote or Disclosure Statements; Final Rule and Proposed Rule [68 FR 41433 July 11, 2003]. Available at: http://www.fda.gov/Food/LabelingNutrition/LabelClaims/NutrientContentClaims/ucm110179.htm. Accessed May 31, 2009. 2003. 12. US Food and Drug Administration. Talking about trans fat: What you need to know. Available at: http:// www.fda.gov/Food/ResourcesForYou/Consumers/ucm079609.htm. Accessed May 31, 2009. May 2006.

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13. Ascherio A, Rimm EB, Giovannucci EL et al. Dietary fat and risk of coronary heart disease in men: cohort follow up study in the United States. BMJ 1996; 313: 84–90. 14. Pietinen P, Ascherio A, Korhonen P et al. Intake of fatty acids and risk of coronary heart disease in a cohort of Finnish men: the alpha-tocopherol, beta-carotene cancer prevention study. Am J Epidemiol 1997; 145: 876–887. 15. Hu FB, Stampfer MJ, Manson JE et al. Dietary fat intake and the risk of coronary heart disease in women. N Engl J Med 1997; 337: 1491–1499. 16. Lopez-Garcia E, Schulze MB, Meigs JB et al. Consumption of trans fatty acids is related to plasma biomarkers of inflammation and endothelial dysfunction. J Nutr 2005; 135: 562–566. 17. Esmaillzadeh A, Azadbakht L. Consumption of hydrogenated versus nonhydrogenated vegetable oils and risk of insulin resistance and the metabolic syndrome among Iranian adult women. Diabetes Care 2008; 31(2): 223–226. 18. Lichtenstein AH, Ausman LM, Jalbert SM, Schaefer EJ. Effects of different forms of dietary hydrogenated fats on serum lipoprotein cholesterol levels. N Engl J Med 1999; 340(25): 1933–1940. 19. Lichtenstein AH, Matthan NR, Jalbert SM et al. Novel soybean oils with different fatty acid profiles alter cardiovascular disease risk factors in moderately hyperlipidemic subjects. Am J Clin Nutr 2006; 84(3): 497–504. 20. Duque-Guimaräes DE, de Castro J, Martinez-Botas J, Sardinha FLC et al. Early and prolonged intake of partially hydrogenated fat alters the expression of genes in rat adipose tissue. [Epub ahead of print (PMID: 19251397)]. 2009. 21. Borzo G. Trans fatty acids linked to high blood pressure. Fam Pract News 2000; 30(20): 18. 22. Mozaffarian D. Trans fatty acids—effects on systemic inflammation and endothelial function. Atheroscler Suppl 2006; 7(2): 29–32. 23. Jorge CE, Janet WR-E, Bernard RA, Walter WC. Dietary fatty acid intakes and the risk of ovulatory infertility. Am J Clin Nutr 2007; 85(1): 231–237. 24. Emilio H, Maria Pilar R. Long-term effects of trans fatty acid intake during pregnancy and lactation: does it have deleterious consequences?. Fut Lipidol 2008; 3(5): 489–494. 25. Morrison JA, Glueck CJ, Wang P. Dietary trans fatty acid intake is associated with increased fetal loss. Fertil Steril 2008; 90(2): 385–390. 26. Anderson NK, Beerman KA, McGuire MA et al. Dietary fat type influences total milk fat content in lean women. J Nutr 2005; 135: 416–421. 27. Morris MC, Evans DA, Bienias JL et al. Dietary fats and the risk of incident Alzheimer disease. Arch Neurol 2003; 60(2): 194–200. 28. Phivilay A, Julien C, Tremblay C et al. High dietary consumption of trans fatty acids decreases brain docosahexaenoic acid but does not alter amyloid-beta and tau pathologies in the 3xTg-AD model of Alzheimer’s disease. Neuroscience 2009; 159(1): 296–307. 29. Thompson AK, Shaw DI, Minihane AM, Williams CM. Trans-fatty acids and cancer: the evidence reviewed. Nutr Res Rev 2008; 21(2): 174–188. 30. Chajès VA, Thiébaut CM, Rotival M et al. Association between serum trans-monounsaturated fatty acids are associated with an increased risk of breast cancer in the E3N-EPIC Study. Am J Epidemiol 2008; 167(11): 1312–1320. 31. Liu X, Schumacher FR, Plummer SJ et al. Trans-fatty acid intake and increased risk of advanced prostate cancer: modification by RNASEL R462Q variant. Carcinogenesis 2007; 28(6): 1232–1236. 32. Risérus U, Arner P, Brismar K, Vessby B. Treatment with dietary trans10cis12 conjugated linoleic acid causes isomer-specific insulin resistance in obese men with the metabolic syndrome. Diabetes Care 2002; 25: 1516–1521. 33. Nutrition Committee AHA. Diet and lifestyle recommendations revision 2006: a scientific statement from the American Health Association. Circulation 2006; 114(1): 82–96. 34. Destaillats F, Moulin J, Bezelgues J-P. Healthy alternatives to trans fats [Letter to the editor]. Nutr Metab 2007; 4: 10. 35. Friesen R, Innis SM. Trans fatty acids in human milk in Canada declined with the introduction of trans fat food labeling. J Nutr 2006; 136: 2558–2561. 36. Stender S, Dyerberg J. Influence of trans fatty acids on health. Nutr Metab 2004; 48(2): 61–66. 37. Monge-Rojas R, Campos H, Fernández Rojas X. Saturated and cis- and trans-unsaturated fatty acids intake in rural and urban Costa Rican adolescents. J Am Coll Nutr 2005; 24(4): 286–293. 38. Johansson L, Borgejordet A, Pedersen JI. Trans fatty acids in the Norwegian diet. Tidsskr Nor Laegeforen 2006; 126(6): 760–763.

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39. Risérus U, Willett WC, Hu FB. Dietary fats and prevention of type 2 diabetes. Prog Lipid Res 2009; 48(1): 44–51. 40. Koletzko B, Decsi T. Metabolic aspects of trans fatty acids. Clin Nutr 1997; 16(5): 229–237. 41. Willett WC. The Mediterranean diet: science and practice. Public Health Nutr 2006; 9(1A): 105–110.

Chapter 6

Fatty Acid Ratios in Free-Living and Domestic Animals Michael A. Crawford, Y. Wang, C. Lehane, and K. Ghebremeskel

Key Points

• Human physiology during evolution would have been adapted to the nature of wild foods, yet there is a striking qualitative and quantitative difference between the fat in wild or extensive meat consumption compared to what we eat today. • The total proportion of ω-3 has fallen 10-fold from a range of 12–16% of the fatty acids in wild bovids to 1.0–2.6% in currently sold meat. • The intensively reared animal carcass ratio is >1 often with between four and nine times the calories coming from fat compared to protein so that a chicken thigh eaten today provides the consumer with 100 more calories from fat than it did in the 1970s. • Most of the fat is of a saturated type and there is a discernable loss of ω-3 fatty acids in the meat of beef and poultry so that the ω6/ω-3 ratio in chickens as purchased was found to be about 9 compared to wild birds in which it is approximately 2. • A high level of fat infiltration in muscle which is purchased as meat has happened because of the intensive conditions of high-energy diets, growth promotion and absence of exercise which encourages weight gain as fat and fat infiltration at the expense of muscle loss. • Human physiology is adapted to wild foods; so drift from the genetic adaptation background contributed to the rise in the Western cluster of non-communicable diseases and the current concern with obesity, metabolic syndrome and mental ill health. Keywords Agriculture · Cardiovascular disease · DHA · EPA · Monounsaturated · Obesity · ω-3 · Mental health · Polyunsaturated · Saturated fats

M.A. Crawford () Institute of Brain Chemistry and Human Nutrition, London Metropolitan University, London, England e-mail: [email protected] F. De Meester et al. (eds.), Modern Dietary Fat Intakes in Disease Promotion, Nutrition and Health, DOI 10.1007/978-1-60327-571-2_6, © Springer Science+Business Media, LLC 2010

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1 Introduction Despite separating from the great apes about 5–7 million years ago, the human genome is little more than 1.5% different from the chimpanzee. This implies that the genome is ancient. It further implies that human physiology and genomics were adapted to wild foods. The evidence of a failure to adapt to changing food composition would be expected to be witnessed by increases in chronic and degenerative disorders as occurred in the last century with the rise in cardiovascular disease from a rarity to the first cause of mortality and the first cost from the burden of ill health by the end of last century. The most worrying aspect of the secular trends in health is that as predicted in 1972,1 brain disorders have now overtaken all others to be the prime cost in the burden of ill health in the EU. For the 25 member states, the cost is put at 386 Cbillion for the 25 member states at 2004 prices. For the cost to the United Kingdom, Lord Warner in a reply to a Parliamentary Question by Lord Morris gave the following data for the rising cost of hospital and related costs which is all that was available in 2004 (see Fig. 6.1). 6000 5000 4000 3000

Cost £M

2000 1000 0 1983

1985

1990

1995

2000

2004

Fig. 6.1 Lord Warner (reply to Lord Morris 2006): Health—rising cost of mental ill health in the United Kingdom

The most powerful predictor of brain disorders and mental ill health is low birth weight. A relationship between low birth weight, maternal/foetal nutrition and risk of heart disease, stroke and diabetes in later life is also evidenced by epidemiology and experiment. The 1972 prediction that brain disorders would follow the rise in cardiovascular disease was based on the fact that the cardiovascular system develops rapidly in the human embryo being almost onethird of the size of the embryo at 24 days. The subsequent development and growth of the foetal brain is intimately dependent on a healthy vascular system. Seventy per cent of the energy sent by the placenta to the foetus is used in human foetal brain growth. Moreover, the placenta is a rapidly growing vascular system. Feeding high-fat diets to pregnant rats has been shown to restrict the transfer of essential fats required by vascular and neural development with vascular dysfunction detectable in the new born. Both the vascular dysfunction and the lipid distortion persist into adulthood adding experimental evidence for David Barker’s concept of prenatal

1

Crawford M and Crawford S (1972) in What We Eat Today, Neville Spearman, London.

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programming obtained from his epidemiological studies. There is an ample experimental and human data which need not be reviewed here, showing that depletion of essentials fats during the vulnerable period of brain development affects neurodevelopment. Hence the likelihood that the increase in brain disorders has been engineered by nutritional distortions which last century precipitated the rise in heart disease is strong. Animal fats and their analogues made a significant contribution to the mortality from heart disease. There is a view that humans evolved as hunters and gatherers which meant eating much meat. If meat was a cause of degenerative disease, it would not be compatible with an upward thrust of cerebral expansion. So why should animal fats be linked to atherosclerosis and heart disease? During the seventeenth century the decision of what the animal ate was taken from the animal when they were enclosed in fields. Before this the animals were eating sedges; herbs and grasses; soft, bushy, leafy material; nuts and seeds in the spring/summer or wet season. Fat would be deposited in preparation for reproduction. In the autumn and winter or dry seasons, browsing would be more common. Autumn browse would include seeds and nuts, rich in polyunsaturated fatty acids [1, 2]. The auditors who compiled the Doomsday Book used the number of oak trees as a measure of the number of pigs a farmer might be expected to have as survival through the winter depended on oak nuts. The enclosures led to the food selection being restricted to pasture plants which became focussed on edible grasses and clovers. Stocking density was increased which paradoxically led to increases in weight gains. This strategy was then intensified and started to resemble animal agriculture as we know it today. More animals, in this case cattle, were introduced into the enclosures and the pastures were grazed low. Instead of cattle becoming lean on this crowded pasture they gained more weight. This is because a high stock density keeps the grass short. Younger grass is very high in energy compared to older and longer grass, which is fibrous. This older grass has seed heads rich in essential PUFA, vitamins and trace elements [3]. Hence intensification resulted in the maintenance of short, energy-dense new grass. The oil-rich vegetation was progressively reduced in favour of water-rich vegetation as natural diversity of vegetation was lost. Pasture management encouraged the growth of edible grasses [1, 4] leading to modern methods of weed control.2 When free-living bovids are kept on open grassland the proportion of essential, polyunsaturated fatty acids in their tissues decrease and saturated fats increase in the meat. The coupling of higher energy food and less exercise because of the enclosures, together with selection for fast weight gain, to maximize market revenue was the first stage towards what was probably unconscious selection for obesity in the animals that are intensively farmed today. Added to this scenario was the growing tendency to feed the animals on alpha-linolenic acid (ω-3) poor, cereal-based feeds, which increased the linoleic acid and reduced the alpha-linolenic acid, i.e. increase the ω6/ω-3 ratio. It has long been recognized that the fatty acids interact with each other competing for the same enzyme systems and for incorporation into cell membranes [5]. Both ω-3 and ω-6 are essential, hence the importance of a natural balance for human nutrition. This balance was being unknowingly distorted by the enclosures and subsequent feeding methods.

2 Banvel (1/2–1 pt/A), 2,4-D amine or ester (1–4 pt/A), a combination of Banvel and 2,4-D, or crossbow (1–4 qt/A) may be sprayed in permanent grass pasture to control many annual and perennial broadleaf weeds (http://ohioline.osu.edu/agf-fact/0017.html)

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We wish to report here the results of total and saturated fat analyses of beef and poultry products as purchased to represent what people are eating. We will compare these products with the data obtained on bovids living in their natural habitat and include venison samples as sold in 2006 for comparison. In addition to the total fat, we wish to describe the current ω-6 to ω-3 fatty acid in meat sampled from typical sales outlets in view of the current interest in the function of these fatty acids in immune, vascular and neural health.

2 Methods The analyses of meat samples were conducted as previously described for the fat and fatty acid composition for the McCance and Widdowson supplement on fatty acids. Meat samples were purchased from supermarkets and farms as named or supplied to us by Channel 4 TV and colleagues in Chelsea Football Club who were interested in the composition of the food they were buying to give to their players. Total lipids from meat were extracted according to the method of Bligh and Dyer [6] and Folch et al. [7]. After extraction, total fatty acids were analysed with a gas–liquid chromatography (HPG 1800B) fitted with a programmable temperature vapourizer injector, a fused silica Omegawax 250 (Supelco) capillary column and a mass ionization detector. Fatty acids were identified by comparing mass spectra obtained against records from the library of the National Institute of Standards and Technology and retention times from various commercial standards. Values of principal fatty acids content were expressed in percentage of total fatty acid methyl ester (% FAME) or total amounts following methods previously reported [8]. The phospholipids were separated from the total lipids by the thin layer chromatography (TLC) on pre-coated silica gel 60 plates (Merck KGaA, Germany), using a developing solvent system of chloroform/methanol/methylamine (65:35:15 by volume) with 0.01% butylated hydroxytoluene (BHT) as an antioxidant. The different phosphoglyceride bands were visualized by spraying the methanolic solution of 2,7-dichlorofluorescein (0.01% wt/vol) on the developed plates and identified by the use of authentic standards. Analar solvents and reagents were used throughout. Heptadecanoic acid (C17:0) was used as an internal standard in the lipid fractions for the quantitative analysis. Fatty acid methyl esters (FAMEs) were prepared by the lipid fraction reacted with 4 ml of 15% acetyl chloride–methanol solution in a sealed vial at 70◦ C for 3 h. FAMEs were separated by a gas–liquid chromatography (HRGC MEGA 2 Series, Fisons Instruments, Milan, Italy) fitted with a BP 20 capillary column (30 m × 32 mm ID, 0.25 μm film, SGE Ltd, UK). Hydrogen was used as a carrier gas. The temperatures of the injector, oven and detector were 240, 195 and 260◦ C, respectively. The FAMEs were identified by comparison of retention times with authentic standards and interpretation of equivalent chain length values. Peak areas were integrated and normalized by using computer software (EZChrom 6.6 chromatography data system, Scientific Software, Inc., San Ramon, CA, USA). Values of principal fatty acids content were expressed as a weight percentage of the total fatty acids, although we address the analysis to the relative amounts of principal PUFA in this study to facilitate comparison with the published data and the data we obtained in the 1970s. The original data were first obtained on 5-ft packed columns with each sample run on columns of contrasting polarities (CONPOL) on polyethylene glycol adipate and Apiezon M to resolve

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overlapping peaks. The disadvantage with the packed columns was that the size of the sample required was greater with the peak sensitivity in the packed columns in the microgram: those of the capillary columns are in the nanogram region. The much greater signal-to-noise ratio of the capillary columns offered greater selectivity which obviated the need to run as CONPOL. At the time when we introduced capillary columns in the late 1970s, we compared their performance on biological samples. With meat samples for fatty acids present at greater than 1% of the total, the agreement with the CONPOL method was better than 5%, so that it is possible to compare the data obtained for the principal fatty acid peaks now with those done previously on dual columns in the late 1960s and 1970s by the same laboratory team as today. The fatty acid proportions in the total were analysed to represent the profile of fatty acids in the food bought to be eaten and are in no manner an analysis of breed or geographical locations, a study of which would require much larger numbers than an analysis of what an individual buys and eats. The ratio of total phospholipid to triglyceride was used to compare the proportion in infiltrated fat to cellular structural fat. The phospholipids are specifically cellular membrane lipids so they are representative largely of the cellular bilayers of the tissue. Moreover, the phospholipids of active cellular material are rich in polyunsaturated fatty acids and in particular the 20 and 22 carbon chain length fatty acids of the ω-6 and ω-3 families. The fatty acids are represented as the mean and the standard deviation of the mean where more than five samples were analysed of the same meat from the same source.

3 Results The overview data for the fatty acid content in proportions of 12 modern beef samples matched to 12 African bovids using the semi-tendinosis muscles (Syncerus caffer—Cape buffalo) are presented in Table 6.1. The data make a striking comparison confirming data reported in 1968. An additional point is that the reduction in the essential polyunsaturated fatty acids seen in the grassland (Queen Elizabeth National Park, Uganda) or parks3 buffalo, compared to the woodland buffalo (Southern Karamoja and Ankole, Uganda), is illustrative of the early transition of cattle in

Table 6.1 Proportion of the polyunsaturated fatty acids in muscle tissue lipids of free-living and domestic bovids Saturated and monounsaturated Essential polyunsaturated Source Number fatty acids (mean ± s.e.m) fatty acids (mean ± s.e.m) Domestic fat stock (beef) All buffalo to date Woodland buffalo “Parks” buffalo

12 12 7 5

98.8 (± 0.3) 78.7 (± 2.4) 71 (± 2.8) 90 (± 2.2)

2.2 (± 0.3) 21.9 (± 2.8) 30 (± 1.3) 10 (± 1.3)

3 The national wildlife parks of Uganda were created on land which had previously been cattle country prior to their decimation throughout Africa by the rinderpest epidemic 1889–1897. The choice was made partly because in the cattle parkland it was easier to see the animals.

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England from diverse plant fodder of the enclosures in the seventeenth century towards a pasture monoculture. The comparison of the domestic and wild carcass fat of ruminants is data from Ledger’s 1968 [9] analysis of 17 species from East Africa and which represents the largest, careful dissection published. The balance in the domestic fat stock is used as common in the United Kingdom. The total carcass fat of 257 East African wild species did not exceed 5%. The carcass lean averaged 78% (s.d. ± 1.8) with a mean carcass fat of 3.8% (s.d. ± 1.7). The data from wild species compare contemporary animal production in which the fat stock carcass is 30% fat and 50% lean. The problem is that the lean is four-fifths water so the actual protein content at a 50% lean is only 10%; this is associated with 30% fat. In Table 6.2 we have calculated the energy from fat and protein, simplifying the numbers to 75% lean and 5% fat for the wild carcass and 50% lean and 30% carcass fat in the beef. The 50% lean is an overestimate as the lean of intensively reared species contains substantial amounts of infiltrated fat between the muscle cells as is evidenced by the high triglyceride to cellular phospholipid ratios in subsequent tables.

Table 6.2 Comparison of the ratio of dietary energy derived from the wild and domestic beef carcass

Carcass lean (%) Fat (%) Protein equivalent Protein calories Fat calories Fat–protein ratio Intensification = ninefold fat a Data from H Ledger, Symposium Zoological Society of London

Modern

Wild

50 30 10 40 270 6.75

75a 5 15 60 45 0.75

21, Nutrition of wild animals.

Even on its own, there is more protein in the carcass of the wild species compared to the domestic in which there is more fat than protein. However, the true discrepancy arises when the protein is multiplied by 4 and the fat by 9 to convert these compartments to calories. It then becomes apparent that the wild species provides more energy as protein while the modern domestic carcass is delivering up to some nine times the amount of fat calories compared to protein for human consumption. Turning to poultry a similar situation is apparent. In 1976 the Royal College of Physicians jointly with the British Cardiac Society on their seminal report on diet and heart disease chaired by Professor A. G. Shaper listed in its recommendations the consumption of less fatty, red meat and more poultry because it was lean with little fat. A search of the literature and our own data reveals that while chicken was at one time a lean low-fat food, it is no longer the same (Table 6.3). Even without our data, this fact is confirmed by the McCance and Widdowson’s data on the fifth and sixth editions. Moreover, the intensification process for chickens has led to a loss of docosahexaenoic acid (Table 6.4), the principal ω-3 fatty acid of the brain’s phosphoglycerides. Under free range condition, the chickens would have access to green and insect sources of alpha-linolenic acid. In so doing, it becomes an important land-based dietary source of docosahexaenoic acid which the chicken synthesizes from alpha-linolenic acid. Data on this loss are given in Table 6.4.

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Table 6.3 Fat–protein calories in chicken 1870–2004

Year 1870 1896 1940 1953 1970 1991 2002 2004 2004

Protein (g/100 g)

Protein (cal/100 g)

Fat/protein ratio (energy)

Total calories

34.2 16.2 92.7

21 22.8 26.2

84 91.2 104.8

0.4 0.2 0.9

118 107 198

12.6 8.6 17.7

113.4 77.4 159.3

20.2 24.3 17.6

80.8 97.2 70.4

1.4 0.8 2.3

194 175 230

16.9

152.1

20.9

83.6

1.8

236

17.1

153.8

18.2

72.8

2.1

227

22.8

205

16.5

65.8

3.1

271

Data source

Fat (g/100 g)

Letheby USDA M&W 1st ed. FAO IBCHN M&W 5th ed. M&W 6th ed. IBCHN, organic IBCHN, farmed

3.8 1.8 10.3

Fat (cal/100 g)

Table 6.4 Poultry data 1980–2006 Year

Data source

Fat (g/100 g)

ω6 (%)

LA (%)

DHA (%)

DHA (mg/100 g)

1980 1998 2004 2004 2006

McCance/IBCHN McCance/IBCHN IBCHN (organic, shop) IBCHN (organic, farm) IBCHN (farmed)

17.5 16.9 17.5 16.7 22.8

14.4 17.5 20.1 21.6 28.5

13.7 15.4 19.2 20.7 27.6

1.03 0.41 Trace 0.42 0.12

170 69 <16 66 25

The proportions of EPA in chicken meat are relatively low, being about one-third of the DHA. The highest figure of 170 mg of DHA/100 g chicken meat reported in the 1970s is comparable to that of the wild species reported here. The phospholipid/triglyceride ratio presented in Table 6.5 is evidence of the balance between cellular phospholipids which represent the “real” muscle (meat) and cell lipids as opposed to the excess storage fats—the triglycerides. In lay terms these triglycerides would be referred to as the “waistline fats”. Note the comparison with the UK venison in which the fat/calorie ratio is reversed with the phospholipid present being greater than the triglyceride (Table 6.5). This high phospholipid/triglyceride ratio reflects the high protein to fat ratio in the venison. The Cape buffalo and Eland [1, 10, 11] are true examples of wild land-based species that might have constituted the hunting and gathering larder during human evolution. Both Cape buffalo and the Eland grow to the size of the largest beef animals of Europe and if culled as young animals provide excellent meat. The Eland has been used for both meat and milk in Askania-Nova, Russia [12]. We have seen young Eland running with the cattle herd of the Karamajong. We were told they had a calming effect on the cattle and were better able to withstand drought. In the drought in the early 1960s, we saw cattle carcasses littering the roadside, in vast numbers, whereas in the semi-arid areas of northern Uganda and Kenya, Eland continued to thrive and breed due to their poikilothermic physiology which is adapted to hot dry conditions.

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Table 6.5 Storage and structural fats in different meats sold for human consumption in the United Kingdom

Organic beef sirloin steak—Daylesford Organic beef fillet steak—Daylesford Organic beef sirloin steak—Sheepdrove Organic beef fillet steak—Sheepdrove Beef braising steak—Drydown Farm Beef steak—Drydown Farm Beef sirloin steak—Drydown Farm Beef ribeye steak—Fairfax Farm Beef leg Beef meat mean values (± s.e.m) Organic chicken breast fillet—Daylesford Organic chicken boneless breast fillet— Daylesford Organic chicken legs—Daylesford Farm Organic chicken breast fillets and skin— Sheepdrove Organic chicken breast fillet—Sheepdrove Organic chicken supreme—Sheepdrove Organic chicken leg part boned—Sheepdrove Chicken breast Chicken big legs Waitrose farmed chicken breast fillets Morrisons Bettabuy chicken breast fillets Meat type Beef meat mean values (± s.e.m) Chicken meat mean values (± s.e.m) Organic venison Eland (Taurotragus oryx—semi-arid bush/woodland—Karamoja, Uganda) Buffalo (Syncerus caffer—wet grassland—Qeen Elizabeth National Park, Uganda)

Triglycerides (mg/100 g)

Phospholipids (mg/100 g)

7215.64 3871.38 6306.92 2937.36 3900.33 1822.93 4266.14 3438.71 5353.74 4345.91 (± 561.5) 210.87 2465.6

462.14 626.18 336.49 459.15 398.16 568.06 341.12 393.2 581.66 462.91 (± 35.7) 491.24 533.7

15.6:1 6.2:1 18.7:1 6.4:1 9.8:1 3.2:1 12.5:1 8.7:1 9.2:1 9.4:1

6498.12 3373.69

567.79 510.44

11.4:1 6.6:1

886.17 3819.91 7578.25 1346.19 13778.81 953.72 2031

509.19 524.27 610.21 490.69 547.31 441.63 530

1.7:1 7.2:1 12.4:1 2.7:1 25.2:1 2.2:1 3.8:1

4346 (± 561.5) 3904 (± 1212.1) 241 214

463 (± 35.7) 523 (± 13.3) 815 783

9.4:1

293

656

Ratio (TG:PL)

0.4:1 4.6:1

7.5:1 0.3:1 0.27 0.44 Mean = 0.34

The essential fatty acid composition of a wild bovid (Syncerus caffer) is given in Fig. 6.2 compared with the same for beef. The beef sample is for whole meat without removal of visible fat as would be cooked and eaten. It is important to note that the organic meats are little different from the standard farm products. The data from UK venison are similar to that of the wild herbivores. Indeed, the same applies to both the balance between cellular phospholipids and the balance of the essential fatty acids as described in Table 6.6. The cellular phospholipids are an important marker of nutritional status. In evolutionary and even recent historical time, meat would have provided a rich source of cellular phospholipid. Today as our data on modern intensive systems show, the consumer is presented with a triglyceride-rich meat. As the triglycerides fatty acid composition is so different with much more saturated and less essential fatty acids, this difference is likely to be relevant to the increase of lipid-related diseases of recent time (Table 6.7).

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Fig. 6.2 Raw buffalo meat (mean of 10) from East Africa compared with beef fillet purchased in the UK supermarket (July 2006)

In Table 6.8 the essential polyunsaturated fatty acid proportions of the fat extracted from beef are compared to UK venison, Cape buffalo and Eland. The low proportions of the essential fatty acids in the beef are likely due to the high proportions of triglyceride fat which dilutes the essential fatty acid content. The buffalo meat contained 1.8 g fat/100 g meat with 145 mg of long-chain ω-3 fatty acids/100 g meat. Eland meat contained 175 mg/100 g meat. The liver of these species contains significantly higher amounts at 548 mg of long-chain ω-3 fatty acids in buffalo liver/100 mg. In addition, we have collected data on several other wild species which are presented to support the data from East Africa on wild bovids.

4 Discussion It has been known for sometime that ω-6 arachidonic and docosahexaenoic acids are specifically incorporated into the brain and are essential for its development and function, with the ω-3 fatty acid being the most limiting and a balance between the ω-6 and ω-3 between 1 and 2 to 1 [11]. As the brain is developed to its most supreme complexity in humans and is what makes us different from other animals, the target for nutrition of these essential fatty acids is therefore the balance for the brain, i.e. in the region between 2 and 1 to 1 long-chain ω-6 to ω-3. The use of ω-3 docosahexaenoic acid in vision and neural function dates back some 500–600 million years. That together with the difficulty of its synthesis from precursor has suggested to us that humans would have had to have a rich source of docosahexaenoic acid in their diet to explain cerebral expansion during evolution [13, 14]. Little discussion is needed of the data presented here as it stands on its own merit and much personal experience that anyone who has eaten game meat will appreciate. Its validity is indisputably supported to be a wealth of background information on wild and intensively reared live

(± 1.23) (± 0.42) (± 0.01) (± 0.03) (±0.03) (±0.67) 2.46 21.53 0.35 0.18 tr 8.37

Organic venison

0.21 0.2 0.18 0.2 0.14 0.24 0.22 0.21

0.04 0.16 0.2 0.1 0.3 0.11 0.13 0.17

0.33 0.24 0.26 0.21 0.04 0.27 0.27 0.25

0.29 0.23 10.05 10.06 12.46 6.22 4.92 10.44 10.03 9.67

12.04 9.49

18.79 18.84 19.12 18.29 16.19 17.15 20.16 19.02

0.19 0.35

5.64 5.75 7.46 8.47 5.94 8.4 5.01 5.48 5.35 6.39 (± 0.45) 10.29 10.33

PL (%)

26.29 25.36 28.66 24.19 15.76 26.2 32.67 25.56

0.19 0.19

0.37 0.24

tr tr tr tr tr tr tr tr tr tr

TG (%)

20.31 20.7

0.34 0.23 0.33 0.24 0.27 0.23 0.29 0.3 0.29 0.28 (± 0.01) 0.1 0.15

PL (%)

26.89 26.45

0.14 0.16 0.13 0.18 0.15 0.12 0.17 0.31 0.16 0.17 (± 0.02) 0.3 0.23

TG (%)

Organic chicken breast fillet—Daylesford Organic chicken boneless breast fillet—Daylesford Organic chicken legs—Daylesford Organic chicken breast fillets and skin—Sheepdrove Organic chicken breast fillet—Sheepdrove Organic chicken supreme—Sheepdrove Organic chicken leg part boned—Sheepdrove Chicken breast Chicken big legs Waitrose farmed chicken breast fillets Morrisons Bettabuy chicken breast fillets Chicken meat mean values (± s.e.m)

PL (%)

ARA (20:4n–6)

12.81 16.02 10.6 13.65 10.38 15.66 10.61 10.7 10.65 12.34 (± 0.76) 19.37 20.35

TG (%)

Linoleic acid (18:3n–6)

1.29 2.05 1.33 1.85 1.47 1.95 1.29 1.36 3.42 1.78 (± 0.23) 23.18 25.51

Organic beef sirloin steak—Daylesford Organic beef fillet steak—Daylesford Organic beef sirloin steak—Sheepdrove Organic beef fillet steak—Sheepdrove Beef braising steak—Drydown Beef steak—Drydown Beef sirloin steak—Drydown Beef ribeye steak—Fairfax Beef leg Beef meat mean values (± s.e.m)

Meat type

Table 6.6 PUFA content of TG and PL in different meats Linoleic acid (18:2n–6)

tr

0.04 0.1 0.04 0.19 0.04 0.04 0.04 0.06 (± 0.01)

0.04 0.1

0.04 0.04 0.04 0.04 0.14 0.04 0.04 0.04 0.1 0.06 (± 0.01) 0.04 0.04

TG (%)

3.47

0.62 0.61 0.41 1.39 0.74 0.7 0.49 0.65 (±0.08)

0.31 0.59

1.86 2.12 5.53 2.53 3.8 1.21 3.56 2.38 2.5 2.83 (± 0.43) 0.63 0.65

PL (%)

EPA (20:5n–3)

0.26

0.13 0.04 0.04 0.17 0.04 0.1 0.12 0.09 (± 0.01)

0.1 0.04

0.07 0.14 0.04 0.04 0.25 0.04 0.04 0.14 0.14 0.1 (± 0.02) 0.13 0.04

TG (%)

TG (%)

0.04 0.04 0.04 0.15 0.04 0 0.04 0.05 (± 0.01)

0.04 0.04

(± 0.12) 3.58 tr

2.54 2.26 2.34 2.71 1.34 2.37 2.28 2.13

1.74 2.11

0.93

2.18 1.76 2.13 4.68 1.62 1.19 1.28 1.97 (± 0.29)

1.54 1.69

0.81 0.34 0.61 0.48 2 0.26 0.68 0.51 1.22 0.77 (± 0.18) 1.82 1.78

PL (%)

DHA (22:6n–3)

3.7 3.59 3.14 3.13 4.08 2.43 tr 4.21 3.36 2.43 3.34 (± 0.21) 1.88 0.04 1.88 0.04

PL (%)

DPA (22:5n–3)

104 M.A. Crawford et al.

19.02 (± 0.42) 21.53

25.56 (± 1.23)

2.46

Chicken meat mean values (± s.e.m) ω6/ω-3 ratio = 9 Organic venison 0.35

0.21 (± 0.01)

0.17 (± 0.02)

TG (%)

0.18

0.17 (± 0.03)

0.28 (± 0.01)

PL (%)

tr

0.25 (± 0.03)

tr

TG (%)

8.37

9.67 (± 0.67)

6.39 (± 0.45)

PL (%)

tr

0.06 (± 0.01)

0.06 (± 0.01)

3.47

0.65 (± 0.08)

2.83 (± 0.43)

PL (%)

TG (%)

PL (%)

Beef meat mean values (± s.e.m)

12.34 (± 0.76)

TG (%)

1.78 (± 0.23)

Meat type

EPA (20:5n–3)

Table 6.7 Means of the PUFA content of TG and PL of the different meats in Table 6.6 Linoleic acid Linoleic acid Arachidonic acid (18:2n–6) (18:3n–6) (20:4n–6)

0.26

0.09 (± 0.01)

0.1 (± 0.02)

TG (%)

3.58

(± 0.21) 2.13 (± 0.12)

3.34

PL (%)

Decosapentaenoic acid (22:5n–3)

tr

0.05 (± 0.01)

TG (%)

0.93

1.97 (± 0.29)

0.77 (± 0.18)

PL (%)

DHA (22:6n–3)

6 Fatty Acid Ratios in Free-Living and Domestic Animals 105

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Table 6.8 Essential fatty acid content of beef compared to three wild species

Fatty acid(%) 18:2n–6 20:3n–6 20:4n–6 22:4n–6 18:3n–3 20:5n–3 22:5n–3 22:6n–3 DHA ω6/ω-3 ratio Total ω-3 (%) tr.<0.10

Beef sirloin steaks (n = 3)

Beef fillet steaks (n = 3) Daylesford

1.85 0.12 0.28 tr 0.68 0.14 0.24 tr 2.1 1.06

3.64 0.23 0.72 Tr 1.38 0.32 0.65 Tr 1.7 2.65

Venison fillet steaks (n = 3)

Buffalo, wet woodland, Semliki

Eland, semi-arid bushland, Karamoja

15.13 0.63 5.52 0.17 6.63 2.52 2.72 0.70 1.3 12.6

16.6 2.3 8.02 0.9 5.2 3.8 5.7 0.9 1.78 15.6

18.5 1.8 9.0 1.2 4.8 3.1 6.3 1.1 2.0 15.3

stock. It is evident there has been a loss of ω-3 fatty acids from intensively reared animal products. This loss is readily understood from the growth in use of cereals for animal feeds and the lack of fresh green fodder in intensive systems. The changes in fat composition have been gradual with possibly four major events. First the enclosures, second electricity, third the development of high-energy foods and growth promoters and fourth the post-World War II intensification with denial of exercise in preparation for market. In addition, the selection process has favoured weight gain even from the time of the enclosures as the heavier the animal the more the money earned at market. This selection continued until today and may well have contributed to what is undeniably obese animals being consumed today from the intensive production system. There has been a common assumption that humans are adaptable. However, the outcome of the human genome project indicates that the bulk of our genome is ancient. There can be little doubt that human physiology was adapted throughout at least 7 million years, and probably much more, to wild foods. In the case of large animal products that adaptation would have been to a phospholipid-rich food with relatively high proportions of long-chain ω-6 and ω-3 fatty acids. This product has been swapped for a high triglyceride, high saturated and diminished long-chain ω-6 essential and particularly ω-3 fats. If adaptation to the changes in food composition were to take place, then they would be exactly those we see in the rise in vascular disease, obesity, certain cancers and now brain disorder: the latter, the most disturbing. Each of these find simple, evidence-based mechanisms in the published literature on the role of dietary fats in human nutrition, vascular, immune and nervous system requirements and health. These were first spelt out in the seminal report by the Royal College of Physicians and British Cardiac Society in 1976 shortly to be followed by the 1978 Joint Expert Consultation of FAO and WHO on the role of dietary fats and oils in human nutrition [15]. Even at that time the FAO/WHO committee was able to call on 21 national and international committee reports. Moreover, their 1978 report called for the excess of animal fat going into human consumption to be addressed and a balanced intake of ω-3 and ω-6. Since then, the evidence has been amplified. The present concern of public health bodies seems to be focused

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on obesity. One wonders to what extent the rise in body fats of intensively reared animals is contributing to this phenomenon.

5 Conclusions The reason for writing this chapter is that conceivable explanations for the obesity including blaming the parents have been publicized, yet the simple truth of the distortion of the protein/fat calorie balance as demonstrated here has not been taken into account. However, chicken is perceived as a low fat product. Yet in 2006 a chicken thigh contained 100 more calories than it did in 1970s. So people, parents, for example, think they are still feeding their children on a low-fat product as it was in their youth. This state is on top of a massive load coming from other sectors. Little needs to be said about what the fat load could mean for the rise in obesity. It is important to note that the changes in fat composition and amount have been taking place over several decades and whatever may be said about producing leaner meat today, there has been a build up of transfer of fat from the animals to humans. The solution to the obesity problem is not a top-down approach of telling people what to do if the fundamental food chain is flawed. The doctor may tell the parents and children to eat a calorie-controlled diet and get lots of exercise. Present animal production does the reverse. The strategy for animal production is high-energy foods, no exercise and weight gain, the opposite of what the doctor tells us. The most worrying phenomenon is derived from the adverse changes in fat composition with the loss of the ω-3 fatty acids as can be seen in the chicken data. The most likely cause is the use of cereals and ω-6-rich feeds with the dietary loss of alpha-linolenic acid and its accessories micronutrient. This deficit would come from absence of access to its source in the green foods of the natural habitats. So there is a double problem with the increase in saturated type fats, the transisomers and linoleic acid (ω-6 parent), all of which will compete with the ω-3 needed for neural development and maintenance. This situation raises concerns about these secular changes in food composition and the rise in brain disorders. It was predicted in 1972 that the rise in vascular disease would be followed by brain disorders [11]. The rationale was that the developing foetal brain is dependent for its development on an efficient vascular system as the foetal brain utilizes 70% of the energy delivered by the placenta. If the vascular system is “under attack” then brain disorder would be expected to follow. We now have serious mental health problems associated with this loss of ω-3 and increase in ω-4 fatty acids [16]. The increase in mental ill health among children has been rising decade by decade over the last 30–40 years and the rise follows the previous rise in cardiovascular disease from country to country. There is now powerful evidence from a study of over 14,000 pregnancies with the follow-up of the children into their teens, which supports the idea of ω-3 consumption during pregnancy being directly related to benefits in subsequent IQ and social scores [17]. According to the health audit published in 2005 [18], the cost of brain disorders has now overtaken all other burdens of ill health. Brain disorders are now at 25% whereas heart disease is at 17%, which until recently was the major cost in the burden of ill health. The cost for brain disorders was estimated at 386 C billion at 2004 prices for the 25 member states of the EU.

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Moreover, mental ill health is predicted by the Global Forum of Health to be in the top three burdens of ill health worldwide by 2020 with heart disease and adverse pregnancy outcomes. All three are inter-related. While obesity is a marker of future ill health and a matter of concern, the threat of a continued increase in brain disorders this century as happened with heart disease in the last century is likely to have a much greater social and political impact. Acknowledgments We express our appreciation to the Mother and Child Foundation for supporting this work. We are also grateful for support from the Lettern Foundation and grateful to Chelsea Football Club for providing the venison. The authors have no conflict of interest to declare.

References 1. 2. 3. 4. 5. 6. 7. 8.

9. 10. 11.

12. 13.

14.

15. 16. 17.

18.

Crawford MA Are our cows killing us? New Scientist. July 4, 16–17, 1968. Crawford MA, Ghebremeskel K. In Food Ethics. New York: Routledge, 54–83, 1996. Crawford MA, Marsh D. The Driving Force- Food, Evolution and the Future. London: Heinemann, 1989. Crawford MA. Fat Animals-Fat Humans. Geneva: World Health, 1991, July–August. Holman RT. Nutritional and metabolic interrelationships between fatty acids. Fed Proc 1964; 23: 1062–1067. Bligh ED, Dyer WJ. A rapid method of total lipid extraction and purification. Can J Biochem Physiol 1959; 37(8): 911–917. Folch J, Lees M, Sloane Stanley GH. A simple method for the isolation and purification from total lipids from animal tissues. J Biol Chem 1957; 226(1): 497–509. Ghebremeskel K, Bitsanis D, Koukkou E, Lowy C, Poston L, Crawford MA. Saturated fat maternal diet in the pregnant rat, reduces docosahexaenoic acid in liver lipids of the neonate and suckling pups. Br J Nutr 1999; 81: 395–404. Ledger HP. Body composition as a basis for a comparative study of some East African mammals. Symp Zool Soc Lond 1968; 21: 289–310. Crawford MA Atherosclerosis on the hoof. World Medicine September 9 1970, (also 9). Crawford MA, Sinclair AJ. Nutritional influences in the evolution of the mammalian brain. In: Elliot, K, Knight, J (Eds.), Lipids, Malnutrition and the Developing Brain. A Ciba Foundation Symposium (19-21 October, 1971). Amsterdam: Elsevier, 267–292, 1972. Treus V, Kravchenko D. Methods of rearing and economic utilization of Eland in the Askaniya Nova Zoological Park. Symp Zool Soc Lond 1968; 21: 395–411. Crawford MA, Bloom M, Broadhurst CL, Schmidt WF, Cunnane SC, Galli C, Ghebremeskel K, Linseisen F, Lloyd-Smith J, Parkington J. Evidence for the unique function of DHA during the evolution of the modern hominid brain. Lipids 1999; 34: S39–S47. Leigh BC, Wang Y, Crawford MA, Cunnane SC, Parkington JE, Schmid WE. Brain-specific lipids from marine, lacustrine, or terrestrial food resources: potential impact on early African Homo sapiens. Comp Biochem Physiol B Biochem Mol Biol 2002; 131(4): 653–673. FAO/WHO expert committee. The Role of Dietary Fats and Oils in Human Nutrition. Geneva: WHO, 1978. Hibbeln JR, Nieminen LR, Blasbalg TL, Riggs JA, Lands WE. Healthy intakes of n-3 and n-6 fatty acids: estimations considering worldwide diversity. Am J Clin Nutr 2006; 83(6 Suppl): 1483S–1493S. Hibbeln J, Davis J, Steer C, Emmett P, Rogers I, Williams C, Golding J. Maternal seafood consumption in pregnancy and neurodevelopmental outcomes in childhood (ALSPAC study): an observational cohort study. Lancet 2007; 369(9561): 578–585. Andlin-Sobocki P, Jönsson B, Wittchen HU, Olesen J. Cost of disorders of the brain in Europe. Eur J Neurol 2005, June; 12(Suppl 1): 1–27. et seq.

Chapter 7

Is Saturated Fat Bad? Uffe Ravnskov

Key Points • For decades a reduction of the intake of saturated fat has been the cornerstone in dietary prevention of cardiovascular disease. The main argument for this advice is its alleged influence on blood cholesterol. However, several recent trials have found no such effect in spite of intakes up to five times higher than the recommended upper limit. Even if true, the effect on blood cholesterol is indirect evidence. The crucial question is if a high intake is harmful or if a reduction leads to health benefits. Almost all epidemiological and experimental studies are in conflict with this assumption; indeed several observations points to the opposite. There seems to be an urgent need for a revision of the present dietary guidelines. Keywords Saturated fat · Animal fat · Cholesterol · Diet · Cardiovascular · Coronary · Heart disease · Stroke prevention

1 Introduction For many years we have been taught that too much fat, in particular saturated fat in our diet may lead to cardiovascular disease. Any idea can be verified if one seeks for confirmation only. According to Karl Popper’s principle a scientific hypothesis demands that it is able to present predictions that can be falsified. By this definition the diet-heart idea is indeed scientific, because there are several such predictions: 1. Atherosclerosis and cardiovascular disease should be more common in populations with a high intake of saturated fat, and increasing intakes should be followed by an increasing prevalence and mortality of these disorders, and vice versa. 2. People with these maladies should have had a higher intake of saturated fat than healthy people. 3. A reduction of the intake of saturated fat should lower the risk. U. Ravnskov () Magle Stora Kyrkogata 9, 22350 Lund, Sweden e-mail: [email protected] F. De Meester et al. (eds.), Modern Dietary Fat Intakes in Disease Promotion, Nutrition and Health, DOI 10.1007/978-1-60327-571-2_7, © Springer Science+Business Media, LLC 2010

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These three logical assumptions have been falsified repeatedly, however. Consequently, objections against the vilification of saturated fat have been put forward [1–6], but have made little impact on the official health policy. Since then even more contradictory findings have been published. This chapter is an attempt to present a review of the full range of studies that in various ways have tested the mentioned predictions. As almost all of them contradict the current view and as some of them even point to a beneficial effect of saturated fat, the only possible conclusion of the accumulated evidence is that the diet-heart idea is unfounded.

2 The Influence of Saturated Fat on the Blood Lipids According to a joint WHO/FAO Expert Consultation [7] “the relationship between dietary fats and CVD, especially coronary heart disease, has been extensively investigated, with strong and consistent associations emerging from a wide body of evidence”. This statement was followed by a reference to a consensus report from the Nutrition Committee of the American Heart Association [8]. The only evidence presented in that paper or in other official documents for an atherogenic effect of saturated fat is its effect on the blood lipids and a single cohort study claimed to have shown that intake of saturated fat is associated with an increased risk of coronary disease [9]. Numerous contradictory epidemiological, pathological and clinical observations as well as unsupportive results from the dietary trials, the most important proof of causality, have been ignored by all guideline authors. The allegation that a high intake of saturated fat raises cholesterol is an indirect evidence. Therefore, even if it were true, it cannot be used as a falsification. However, it seems relevant to analyse this question as well because of its major role in the WHO guidelines. The idea was first put forward by Ancel Keys, although in his first studies he claimed that the crucial factor was the total fat intake. One of his arguments was an impressive diagram showing an extremely strong association between the average cholesterol concentration and the total intake of fat in 16 populations [10]. Unfortunately Keys gave no references to the studies he had included in the diagram, and it is easy to find populations with extremely low cholesterol in spite of a huge intake of fat. In his later, much-quoted study Seven Countries he changed his mind and pointed to saturated fat as the determining factor. The reason was that in Seven Countries no association was found with the total fat intake. Keys’ idea was questioned by Raymond Reiser already in 1973. In a thorough review of 40 trials he pointed at several types of methodological and interpretational errors [11]. Instead of natural saturated fat many authors had used vegetable oils saturated by hydrogenation, and cholesterol-raising effects were attributed to an increased intake of saturated fat, when it could be due to a decreased intake of polyunsaturated fat as well, or vice versa. In spite of these flaws several authors maintain that saturated fat raises cholesterol level, whereas monounsaturated and in particular polyunsaturated fat lower it, and some saturated fatty acids may be neutral [12–16]. These conclusions have been based mainly on mathematical formulas using data from a large number of trials. But as almost all trial directors have changed the intake of several fats at the same time, in many cases without controlling for intake of trans fat, it is obviously difficult to rule out the effect of each type of fat.

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Even if saturated fat should be hypercholesterolemic the effect must be small. In a review of eight trials where the intake was reduced by 30–40% the net reduction of cholesterol was only 0–4% [17], and other studies have shown no effect at all. In experiments for instance, where carbohydrates were substituted with saturated fat, not even intakes between 20 and 50% of calories influenced total or LDL cholesterol (Table 7.1) [18–27]. Table 7.1 Changes of blood lipids after a low-carbohydrate diet rich in saturated fat in ten trials. In all trials the concentration of triglycerides went down significantly Noakes et al. [18] 12 weeks 18 None None None Meckling et al. [19] 10 weeks 20 None None Up Sondike et al. [20] 12 weeks 22 None None None Sharman et al. [21] 6 weeks 25 None None None Hays et al. [22] 52 weeks 50 None None None Westman et al. [23] 6 months + Down Down Foster et al. [24] 12 months + None None Up Yancy et al. [25] 24 weeks + Down None Up Seshadri et al. [26] 6 months + None None None Brehm et al. [27] 4 months + None None Up + Means that the intake of saturated fat was unlimited.

An argument for a hypercholesterolemic effect is the increased levels of LDL receptors on mononuclear cells seen after a reduction of dietary saturated fat without changing the intake of unsaturated fat, but the authors did not control for trans fat [28]. That other factors may override a possible hypercholesterolemic effect is obvious from studies of populations who live almost entirely on animal food, but have the lowest cholesterol values ever measured in healthy people [29–31]. In accordance, no cross-sectional study of the dietary habits within a population has found any association between the intake of saturated fat and the concentration of cholesterol in the blood [1]. In the above-mentioned low-carbohydrate trials, a high intake of saturated fat had no adverse effects on other lipids either on the contrary, HDL cholesterol remained unchanged or went up and triglycerides went down significantly (Table 7.1) [18–27], whereas a reduction of the intake had the opposite effects [32–34]. As cardiovascular disease is stronger associated with small, dense LDL than with other lipid fractions it is also contradictory that high intakes of saturated fat are followed by an increase of the size of LDL [35, 36]. Effects of saturated fat on the blood lipids are surrogate outcome, however. The crucial question is whether a high intake of saturated fat is deleterious to health and whether a reduction of the intake is beneficial.

3 Ecological Studies There is little evidence from epidemiological studies that high intakes of saturated fat lead to cardiovascular disease. Ancel Keys introduced the idea that dietary fat plays a pathogenic role in heart disease. His main argument was a strong, curvilinear correlation between the heart mortality and the total amount of fat available for consumption in six countries [37]. However, Keys had selected his data. At that time figures for fat consumption and heart mortality were obtainable from 22 countries and if all of them were included the association became trivial [38], and an

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analysis based on the totality of more recent data that included 35 countries found an inverse association [1]. These studies concerned total fat, but similar data for saturated fat are contradictory as well as appear best from dynamic population studies. Several authors of such studies have used concurrent trends of saturated fat consumption and coronary mortality in a single country as an argument for causality. Parallel changes may occur by chance, however, clearly demonstrated by a review of 103-time periods in 35 countries. Here, consumption of saturated fat increased in 63 periods; in 33 of these periods heart mortality increased as well, but in 10 periods it was unchanged and in 23 it went down [1].

4 Cross-Sectional Studies In a review of cross-sectional studies of the association between intake of saturated fat and coronary heart disease (CHD) an association was found in a few only, whereas more than 30 studies were partly or totally contradictive [1, 39]. A few of the most contradictory observations are worth mentioning. In seven studies of American Indians coronary mortality was only 10–50% of the mortality of white Americans, and degree of atherosclerosis was much smaller although their intake of saturated fat was similar or higher [1]. A study of Japanese emigrants in the United States apparently was in support and is often used as an argument because after migration their low cholesterol rose to American levels, as did their risk of dying from CHD. However, the determining factor was not the diet or their cholesterol but their way of living. Those who maintained their cultural traditions were protected against CHD, although their cholesterol level went up. Even more striking was that immigrants who became accustomed to the American way of life, but preferred the lean Japanese food, had CHD twice as often as those who maintained Japanese traditions, but preferred high-fat American food [1]. In a 5-year follow-up study of more than 1 million male employees of the Indian railways Malhotra found that the lowest and highest rates of coronary mortality were seen in Punjab and Madras, 20 and 135 per 100,000 employees, respectively, and the mean age at death was 12 years lower in Madras than in Punjab. But in Punjab people ate about 17 times more fat than in Madras, the main part of which was of animal origin. In addition more people smoked in that area [1]. In Seven Countries, considered as one of the strongest argument for the diet-heart idea, Keys selected 16 cohorts in 7 countries and found an association between intake of saturated fat and the prevalence and 5-year incidence of coronary mortality [40]. But within each country there was little or no association at all, although all risk factors including the intake of saturated fat were similar. Coronary mortality for instance was more than twice as high in Crevalcore, Italy, than in Montegiorgio, five times higher in Karelia than in West Finland and 16–17 times higher on Corfu than on Crete. In addition, no association was seen between intake of saturated fat and major ECG abnormalities at entry. The latter finding has more importance considering that the ECGs were analysed by specialists in the American centre, whereas the cause of death was determined by local doctors with varying competence.

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5 Cohort and Case–Control Studies of Saturated Fat Intake The diet of coronary patients and healthy individuals has been compared in numerous cohort and case–control studies. In a previous review of 28 cohorts in 21 studies patients with CHD had eaten significantly more saturated fat than the controls in three cohorts, but the differences were trivial; in one cohort they had eaten significantly less and in the other 24 cohorts no differences were seen [1]. No difference was seen either in two recent, large cohort studies [41, 42], or in the study referred to by the WHO guideline authors. In the latter the statistical significance disappeared after controlling for other dietary factors [9]. No difference in fat intake was seen either in three case–control studies between patients with CHD and control individuals of the same age and sex [1]. It can be argued that case–control studies may be confounded by changes in the diet after the diagnosis of heart disease, but the mentioned studies were performed between 1958 and 1968 before dietary advices had become the standard treatment. Even more contradictory are the findings in stroke patients. In ten prospective cohort studies of healthy people the authors compared the intake of saturated fat in those who had stroke at followup with the intake of the others. In seven of the studies stroke patients had eaten significantly less saturated fat than had the non-stroke individuals; in the rest no difference was found (Table 7.2) [43–52]. Table 7.2 Association between intake of saturated fat and stroke in ten cohort studies n Ischemic Haemorrhagic Stemmerman et al. [43] Takeya et al. [44] McGee et al. [45] Gillmann et al. [46] Ross et al. [47] Seino et al. [48] Iso et al. [49] He et al. [50] Iso et al. [51] Sauvaget et al. [52] ∗ p < 0.05; ∗∗ p < 0.01.

6,832 1,366 7,895 7,084 832 18,244 2,283 85,761 43,732 4,775 3,731

None Inverse∗ None Inverse∗ Inverse∗ Inverse∗ None

Total stroke

None None Inverse∗

None Inverse∗ None Inverse∗∗

None

A relevant objection against such studies is that dietary information is inaccurate. A more reliable way to evaluate previous intakes is analyses of the short fatty acids 12:0–15:0 in fat cells, because their concentrations reflect intake of saturated fat during the last weeks or months. The strongest associations have been between the intake and the concentrations of the short chain acids 12:0–15:0 [53–57], and of the total numbers [58–61], but weakly or not at all of the longer ones, probably because a high intake of simple carbohydrates stimulates endogenous synthesis of the long-chain saturated fatty acids [62]. In three case–control studies of patients with myocardial infarction and healthy control individuals no difference was found as regards the content of the short-chain saturated fatty acids; in two studies it was even significantly lower in the patients (Table 7.3) [63–67]. These studies concerned only patients with first myocardial infarction [64–67] or patients who were not on a diet [63], and a diet bias is therefore unlikely.

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Table 7.3 Case–control studies of the content of short-chain saturated fatty acids in the fat tissue of patients with myocardial infarction and of healthy control individuals Content in cases compared with controls Authors

Cases/controls n

Kirkeby et al. [63] Wood et al. [64] Kark et al. [65] Clifton et al. [66] Pedersen et al. [67] ∗ p < 0.05; ∗∗ p < 0.01.

27/68 28/343 180/492 79/167 100/98

12:0

14:0

15:0

Less∗∗ No difference

No difference No difference No difference No difference Less∗

Less∗∗

6 Saturated Fat Intake and Atherosclerosis It is true that rodents fed by saturated fat develop premature atherosclerosis. However, there is a great problem with these experimental models because although thousands of researchers have tried for almost a century, no one has ever succeeded in producing an occluding thrombosis or a myocardial infarction by this way alone. If high intakes of saturated fat should lead to atherosclerosis in human beings as well, people with high intakes should be more atherosclerotic than people with low intakes. No such association has been found in any study. In the International Atherosclerosis Project, 15 populations were ranked by raised atherosclerosis and by selected diet components. Degree of atherosclerosis was associated with the total fat intake, but not with the intake of saturated fat [68]. In cohort studies of healthy individuals followed for several years, post-mortems of those who had died at follow-up found no association either between intake of saturated fat and degree of atherosclerosis [1]. No association was found either between the content of 14:0 and 15:0 saturated fatty acids in the fat tissue and degree of atherosclerosis, determined either by autopsy or by coronary angiography [69, 70]. Angiographic follow-up studies have given disparate results. In a trial including 50 men with CHD, where a low-fat diet was compared with usual care, progress of the angiographic changes over 39 months was associated with intakes of palmitic and stearic acids [71]. However, the group that ate the low-fat diet was also instructed to increase their intake of fish, fruit and vegetables, and in many studies intake of such food have been found inversely associated with the risk of CHD. In the MARGARIN study hypercholesterolemic individuals were followed for 2 years after having received dietary advice [72]. At follow-up associations between intake of saturated fat and the changes of intima-media thickness of the coronary and femoral arteries measured by ultrasound were not significant in multivariate regression analyses. When the patients were grouped into quintiles of change of saturated fat intake, a weak association was seen with the changes of the femoral, but not with the changes of the coronary arteries. However, similar advices were given in that study resulting in a diet bias, because vascular changes were inversely associated with intake of fruit. As the effect of a reduced intake of saturated fat is said to lower cholesterol, it is also contradictory that LDL cholesterol was lowest in those whose intake of saturated fat had increased during the study period. In contrast, a highly significant inverse association was found between intake of saturated fat and progress of angiographic lesions in a 3-year follow-up study of 235 postmenopausal women

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with CHD [73]. No dietary advices were given in that study; instead the dietary intakes were recorded meticulously.

7 Saturated Fat and Type 2 Diabetes Diabetes is one of the strongest risk factors for cardiovascular disease (CVD). Epidemiological studies have found a high intake of saturated fat to be associated with higher fasting blood glucose and a greater risk of developing type 2 diabetes, and several such studies are cited in the WHO guidelines. The associations were weak, however, and in the largest study that included more than 50,000 individuals the association disappeared after correction for other factors. The authors concluded that an incomplete control of physical activity and other dietary factors might have influenced the results in the previous studies [74]. That a high intake of saturated fat should predispose for type 2 diabetes is also contradicted by experiments with diets poor in carbohydrates and rich in saturated fat. No worsening of the diabetic condition were seen in these experiments; on the contrary most of them showed an improvement of insulin sensitivity, a lowering of HbA1C and some of the patients were able to stop or lower their antidiabetic treatment [19, 21, 22, 25, 26, 28, 74, 75].

8 Saturated Fat and Body Weight Obesity is also one of the most important risk factors for CVD. Fat has more calories per weight unit than have carbohydrates and protein. This is one of the main arguments for the advice to obese patients to exchange dietary fat with carbohydrates, although there is no evidence that fat per ingested calorie is more fattening than carbohydrates. The increase of mean body weight seen in many Western countries since the introduction of the low-fat diet rather points at the opposite. Meta-analyses of controlled trials of calorie restriction by fat reduction have found that this regime may lead to weight loss, but the effect is trivial and is not sustainable. Willett and Leibel have pointed at serious errors in most of these studies; many of them were not randomised, there were multiple reports from the same trial, fat reduction was combined with increased physical activity and other weight-reducing measures and long-term studies were excluded. Their most serious objection is that the fat reduction and control groups did not receive a comparable intensity of dietary instruction and motivation [76]. A strong argument against the idea that a high intake of animal fat is more fattening than a low-fat diet is also that in all trials mentioned in Table 7.1 a greater weight loss was seen in those who were instructed to follow a high-fat diet than in those on a low-fat diet.

9 Dairy Products In many populations a major contribution of saturated fat comes from dairy products and all authoritative guidelines recommend a restriction of such food. However, in a meta-analysis of ten cohort studies including more than 400,000 individuals Elwood et al. found that compared with

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low consumers the risks of myocardial infarction, ischemic stroke and all cardiovascular events in high consumers were 0.87 (0.74–1.03), 0.83 (0.77–0.90) and 0.84 (0.78–0.90), respectively [77]. In a thorough review of the associations between dairy products and CVD Tolstrup found no strong evidence in support either [78]. Besides, in a study of adolescents the serum level of the low-chain fatty acids 4:0–10:0, 12:0 and 14:0 that closely reflect the intake of milk [55] was inversely associated with serum cholesterol [79]. The studies of fat tissue fatty acids mentioned above are contradictive as well.

10 The Dietary Trials The most important argument for causality is improvement or disappearance of the disease after decrease or discontinuation of the exposure to the suspected causal factor. Up to 1998 relevant data had been published from nine randomised, controlled trials where the only intervention was a change of dietary fat. Two meta-analyses of these trials found no significant effect, neither on cardiovascular nor on total mortality [1, 80, 81], and as mentioned above, most trials comparing high carbohydrate/low saturated fat diets with low carbohydrate/high saturated fat have found a better outcome as regards body weight and metabolic control in the latter ones. In The Women’s Health Initiative Dietary Modification Trial, the largest dietary trial ever performed, almost 50,000 postmenopausal women were randomly assigned to an intervention or comparison group. The intervention group received intensive behaviour modification designed to reduce total fat intake and increase intakes of vegetables/fruit and grains. After 8 years no significant differences were seen as regards the risk of CHD, stroke or CVD [82].

11 Conclusion The idea that too much saturated fat in the diet is harmful to human health has no support from ecological, dynamic population or case–control studies of the association between dietary saturated fat, or tissue saturated fatty acids, and cardiovascular disease, nor from meta-analyses of randomised, controlled, unifactorial dietary trials. Even if the author of this review has studied the scientific literature on this issue meticulously for 18 years, supportive studies may have been overlooked. However, a scientific hypothesis must be in accord with all observations; a few supportive studies cannot outweigh more than hundreds of studies that have falsified the hypothesis. Recently a joint FAO/WHO expert consultation about dietary fat was published. The conclusions about saturated fat were that the evidence is unsatisfactory and unreliable to judge about its influence on risk of CHD [83, p.191], diabetes or overweight [83, p.239].

References 1. Ravnskov U. The questionable role of saturated and polyunsaturated fatty acids in cardiovascular disease. J Clin Epidemiol 1998; 51: 443–460. 2. Olson R. Is it wise to restrict fat in the diets of children? J Am Diet Assoc 2000; 100: 28–32.

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9. 10. 11. 12. 13. 14. 15. 16. 17. 18.

19.

20. 21. 22.

23. 24. 25. 26.

27.

28. 29. 30. 31.

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61. Knutsen SF, Fraser GE, Beeson WL, Lindsted KD, Shavlik DJ. Comparison of adipose tissue fatty acids with dietary fatty acids as measured by 24-hour recall and food frequency questionnaire in black and white adventists: the adventist health study. Ann Epidemiol 2003; 13: 119–127. 62. Hudgins LC, Hellerstein MK, Seidman CE, Neese RA, Tremaroli JD, Hirsch J. Relationship between carbohydrate-induced hypertriglyceridemia and fatty acid synthesis in lean and obese subjects. J Lipid Res 2000; 41: 595–604. 63. Kirkeby K, Ingvaldsen P, Bjerkedal I. Fatty acid composition of serum lipids in men with myocardial infarction. Acta Med Scand 1972; 192: 513–519. 64. Wood DA, Butler S, Riemersma RA et al. Adipose tissue and platelet fatty acids and coronary heart disease in Scottish men. Lancet 1984; 2: 117–121. 65. Kark JD, Kaufmann NA, Binka F, Goldberger N, Berry EM. Adipose tissue n-6 fatty acids and acute myocardial infarction in a population consuming a diet high in polyunsaturated fatty acids. Am J Clin Nutr 2003; 77: 796–802. 66. Clifton PM, Keogh JB, Noakes M. Trans fatty acids in adipose tissue and the food supply are associated with myocardial infarction. J Nutr 2004; 134: 874–879. 67. Pedersen JI, Ringstad J, Almendingen K, Haugen TS, Stensvold I, Thelle DS. Adipose tissue fatty acids and risk of myocardial infarction–a case-control study. Eur J Clin Nutr 2000; 54: 618–625. 68. Scrimshaw NS, Guzmán MA. Diet and atherosclerosis. Lab Invest 1968; 18: 623–628. 69. Scott RF, Daoud AS, Gittelsohn A, Opalka E, Florentin R, Goodale F. Lack of correlation between fatty acid patterns in adipose tissue and amount of coronary arteriosclerosis. Am J Clin Nutr 1962; 10: 250–256. 70. Lang PD, Degott M, Heuck CC, Opherk D, Vollmar J. Fatty acid composition of adipose tissue, blood, lipids, and glucose tolerance in patients with different degrees of angiographically documented coronary arteriosclerosis. Res Exp Med 1982; 180: 161–168. 71. Watts GF, Jackson P, Burke V, Lewis B. Dietary fatty acids and progression of coronary artery disease in men. Am J Clin Nutr 1996; 64: 202–209. 72. Bemelmans WJ, Lefrandt JD, Feskens EJ, Broer J, Tervaert JW, May JF, Smit AJ. Effect of an increased intake of alpha-linolenic acid and group nutritional education on cardiovascular risk factors: the Mediterranean Alpha-linolenic Enriched Groningen Dietary Intervention (MARGARIN) study. Am J Clin Nutr 2002; 75: 221–227. 73. Mozaffarian D, Rimm EB, Herrington DM. Dietary fats, carbohydrate, and progression of coronary atherosclerosis in postmenopausal women. Am J Clin Nutr 2004; 80: 1175–1184. 74. van Dam RM, Willett WC, Rimm EB, Stampfer MJ, Hu FB. Dietary fat and meat intake in relation to risk of type 2 diabetes in men. Diabetes Care 2002; 25: 417–424. 75. Boden G, Sargrad K, Homko C, Mozzoli M, Stein P. Effect of a low-carbohydrate diet on appetite, blood glucose levels, and insulin resistance in obese patients with type 2 diabetes. Ann Intern Med 2005; 142: 403–411. 76. Willett WC, Leibel RL. Dietary fat is not a major determinant of body fat. Am J Med 2002; 113: 47S–59S. 77. Elwood PC, Pickering JE, Fehily AM, Hughes J, Ness AR. Milk drinking, ischaemic heart disease and ischaemic stroke. II. Evidence from cohort studies. Eur J Clin Nutr 2004; 58: 718–724. 78. Tolstrup T. Dairy products and cardiovascular disease. Curr Opin Lipidol 2006; 17: 1–10. 79. Samuelson G, Bratteby LE, Mohsen R, Vessby B. Dietary fat intake in healthy adolescents: inverse relationships between the estimated intake of saturated fatty acids and serum cholesterol. Br J Nutr 2001; 85: 333–341. 80. Hooper L, Summerbell CD, Higgins JP et al. Dietary fat intake and prevention of cardiovascular disease: systematic review. BMJ 2001; 322: 757–763. 81. Ravnskov U. Diet-heart disease hypothesis is wishful thinking. BMJ 2002; 324: 238. 82. Howard BV, Van Horn L, Hsia J, Manson JE, Stefanick ML, Wassertheil-Smoller S et al. Low-fat dietary pattern and risk of cardiovascular disease: the women’s health initiative randomized controlled dietary modification trial. JAMA 2006; 295: 655–666. 83. Burlingame B, Nishida C, Uauy R, Weisell R (ed.). Fats and fatty acids in human nutrition. Joint FAO/WHO expert consultation. Ann Nutr Metabol 2009; 55: 1–302.

Chapter 8

Alteration of Human Body Composition and Tumorigenesis by Isomers of Conjugated Linoleic Acid Nirvair S. Kelley, Neil E. Hubbard, and Kent L. Erickson

Key Points • Mixed isomers of conjugated linoleic acid improved the lean body mass/adipose tissue ratio, decrease risk of cardiovascular disease, improve insulin sensitivity, and decrease risk and prevention of cancer in animal models. • Conjugated linoleic acid and its relationship with human body composition and with cancer do not corroborate the animal studies and thus, this natural or synthetic group of fatty acids cannot be recommended as a supplement that can be used to improve human health. Keywords Conjugated linoleic acid · Body composition · Obesity · Cancer

1 Introduction Conjugated linoleic acid (CLA) is a collective term for isomers of linoleic acid that have conjugated double bonds. Depending on the position and geometry of the double bonds, several isomers of CLA have been reported [1]. Most of the published studies have used a mixture of CLA isomers generally comprised of two major forms, cis 9, trans 11-CLA (c9, t11-CLA) and trans 10, cis 12-CLA (t10, c12-CLA) and a number of minor isomers (t7, t9-CLA, c9, c11-CLA, t9, t11-CLA, c10, c12-CLA, t10, t12-CLA, t11, t13-CLA, c11, c13-CLA). Major dietary sources of c9, t11-CLA, rumenic acid, are ruminant meats and dairy products. Partially hydrogenated oils like shortening and margarines are the sources of t10, c12-CLA, and other isomers. The average intake of CLA in the United States has been estimated to be less than 0.5 g/day [2]; however, actual intakes by individuals consuming processed oils may be several fold greater because the concentration of all CLA isomers in partially hydrogenated soybean oil was 9.8% of the total fatty acids and that of t10, c12-CLA was 2.6% [2].

K.L. Erickson () Department of Cell Biology and Human Anatomy, School of Medicine, University of California, One Shields Ave., Davis, CA 95616-8643, USA e-mail: [email protected] F. De Meester et al. (eds.), Modern Dietary Fat Intakes in Disease Promotion, Nutrition and Health, DOI 10.1007/978-1-60327-571-2_8, © Springer Science+Business Media, LLC 2010

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Feeding a mixture of CLA isomers to animal models has been reported to alter body weight and composition, carcinogenesis, diabetes, atherogenesis, immune status, and other health parameters [1, 3–6]. There are now a considerable number of papers that describe the effects of CLA on obesity, body composition, immune, and lipid status in human subjects, but the number of papers regarding the effects of CLA on cancer in humans is limited. In this chapter we will focus on the effects of CLA (mixture and individual isomers) on body composition and cancer in human subjects.

2 CLA and Human Body Composition CLA supplementation has been reported to decrease depot fat in a number of animal models including mice, rats, hamsters, and pigs [7, 8]. In several studies, CLA also increased fat deposition in liver, muscle, and other tissues. The body fat-lowering effects of CLA in animal models provided the basis on which human studies with CLA were initiated. Twenty-two human studies describing the effects of CLA on human body composition have been published (Table 8.1). Several different methods have been used to determine the body composition. While four-compartment model is considered the gold standard to determine body composition, several alternative methods used in human studies were skin fold thickness, bioelectric impedance, total-body electric conductivity, dual energy X-ray absorptiometry (DEXA), and ultra sound. The standard errors of estimate to determine percent lean and fat body mass varied from 2 to 4% among the different methods [9–11]. The amount of the CLA supplements ranged from 0.6 to 7.5 g/day for durations of 4 weeks–2 years. All these were free living studies with the exception of one study that was conducted in a metabolic unit with strict controls of diet and exercise [12]. Four of these human studies investigated the effects of supplements enriched in c9, t11CLA and two out of the four also included supplements enriched in t10, c12-CLA, with the remaining 18 studies using a mixture of CLA isomers. Supplementation with c9, t11-CLA (0.6– 3 g/day served for 3–6 months) did not alter body weight, body fat, or lean body mass [13–16]. Similar amounts and duration of t10, c12-CLA supplementation also did not alter body weight or composition [14, 16]. Seven studies conducted with a mixture of CLA isomers 3.2–7.5 g/day, for 12 weeks–1 year, reported no change in body weight or body composition [12, 17–22]. Thus, in half the studies, 11 out of the 22, investigators reported no effect of CLA isomers on body weight or composition in humans. The remaining 50% of the studies reported a decrease in body weight or fat mass or increase in lean body mass. The data in those studies reporting beneficial effects of CLA on body composition are not convincing. The authors of most of those studies either have CLA-related patents or the studies were supported by the supplement manufacturers. In three studies [23–25], there were no controls for diet and exercise; the larger decrease in energy intake in the CLA groups compared to those in the placebo groups may account for the differences in body weight and composition. In one study, there was no difference between placebo and CLA groups if the results were expressed as absolute amount of fat; the decrease was significant only if the results were expressed as percent body fat [26]. Results of another study may be confounded because the self-reported energy intake was lower than would be necessary for weight maintenance for the given weight and body composition of

3 g/day RA (n = 13) or olive oil (n = 12), 3 months Regular vs 10× RA-enriched butter, 4 weeks

Healthy men, 20–47 years, BMI 18–34, 25/group, increased dose every 8 weeks, and CO

RA (n = 24) or pure t10, c12-CLA (n = 25), 0.6, 1.2, or 2.4 g/day, 8 weeks then CO after 6 weeks WO Healthy M and W, 35–65 years, 3 g/day safflower oil (n = 15), 1.5 BMI 25–30, parallel or 3.0 g RA/day (n = 18 each) or t10, c12-CLA (n = 15 each), 18 weeks Healthy women, 20–41 years, BMI 3.9 g/day CLA mix (n = 9) or <25, parallel sunflower oil (n = 7) in MRU, 9 weeks Healthy women, 19–24 years, 2.1 g/day CLA mix or soybean oil, BMI< 30, CO no WO, 45 days Healthy M and W, mean age 29 3.76 g/day CLA mix (n = 21) or years, mean BMI 25; parallel placebo (n = 23) 14 weeks Healthy men, 35–60 years, BMI 4.5 g/day CLA mix (n = 21) or <27, parallel olive oil (n = 19) 12 weeks

Obese men, 35–65 years, BMI 27–35, parallel Overweight and obese men, 18–55 years, mean BMI 31, CO

CLA increased insulin and decreased leptin No effect of CLA on BC and blood lipids No effect of CLA mix on BC No effect of CLA on BC

NC BW or FFM, assessed = TOBEC NC BF, assessed = skin fold thickness NC BW, BMI, BFM, and FFM, assessed = DEXA NC in BMI or BC, assessed = BI

NC BFM and LBM, assessed = DEXA

Taylor [21]

Nazare [19]

Petridou [20]

Zambell [12]

Malpuech-Brugere [14]

Tricon [16]

Desroches [13]

Short-term intake of RA had no benefit or AE No effect either isomer on BC within 6 months, LDL:HDL-C ↑ by t10, c12-CLA No effect of either isomer on BC within 18 weeks

Riserus [29]

Author/reference

RA did not alter BC

Comments

No effect of isomers on BW, BF, or FFM-skin fold thickness and BMI

NC in BMI and BFM, assessed = BI No difference in visceral and subcutaneous fat, assessed = CT

Table 8.1 Effects of CLA isomers on body weight and composition in human subjects Subjects and design Intervention Results—methods

8 Alteration of Human Body Composition and Tumorigenesis 123

Overweight M and W, 18–44 years, BMI 25–30, parallel

Overweight M and W, 20–50 years, BMI 25–30, 3 parallel groups

All subjects who completed the above study [24] took CLA for an additional year Overweight M and W, 18–65 years, BMI 28–32, parallel Obese M and W, 18–50 years, BMI 27–35, parallel

Healthy M and W 18–65 years, BMI 25–30; 3 parallel groups

Healthy M and W, 21–45 years, BMI <30, parallel Healthy M and W, 18–65 years, BMI <28, parallel

Table 8.1 (continued) Subjects and design

4.5 g/day CLA mix (n = 42) or olive oil (n = 41) 6 months 7.5 g/day CLA mix (n = 23) or olive oil (n = 27), 12 week wt loss, 16 week wt maintenance; 3rd phase 24 week all subjects took CLA 3 week wt loss then 13 week 1.8 g/day CLA mix (n = 13) or 3.6 g (n = 13), or olive oil 1.9 g (n = 14) 4 g/day CLA mix (n = 22) or safflower oil (n = 18) 6 months

3.9 g/day CLA mix or high oleate safflower oil, 12 weeks 8 week wt loss, then 3.4 g/day CLA mix (n = 40) or olive oil (n = 43), 1 year 4.5 g/day olive oil (n = 50), CLA mix as TG 3.5 g (n = 52) or FFA 3.6 g (n = 55), 1 year 3.4 g/day CLA mix as TG (n = 125), 1 year

Intervention

Comments

CLA improved FFM but not BW

Self-reported energy intake lower than expected, which may confound results

Prevented holiday wt gain, ↓ BFM, assessed = four-compartment model

CLA mix does not ↓ BFM; ↓ HDL-C

CLA does not provide continued ↓ in BFM; several adverse effects Fat loss mainly in legs

NC BW, ↑ FFM, assessed = CT

↓ BFM and ↑ LBM, assessed = DEXA NC BW and BFM, assessed = Bod Pod

No further ↓ BFM with CLA, assessed = DEXA

NC in BC, assessed = skin folds, No effect of CLA mix on DEXA, and CT BC CLA did not prevent wt or fat CLA did not prevent wt regain, assessed = DEXA regain lost by caloric restriction Both forms of CLA ↓ BFM and CLA mix both as FFA and ↑ LBM, assessed = DEXA TG ↓ BFM

Results—methods

Watras [27]

Kamphuis [26]

Whigham [22]

Gaullier [23]

Gaullier [25]

Gaullier [24]

Larsen [18]

Lambert [17]

Author/reference

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4.2 g/day CLA mix (n = 14) or olive oil (n = 10), 4 weeks 3.2 or 6.4 g/day CLA mix (n = 16 each) or 8 g/day safflower oil (n = 12), 12 weeks 9 g/day olive oil (n = 8), 1.7, 3.4, 5.1 or 6.8 g/day CLA mix (n = 7–11/group), 12 weeks 1.8 g/day CLA mix (n = 10) or hydrogel (n = 10), 12 weeks 4.2 g/day CLA mix (n = 26) or olive oil (n = 24), 12 weeks

Obese men, 39–64 years, mean BMI 32, parallel

Obese M and W, 18–50 years, BMI 30–35, parallel

NC BW, BMI, SAD ↓ BF, assessed = three-compartment model

NC BW or BMI; BF↓ in 3.4 and 6.8 g, not in 5.1 g, assessed = DEXA NC BW; ↓ BF, assessed = IR

Small number of subjects in the subgroup Small number of subjects, insensitive method Similar NS ↑ in LBM found in other treatment groups Effect not dose dependent, duration of exercise varied Small sample size and large variance Indirect calculation of BF may not be precise

Comments

Smedman [30]

Thom [53]

Blankson [32]

Steck [31]

Riserus [15]

Laso [28]

Author/reference

List of abbreviations: AE, adverse effects; BC, body composition; BI, bioelectrical impedance; BF, body fat; BFM, body fat mass; BW, body weight, BMI, body mass index; CO, cross over; CT, computed tomography; DEXA, dual-energy X-ray absorptiometry; FFA, free fatty acid; FFM, fat-free mass; g, grams; IR, infrared light; LBM, lean body mass; M, men; MRU, metabolic research unit; MS, multiple sclerosis; NC, no change; NS, nonsignificant; RA, rumenic acid; SAD, sagittal abdominal diameter; TG, triglyceride; TOBEC, total-body electrical conductivity; WO, wash out; W, women.

M and W, 18–30 years, BMI <25, parallel Healthy men, 23–63 years, parallel

M and W, > 18 years, BMI 25–35, parallel

BF ↓ in a sub-group (n = 10) of CLA with BMI <30, assessed = DEXA NC in BW or BMI, but CLA ↓ SAD

3 g/day (n = 30) CLA mix or control (n = 30) 12 week

M and W with MS, 35–65 years, 25–35 BMI, parallel

6.4 g/day CLA ↑LBM, assessed = DEXA

Results—methods

Intervention

Table 8.1 (continued) Subjects and design

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the subjects [27]. One publication ([26] in Table 8.1) included subjects with body mass index (BMI) between 25 and 35 [28]. If the data for all subjects within two groups were compared there were no differences between the CLA and placebo groups in the lean body mass gain or fat loss. If the subjects within the CLA and placebo groups were divided into two subgroups (BMI ≤30 or BMI >30), there was a greater fat loss in the CLA group for subjects with BMI less than 30 and there was greater fat loss in the placebo compared to the CLA group for subjects with BMI >30. These are small changes within the estimation errors of the assay system and are probably not due to the treatments. One research group has published three studies regarding the effect of CLA on body composition; one of these studies was with c9, t11-CLA [15] and the other two were with a mixture of CLA isomers [29, 30]. The study with c9, t11-CLA reported no change in body composition. Both studies with the CLA mixtures found small but significant decreases in body fat. One of these studies reported a reduction of 1.5 cm in sagittal abdominal diameters in the CLA group and 0.7 cm in the placebo group within 4 weeks of supplementation [29]. This is a rather crude method to assess body composition, and we believe the difference between the placebo and treatment groups is too small and is probably within the estimation error of the methods used to assess the abdominal fat. Therefore, it should not be attributed to the effects of CLA. The other study determined body composition by evaluating sagittal abdominal diameter and the threecompartment model based on skin fold thickness, body water, and bioelectric impedance [30]. In this study the sagittal diameter, body weight, and BMI were not altered even after 12 weeks of CLA supplementation. However, body fat as computed by the three-compartment model, decreased by 1.2 and 3.8% in the placebo and CLA groups, respectively. The three-compartment model is not as accurate as the gold standard four-compartment model, and effects observed may be due to artifacts of the assay system. One group of investigators [31] supplemented subjects with 3.2 or 6.4 g/day mixed isomers of CLA or 8 g/day of safflower oil for 12 weeks and determined body composition with DEXA. The investigators reported a significant increase (0.64 kg) in the lean body mass for the group taking the 6.4 g/day supplement of CLA, but increases in lean body mass in the 3.2 g/day CLA group (0.65 kg) and in the placebo group (0.33 kg) were not significant. There was no change in the fat mass in either group. These changes are random and within the errors of estimation of the DEXA and probably cannot be attributed to the effects of CLA. In a study supported by a grant from the manufacturers of CLA, investigators [32] used a placebo group and four groups with 1.7, 3.4, 5.1, or 6.8 g/day CLA. Subjects in all groups participated in either light or intensive exercise; the number of subjects in the two levels of exercise varied among the CLA groups. Fat mass, as determined by DEXA, decreased significantly in the groups taking supplements of 3.4 and 6.8 g/day but not in 1.7 or 5.1 g/day CLA. These authors concluded that CLA intake of greater than 3.4 g/day reduced body fat. However, fat loss was not significant in the group receiving 5.1 g/day CLA. Furthermore, the changes of 1.65 kg in fat mass observed were within the prediction error for DEXA. Lean body mass increased significantly only in the group receiving 6.8 g/day CLA. This group also reported the maximum increase in the number of hours spent with intensive exercise. Those confounding variables make it difficult to distinguish whether the increase in lean body mass was due to increased exercise or CLA supplementation. There are ambiguous results regarding the effects of CLA on body composition: some reports show no effects on both lean body mass and body fat, others show increases in lean body mass but no change in fat mass and still others show a reduction in body fat, but no change in lean

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body mass. Taken together, the published reports do not consistently support improvement in body composition with CLA supplementation. Changes in lean body mass or body fat are all within the estimation errors of the methods used. These discrepancies are caused by a number of factors including the type, amount, and duration of CLA supplemented; absence of controls for diet and exercise levels; fatty acid and macronutrient composition of the basal diet; methods used; and investigator bias. These factors should be controlled for to determine any effect of CLA on body composition in humans. These results disagree with those reported from animal studies mainly because of the age of animals and the amount of CLA used. The doses of CLA found effective in reducing body fat in animal models would translate to 30–60 g/day for a person of 70 kg and thus could not be provided through normal nutritional sources.

3 CLA and Cancer The relationship of CLA with tumorigenesis in animal models has been reviewed by several authors in detail within the last several years [3, 4, 33, 34]. Dietary CLA in general has been shown in carcinogen-induced and transplantation rodent models to prevent or reduce tumorigenesis at most sites tested [3, 4, 35]. More recent studies that have focused on differentiating the effects of separate isomers of CLA rather than mixtures have allowed for more specific conclusions (reviewed in [4]). Most studies with the c9, t11-CLA isomer with multiple tumor types studied have reported a reduction in tumorigenesis whereas a few report no effect. Studies with the t10, c12-CLA isomer are less consistent with some reporting a reduction in tumorigenesis or no effect. One study with one mouse model of mammary tumorigenesis reported that t10, c12-CLA enhanced tumor formation [36]. CLA isomers have also been shown in vitro to alter the growth or induce cell death of not only animal tumor cell lines but also in several different human tumor cell lines and tissues. While some of the initial in vitro studies with human cell lines incorporated mixtures of CLA isomers, more recent studies have focused on differences among specific isomers on cell lines derived from mammary gland, prostate, and digestive tract [4]. For example, in vitro growth of human breast cancer cell line, MCF-7 treated with c9, t11-CLA or t10, c12-CLA was reduced significantly [37]. In that study, t10, c12-CLA but not c9, t11-CLA inhibited growth induced by insulin and estrogen. Also, t10, c12-CLA but not c9, t11-CLA increased apoptosis and so these isomers must have different mechanisms for altering the proliferation of MCF-7 cells. In addition to the differences among the two isomers with MCF-7 growth, the t10, c12-CLA isomer has been shown to inhibit cell growth of colon, colorectal, and gastric cancer cell lines and, in general, to a much greater extent than c9, t11-CLA. However, the c9, t11-CLA isomer was more potent than t10, c12-CLA in inhibiting the growth of colon cell lines [38, 39]. In most studies with prostate cell lines, both isomers inhibited cell growth with effects of t10, c12-CLA being greater than those of c9, t11-CLA [39–42]. Thus, there is no clear conclusion that can be made with respect to the effect of separate isomers on all human tumor cell lines in vitro; effects vary with tumor type, concentration, and duration of CLA administration. While a larger number of studies were on specific isomers c9, t11-CLA and t10, c12-CLA, a few studies have used several other isomers [40, 43]. For example, one study examined the effects of five individual CLA isomers on the growth of MCF-7 cells [40]. Besides a range of effects by the different isomers, the c9, t11-CLA isomer did not inhibit cell growth. More recent

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in vitro studies with human tumor cell lines or tissues from various sites and CLA have sought to determine mechanistic effects of the fatty acids. For example, CLA diminished the carcinogenic induction of 17 β-estradiol (E2) in estrogen-responsive breast epithelial tissues. In one cultured cell type, CLA-induced cell apoptosis in estrogen receptor-α (ERα) transfected MDA-MB-231 cells but not in the wild-type MDA-MB-231 [44]. Those results demonstrated that ERα played an important role in CLA-induced apoptosis in a human breast tumor cell line. In another study, culture of T47D breast cancer cells with a mixture of CLA isomers reduced the expression of the S14 and fatty acid synthase (FAS) genes [45]. The mixture as well as pure c9, t11 and t10, c12-CLA isomers inhibited T47D cell growth. Similar effects were observed in MDA-MB-231 breast cancer cells. In addition, CLA suppressed levels of S14 and FAS mRNAs in liposarcoma cells. The investigators concluded that CLA reduction of tumor lipogenesis, by suppression of S14 and FAS gene expression, was a mechanism for the anticancer effect of CLA. Reports in the literature with dietary CLA and human health are rare. Most describe the effects of CLA on the risk of heart disease or obesity/lean body mass while only a few describe the effects on cancer risk. There have been some studies that have attempted to correlate serum or tissue CLA levels with cancer risk. In one case–control study, the investigators measured serum CLA levels in pre- and postmenopausal women with breast cancer and population-matched controls [46]. Lower serum CLA was associated with a higher risk of breast cancer among postmenopausal women. In another study, no significant link was found between CLA levels in breast adipose tissue and tumorigenesis [47]. The same group reported that there was no association between CLA in breast biopsy samples and risk of subsequent metastasis [48]. There have also been a few studies attempting to correlate dietary CLA intake with cancer. In one, investigators used data from the Netherlands Cohort Study on Diet and Cancer and found a slight positive correlation between CLA intake and breast cancer incidence [49]. In another study of women from the Swedish mammography cohort, investigators observed an odds ratio of 0.71 between the highest and lowest quartiles of intake when compared with colorectal cancer incidence, thus suggesting that higher CLA intake could decrease the incidence [50].

4 Potential Adverse Effects of Specific CLA Isomers A large amount of animal data supporting the beneficial effects of CLA comes from studies with primarily mixtures of isomers. More recent studies in animals, generally, have used separate isomers. This has allowed investigators to observe possible differential effects of the separate isomers including both beneficial and detrimental. Similar to animal studies, initial human studies mainly used mixed isomers. However, within the last several years, investigators have attempted to elucidate differential effects among the separate isomers. The marked variation among those human studies may reflect isomer-specific effects associated with many other variables in the study design. Detrimental effects have been observed in a few studies after supplementation with the t10, c12-CLA isomer. A number of apparent deleterious effects of CLA have recently been reported in animals as well and they involved use of the pure t10, c12-CLA isomer. This may be a problem since t10, c12-CLA can be found in the human diet and is a major component in commercially available CLA supplements. For example, in a recent study with postmenopausal women, t10, c12-CLA had several adverse effects on markers of coronary vascular disease, whereas the c9, t11-CLA isomer did not [51]. Other investigators reported that the t10, c12CLA isomer induced an increase in isoprostane secretion, an indicator of eicosanoid formation

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and of lipid peroxidation in urine of healthy and obese volunteers [52]. While intervention studies in humans need to be performed, it appears that there may be differential effects among CLA isomers and that adverse effects may be related to one isomer in particular. Use of mixtures of CLA isomers in the future for health benefits may contain a very different composition based on observations with separate isomers.

5 Conclusions Since the discovery of CLA and its reported anticarcinogenic effect, many studies with mixed isomers have been performed with most showing that CLA is beneficial. The greatest consistent effect of CLA intake appears to be reduction of adiposity and tumor incidence in animal models. Unfortunately, those benefits have not been confirmed in humans for a multitude of reasons. However, what is now clear is that experiments need to be designed so as to focus on separate isomers. That is important since CLA is commercially available as supplements and may contain isomers that could be not only beneficial but also detrimental. Currently, CLA supplementation cannot be recommended as it is not clear that the beneficial effects observed in many of the animal studies can be translated to humans. Appropriate interventional clinical trials will be required to determine which isomers of CLA are safe and whether it has the same functions in humans as in animals.

References 1. Kelley DS, Erickson KL. Modulation of body composition and immune cell functions by conjugated linoleic acid in humans and animal models: benefits vs. risks. Lipids 2003; 38: 377–386. 2. Kelley DS, Vemuri M, Adkins Y, Gill SH, Fedor D, Mackey BE. Flaxseed oil prevents trans-10, cis-12conjugated linoleic acid-induced insulin resistance in mice. Br J Nutr 2009; 101(5): 701–708. 3. Belury MA. Inhibition of carcinogenesis by conjugated linoleic acid: potential mechanisms of action. J Nutr 2002; 132: 2995–2998. 4. Kelley NS, Hubbard NE, Erickson KL. Conjugated linoleic acid isomers and cancer. J Nutr 2007; 137: 2599–2607. 5. Larsen TM, Toubro S, Astrup A. Efficacy and safety of dietary supplements containing CLA for the treatment of obesity: evidence from animal and human studies. J Lipid Res 2003; 44: 2234–2241. 6. Wang Y, Jones PJ. Dietary conjugated linoleic acid and body composition. Am J Clin Nutr 2004; 79: 1153S–1158S. 7. Navarro V, Fernandez-Quintela A, Churruca I, Portillo MP. The body fat-lowering effect of conjugated linoleic acid: a comparison between animal and human studies. J Physiol Biochem 2006; 62: 137–147. 8. Silveira MB, Carraro R, Monereo S, Tebar J. Conjugated linoleic acid (CLA) and obesity. Public Health Nutr 2007; 10: 1181–1186. 9. Pineau JC, Guihard-Costa AM, Bocquet M. Validation of ultrasound techniques applied to body fat measurement. A comparison between ultrasound techniques, air displacement plethysmography and bioelectrical impedance vs. dual-energy X-ray absorptiometry. Ann Nutr Metab 2007; 51: 421–427. 10. Prior BM, Cureton KJ, Modlesky CM et al. In vivo validation of whole body composition estimates from dual-energy X-ray absorptiometry. J Appl Physiol 1997; 83: 623–630. 11. Wattanapenpaiboon N, Lukito W, Strauss BJ, Hsu-Hage BH, Wahlqvist ML, Stroud DB. Agreement of skinfold measurement and bioelectrical impedance analysis (BIA) methods with dual energy X-ray absorptiometry (DEXA) in estimating total body fat in Anglo-Celtic Australians. Int J Obes Relat Metab Disord 1998; 22: 854–860.

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12. Zambell KL, Keim NL, Van Loan MD et al. Conjugated linoleic acid supplementation in humans: effects on body composition and energy expenditure. Lipids 2000; 35: 777–782. 13. Desroches S, Chouinard PY, Galibois I et al. Lack of effect of dietary conjugated linoleic acids naturally incorporated into butter on the lipid profile and body composition of overweight and obese men. Am J Clin Nutr 2005; 82: 309–319. 14. Malpuech-Brugere C, Verboeket-van de Venne WP, Mensink RP et al. Effects of two conjugated linoleic acid isomers on body fat mass in overweight humans. Obes Res 2004; 12: 591–598. 15. Riserus U, Berglund L, Vessby B. Conjugated linoleic acid (CLA) reduced abdominal adipose tissue in obese middle-aged men with signs of the metabolic syndrome: a randomised controlled trial. Int J Obes Relat Metab Disord 2001; 25: 1129–1135. 16. Tricon S, Burdge GC, Kew S et al. Opposing effects of cis-9,trans-11 and trans-10,cis-12 conjugated linoleic acid on blood lipids in healthy humans. Am J Clin Nutr 2004; 80: 614–620. 17. Lambert EV, Goedecke JH, Bluett K et al. Conjugated linoleic acid versus high-oleic acid sunflower oil: effects on energy metabolism, glucose tolerance, blood lipids, appetite and body composition in regularly exercising individuals. Br J Nutr 2007; 97: 1001–1011. 18. Larsen TM, Toubro S, Gudmundsen O, Astrup A. Conjugated linoleic acid supplementation for 1 y does not prevent weight or body fat regain. Am J Clin Nutr 2006; 83: 606–612. 19. Nazare JA, de la Perriere AB, Bonnet F et al. Daily intake of conjugated linoleic acid-enriched yoghurts: effects on energy metabolism and adipose tissue gene expression in healthy subjects. Br J Nutr 2007; 97: 273–280. 20. Petridou A, Mougios V, Sagredos A. Supplementation with CLA: isomer incorporation into serum lipids and effect on body fat of women. Lipids 2003; 38: 805–811. 21. Taylor JS, Williams SR, Rhys R, James P, Frenneaux MP. Conjugated linoleic acid impairs endothelial function. Arterioscler Thromb Vasc Biol 2006; 26: 307–312. 22. Whigham LD, O‘Shea M, Mohede IC, Walaski HP, Atkinson RL. Safety profile of conjugated linoleic acid in a 12-month trial in obese humans. Food Chem Toxicol 2004; 42: 1701–1709. 23. Gaullier JM, Halse J, Hoivik HO et al. Six months supplementation with conjugated linoleic acid induces regional-specific fat mass decreases in overweight and obese. Br J Nutr 2007; 97: 550–560. 24. Gaullier JM, Halse J, Hoye K et al. Conjugated linoleic acid supplementation for 1 y reduces body fat mass in healthy overweight humans. Am J Clin Nutr 2004; 79: 1118–1125. 25. Gaullier JM, Halse J, Hoye K et al. Supplementation with conjugated linoleic acid for 24 months is well tolerated by and reduces body fat mass in healthy, overweight humans. J Nutr 2005; 135: 778–784. 26. Kamphuis MM, Lejeune MP, Saris WH, Westerterp-Plantenga MS. The effect of conjugated linoleic acid supplementation after weight loss on body weight regain, body composition, and resting metabolic rate in overweight subjects. Int J Obes Relat Metab Disord 2003; 27: 840–847. 27. Watras AC, Buchholz AC, Close RN, Zhang Z, Schoeller DA. The role of conjugated linoleic acid in reducing body fat and preventing holiday weight gain. Int J Obes (Lond) 2007; 31: 481–487. 28. Laso N, Brugue E, Vidal J et al. Effects of milk supplementation with conjugated linoleic acid (isomers cis-9, trans-11 and trans-10, cis-12) on body composition and metabolic syndrome components. Br J Nutr 2007; 98: 860–867. 29. Riserus U, Arnlov J, Brismar K, Zethelius B, Berglund L, Vessby B. Sagittal abdominal diameter is a strong anthropometric marker of insulin resistance and hyperproinsulinemia in obese men. Diabetes Care 2004; 27: 2041–2046. 30. Smedman A, Vessby B. Conjugated linoleic acid supplementation in humans—metabolic effects. Lipids 2001; 36: 773–781. 31. Steck SE, Chalecki AM, Miller P et al. Conjugated linoleic acid supplementation for twelve weeks increases lean body mass in obese humans. J Nutr 2007; 137: 1188–1193. 32. Blankson H, Stakkestad JA, Fagertun H, Thom E, Wadstein J, Gudmundsen O. Conjugated linoleic acid reduces body fat mass in overweight and obese humans. J Nutr 2000; 130: 2943–2948. 33. Mensink RP. Metabolic and health effects of isomeric fatty acids. Curr Opin Lipidol 2005; 16: 27–30. 34. Wahle KW, Heys SD, Rotondo D. Conjugated linoleic acids: are they beneficial or detrimental to health? Prog Lipid Res 2004; 43: 553–587. 35. Bhattacharya A, Banu J, Rahman M, Causey J, Fernandes G. Biological effects of conjugated linoleic acids in health and disease. J Nutr Biochem 2006; 17: 789–810. 36. Meng X, Shoemaker SF, McGee SO, Ip MM. t10,c12-Conjugated linoleic acid stimulates mammary tumor progression in Her2/ErbB2 mice through activation of both proliferative and survival pathways. Carcinogenesis 2008; 29: 1013–1021.

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37. Chujo H, Yamasaki M, Nou S, Koyanagi N, Tachibana H, Yamada K. Effect of conjugated linoleic acid isomers on growth factor-induced proliferation of human breast cancer cells. Cancer Lett 2003; 202: 81–87. 38. Beppu F, Hosokawa M, Tanaka L, Kohno H, Tanaka T, Miyashita K. Potent inhibitory effect of trans9, trans11 isomer of conjugated linoleic acid on the growth of human colon cancer cells. J Nutr Biochem 2006; 17: 830–836. 39. Palombo JD, Ganguly A, Bistrian BR, Menard MP. The antiproliferative effects of biologically active isomers of conjugated linoleic acid on human colorectal and prostatic cancer cells. Cancer Lett 2002; 177: 163–172. 40. De la Torre A, Debiton E, Durand D et al. Conjugated linoleic acid isomers and their conjugated derivatives inhibit growth of human cancer cell lines. Anticancer Res 2005; 25: 3943–3949. 41. Kim EJ, Shin HK, Cho JS et al. trans-10,cis-12 conjugated linoleic acid inhibits the G1–S cell cycle progression in DU145 human prostate carcinoma cells. J Med Food 2006; 9: 293–299. 42. Ochoa JJ, Farquharson AJ, Grant I, Moffat LE, Heys SD, Wahle KW. Conjugated linoleic acids (CLAs) decrease prostate cancer cell proliferation: different molecular mechanisms for cis-9, trans-11 and trans-10, cis-12 isomers. Carcinogenesis 2004; 25: 1185–1191. 43. Tanmahasamut P, Liu J, Hendry LB, Sidell N. Conjugated linoleic acid blocks estrogen signaling in human breast cancer cells. J Nutr 2004; 134: 674–680. 44. Wang LS, Huang YW, Liu S, Yan P, Lin YC. Conjugated linoleic acid induces apoptosis through estrogen receptor alpha in human breast tissue. BMC Cancer 2008; 8: 208. 45. Donnelly C, Olsen AM, Lewis LD, Eisenberg BL, Eastman A, Kinlaw WB. Conjugated linoleic acid (CLA) inhibits expression of the Spot 14 (THRSP) and fatty acid synthase genes and impairs the growth of human breast cancer and liposarcoma cells. Nutr Cancer 2009; 61: 114–122. 46. Aro A, Mannisto S, Salminen I, Ovaskainen ML, Kataja V, Uusitupa M. Inverse association between dietary and serum conjugated linoleic acid and risk of breast cancer in postmenopausal women. Nutr Cancer 2000; 38: 151–157. 47. Chajes V, Lavillonniere F, Ferrari P et al. Conjugated linoleic acid content in breast adipose tissue is not associated with the relative risk of breast cancer in a population of French patients. Cancer Epidemiol Biomarkers Prev 2002; 11: 672–673. 48. Chajes V, Lavillonniere F, Maillard V et al. Conjugated linoleic acid content in breast adipose tissue of breast cancer patients and the risk of metastasis. Nutr Cancer 2003; 45: 17–23. 49. Voorrips LE, Brants HA, Kardinaal AF, Hiddink GJ, van den Brandt PA, Goldbohm RA. Intake of conjugated linoleic acid, fat, and other fatty acids in relation to postmenopausal breast cancer: the Netherlands Cohort Study on Diet and Cancer. Am J Clin Nutr 2002; 76: 873–882. 50. Larsson SC, Bergkvist L, Wolk A. High-fat dairy food and conjugated linoleic acid intakes in relation to colorectal cancer incidence in the Swedish Mammography Cohort. Am J Clin Nutr 2005; 82: 894–900. 51. Tholstrup T, Raff M, Straarup EM, Lund P, Basu S, Bruun JM. An oil mixture with trans-10, cis-12 conjugated linoleic acid increases markers of inflammation and in vivo lipid peroxidation compared with cis-9, trans-11 conjugated linoleic acid in postmenopausal women. J Nutr 2008; 138: 1445–1451. 52. Smedman A, Vessby B, Basu S. Isomer-specific effects of conjugated linoleic acid on lipid peroxidation in humans: regulation by alpha-tocopherol and cyclo-oxygenase-2 inhibitor. Clin Sci (Lond) 2004; 106: 67–73. 53. Thom E, Wadstein J, Gudmundsen O. Conjugated linoleic acid reduces body fat in healthy exercising humans. J Int Med Res 2001; 29: 392–396.

Chapter 9

Insulin Resistance and Non-alcoholic Fatty Liver Disease Induced by Conjugated Linoleic Acid in Humans Madhuri Vemuri and Darshan S. Kelley

Key Points • Mixed isomers of conjugated linoleic acid and purified t10, c12-CLA decreased body weight and body fat mass in animal models but not humans. • Conjugated linoleic acid supplementation in humans have been shown to cause insulin resistance and fatty liver. Because of lack of any significant health benefit from CLA consumption and its associated risks on insulin resistance and fatty liver, this natural or synthetic group of fatty acids cannot be recommended as a supplement that can be used to improve human health. Keywords Conjugated linoleic acid · Insulin resistance · Diabetes · Fatty liver

1 Introduction Conjugated linoleic acid (CLA) refers to the positional and geometric isomers of linoleic acid (18:2, n–6) [1]; more than two dozen isomers of CLA have been identified [2]. The two major CLA isomers that have been studied most extensively are 18:2 cis-9, trans-11 (c9, t11-CLA) or rumenic acid and 18:2 trans-10, cis-12 (t10, c12-CLA). c9, t11-CLA is found predominantly in ruminant meat and milk products with approximate concentrations of 0.4 and 1% of total fatty acids, respectively [3]. t10, c-12 CLA is primarily a product of food processing and is present in partially hydrogenated vegetable oils like margarine and shortenings [4]. Concentration of this isomer varies with the duration and method of hydrogenation; its concentration in partially hydrogenated soybean oil reached up to 2.6% of total fatty acids, while that of total trans-fatty acids reached up to 10% [5]. The average intake of CLA in the United States has been estimated

D.S. Kelley () Western Human Nutrition Research Center, ARS, USDA, Department of Nutrition, University of California, Davis, CA 95616, USA e-mail: [email protected] Reference to a company or product name does not imply approval or recommendation of the product by the US Department of Agriculture to the exclusion of others that may be suitable. F. De Meester et al. (eds.), Modern Dietary Fat Intakes in Disease Promotion, Nutrition and Health, DOI 10.1007/978-1-60327-571-2_9, © Springer Science+Business Media, LLC 2010

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to be 0.5 g/day [6], however, the actual intake may be much higher than that because the food labels do not include CLA while listing total trans-fatty acids. Furthermore, a number of people take CLA supplements to reduce fat mass and body weight, increase muscle mass, and reduce risk for cancer and cardiovascular disease. While these presumed benefits have not been confirmed in humans, several adverse effects (insulin resistance, fatty liver, lipid peroxidation, and inflammation) of CLA have been confirmed in both humans and animal models [7, 8]. In this chapter we will focus on the effects of CLA (mixtures and individual isomers) on insulin resistance (IR) and nonalcoholic fatty liver disease (NAFLD) primarily in human subjects; results from animal studies will be used to discuss the mechanisms involved. We will also summarize the effects of CLA on weight loss because of its association with IR and NAFLD. Finally, we will discuss reasons for the inconsistency of results and the potential mechanisms by which CLA may cause IR and NAFLD.

2 CLA and Weight Loss Studies conducted with different rodent models, pigs and chicken have shown that CLA, reduced body fat in comparison to feeding vegetable oils free of CLA [9–11]. However, results from human studies investigating the effects of CLA on weight loss have not been consistent [3]. A recent meta-analysis of human trials concluded that given at an average dose of 3.2 g/day, CLA produced a modest loss in body fat in humans [12]. The principle author of this analysis acknowledged having CLA patents. Twelve papers were not included in this meta-analysis, either because they did not meet the inclusion criteria or because they were published after the metaanalysis. Among the 12 papers not included, none reported a significant weight loss after CLA supplementation and 3 reported a loss of fat mass [3]. None of the studies in normal weight human subjects (BMI 20–25 kg/m2 ) consuming 0.6–6 g/day CLA mixture for 4–14 weeks reported any weight loss [3] but five of these studies found moderate reduction in body fat mass [13–17]. However, in two of these studies [13, 16], the subjects in both CLA and control groups were undergoing physical training, three times a week, which is a potential confounder. In one of these studies, authors reported a decrease in waist:hip ratio, fat mass, waist, and hip girths at the end of the study in all treatment groups including the control group [17]. This indicates that the weight loss in this study may not have been necessarily due to CLA. Fat loss in the other two studies were well within the estimation errors of the methods used [14, 15]. In overweight (BMI 25–30 kg/m2 ) and obese subjects (>30 kg/m2 ), only 4 out of 16 studies reported a significant reduction in both body weight and fat mass and two more reported a reduction in fat mass only [3]. Thus, the evidence supporting weight loss claims with CLA in humans is very minimal.

3 CLA and Insulin Resistance Insulin is an important hormone as it regulates the absorption, use, and storage of fuel in insulinsensitive tissues such as muscle, liver, and adipose tissue. IR was originally defined by Berson and Yalow in 1970 as a state (of a cell, tissue system, or body) in which greater than normal

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amounts of insulin are required to elicit a quantitatively normal response [18]. It often precedes noninsulin-dependent diabetes (NIDD), where insulin demand exceeds what pancreatic β-cells can produce. The consequences of IR depend on the site of signal dysfunction, whether it is liver or peripheral tissue. In peripheral IR, there is reduced glucose transport from blood to skeletal muscle and elevated free fatty acids, whereas hepatic IR results in uncontrolled glucose production and release from the liver. IR and NAFLD often coexist or develop in parallel and form a vicious cycle [19]. According to the 2005 NHANES survey, more than 40% of people aged 20 and above in the United States had hyperglycemic conditions (diabetics 12.9%; impaired fasting glucose 25.7%, impaired glucose tolerance 13.8%) [20]. These numbers are higher than those reported by NHANES 2002 (10% diabetic and 35% hyperglycemic) [21, 22]. Several human studies have examined the effects of CLA supplementation on markers of IR such as circulating glucose, insulin, and homeostatic model of assessment (HOMA) of IR, while only a few have examined its effects on NAFLD. Here we will briefly discuss the human studies that examined the effect of CLA supplementation on markers of insulin sensitivity. While there are dozens of studies which reported CLA-induced IR in a number of animal models (rats, mice, hamsters, chicken, pig, and fish), the data from human studies are limited. Supplementing diets of mice with a mixture of CLA isomers (0.1–1.5 wt%) caused a greater than 10-fold increase in circulating insulin [23]. Subsequent studies in mice with individual isomers demonstrated that t10, c12-CLA but not c9, t11-CLA caused both IR and NAFLD [24, 25]. Paradoxically, CLA improved insulin sensitivity in diabetic rats and mice, which may be from a reduction in depot fat [26–28]. We found 17 published studies in which the effects of CLA supplementation on IR in human subjects were investigated (Table 9.1); six reported deterioration, nine reported no effect, and two reported improvement in insulin sensitivity after CLA supplementation. Moloney et al. [29] reported a deterioration in insulin sensitivity after supplementing a mixture of CLA isomers (3 g/day, 8 weeks) to diabetic patients with diet-controlled blood glucose. In this study, CLA increased glucose concentrations in fasting blood, as well as after an oral glucose tolerance test (OGTT). HOMA-IR also increased in this study. Similarly, Thrush et al. [30] found a significant decrease in insulin sensitivity as measured by glucose tolerance test (GTT), after providing supplements of 4 g/day of CLA mixture for 12 weeks to nondiabetic overweight humans. Tricon et al. [31] compared the effects of different doses of two purified CLA isomers on markers of IR in healthy men in a cross-over design study. They supplemented either c9, t11-CLA (0.59, 1.19, and 2.38 g/day) or t10, c12-CLA (0.63, 1.26, and 2.52 g/day) for 8 weeks with a 6-week wash-out period in between. t10, c12-CLA, but not c9, t11-CLA significantly increased mean plasma glucose. However, there were no differences in plasma insulin concentrations or indexes of IR, and insulin sensitivity as calculated by HOMA-IR and revised quantitative insulin-sensitivity check index (QUIKI) between the treatments. Riserus et al. [32, 33] conducted two studies with mixtures or purified isomers of CLA in men with abdominal obesity. In one study they provided supplements of 3.4 g/day of a CLA mixture or purified t10, c12-CLA or a placebo for 12 weeks. t10, c12-CLA markedly decreased insulin sensitivity as determined by euglycemic–hyperinsulinemic clamp method, one of the most accurate methods for measuring insulin resistance. On the other hand, supplementing with the same amount of CLA mixture did not affect plasma concentrations of glucose or insulin. In this study, t10, c12-CLA also increased plasma concentrations of pro-insulin, pro-insulin to insulin ratio, and C-peptide concentrations [34]. An increased pro-insulin concentration is related

17 healthy women, 20–41 yrs, RDPC, parallel

53 healthy men and women (27 men, 26 women), 23–63 yrs, RDPC, parallel

60 abdominally obese men, 35–65 yrs, RDPC, parallel

25 abdominally obese men, 35–65 yrs, RDPC, parallel

49 healthy males, 20–47 yrs, RDPC, cross-over design

16 young, healthy, sedentary men and women (12 female, 4 male), 21.5 ± 0.4 yr, RDPC, parallel

32 subjects with stable diet controlled type 2 diabetes, 56–65 yrs, RDPC, parallel

Medina et al. [37]

Smedman et al. [15]

Riserus et al. [32]

Riserus et al. [33]

Tricon et al. [31]

Eyjolfson et al. [43]

Moloney et al. [29]

Intervention—8 wks CLA mix (n = 16) or placebo (palm+ soybean oil) n = 16, 3 g/d

Stabilization—30 d Intervention—64 d CLA mix (n = 10) or placebo (SF oil) (n = 7), 3 g/d Stabilization—2 wks Intervention—12 wks, CLA mix or placebo (olive oil) 4.2 g/d Intervention—12 wks (1) CLA mix (n = 19) (2) Purified t10, c12-CLA (n = 19) (3) Placebo (olive oil) (n = 19) 3.4 g/d each supplement Intervention—12 wks Purified c9, t11-CLA or placebo (olive oil) 3 g/d Intervention—24 wks, 8 wks/dose Washout—6 wks (1) 80% c9, t11-CLA (0.59, 1.19, 2.38 g/d) n = 24 (2) 80% t10, c12-CLA (0.63, 1.26, 2.52 g/d) n = 25 Intervention—8 wks CLA mix (n = 10) or placebo (safflower oil) (n = 6), 4 g/d

Table 9.1 Conjugated linoleic acid and insulin resistance Authors Subjects and design Intervention

t10, c12-CLA group, IR ↑ 19 %, glycemia ↑4%, HDL ↓ -4% compared to placebo. CLA mix group, fasting insulin and glucose NC, HDL ↓ -2%. Placebo NC c9, t11-CLA insulin sensitivity ↓ 15%, lipid peroxidation ↑. Placebo NC t10, c12-CLA-fasting plasma glucose, TG and LDL: HDL ↑, plasma insulin, HOMA-IR and QUICKI NC. c9, t11-CLA-TG and total cholesterol: HDL↓ Placebo NC. OGTT, fasting plasma insulin ↓, plasma glucose NC, ISI ↑ (6/10), insulin response and AUC NC, glucose response and AUC NC. Placebo NC CLA mix- fasting glucose ↑ 6.3%, HOMA, OGIS, and ISI ↓. Placebo NC

CLA mix reduced insulin sensitivity in diabetic subjects

Small sample size, young healthy subjects, ISI ↓ 6, NC 2, ↑ 2

Only study that reported ↑ insulin resistance with c9, t11-CLA Study shows opposing effects of the two isomers on blood lipids. t10, c12 CLA but not c9, t11-CLA reduced insulin ↑ fasting glucose sensitivity in diabetic

IR measured by euglycemic– hyperinsulinemic clamp

Metabolic unit study; moderate effect may be due to healthy subjects, small n and CLA mix Lack of effect may be due to healthy subjects and CLA mix

Fasting plasma insulin ↑ 10% (NS), glucose NC, plasma leptin ↓. Placebo NC. Fasting plasma glucose ↑ (NS), insulin NC. Placebo NC

Comments

Results

136 M. Vemuri and D.S. Kelley

Open extension of Gaullier 2004 study 125 overweight men and women 83 healthy male (n = 18) and female (n = 65), 18–65 yrs, 41 in euglycemic insulin clamp, RDPC, parallel 101 healthy subjects, 10-65y, RDPC, parallel

Gaullier et al. [35]

Lambert et al. [44]

Larsen et al. [39]

64 regularly exercising male [26] and female [38], 21–45 yrs, RDPC, parallel

180 overweight men and women, 18–65 yrs, RDPC, parallel

Gaullier et al. [38]

Syvertsen et al. [40]

46 obese healthy subjects, 18–50 yrs, RDPC in phases I and II and open label in phase III

Whigham et al. [12]

Table 9.1 (continued) Authors Subjects and design Intervention

Wt loss phase—8 wks, intervention—1 yr CLA mix TG (n = 38) or Placebo (olive oil) (n = 39) 3.4 g/d Intervention—12 wks, CLA mix or placebo (S Foil) 3.9 g/d

Phase I: 12 wks, low calorie diet, 6 g/d CLA mix or placebo (SF oil), Phase II: 16 wks, wt. maintenance diet, 6 g/d CLA mix or placebo, Phase III: 5 months, wt. maintenance diet, all subjects 6 g/d CLA mix Intervention—1 yr (1) 80% CLA mix FFA (n = 61), (2) 76% CLA mix TG (n = 60), (3) Placebo (olive oil) n = 59, 4.5 g/d Intervention—12 months All subjects 3.4 g/d CLA mix TG Intervention–6 months CLA mix (n = 39) or placebo (olive oil) (n = 39) 3.4 g/d

NC may be due to using CLA mix and ↓ caloric intake

Fasting plasma insulin and glucose NC, HbA1c ↑ in all groups. CLA TG—leptin and HDL ↓.

Plasma insulin ↓ in women but not men at 120 min, plasma glucose NC, HOMA and QUICKI NC. Placebo NC

Fasting plasma insulin and glucose NC, HOMA NC. Placebo NC

Subjects had to loose >8% of body wt in 8 wks before enrolling in study which may have caused the NC CLA effect on insulin questionable because it showed change only at 1 time point and only in women.

Lack of effect may be due to healthy subjects and using CLA mix

Long-term consumption of CLA mix ↑ IR and liver AST

Subjects on wt loss diet for first 12 wks and on wt. maintenance there after, both of which can impact insulin sensitivity

CLA mix- fasting serum glucose ↑ at wk 2 but not at other time points. HOMA, NC

Compared to baseline, fasting glucose NC, fasting insulin and AST ↑, leptin ↓ Fasting plasma insulin, glucose, HOMA and QUICKI NC. Placebo NC

Comments

Results

9 Insulin Resistance and Non-alcoholic Fatty Liver Disease 137

60 healthy men and women with signs of metabolic syndrome, 35–65 yrs, RDPC, parallel Nine overweight nondiabetic subjects, 31.2 ± 3.7 yrs, open labeled, no placebo 38 healthy young men, 19–35 yrs, RDPC, parallel

Laso et al. [41]

Intervention

Intervention—5 wks, (1) 4.6 g/d CLA mix in butter (n = 18)

Intervention—12 wks 4 g/d CLA mix

Intervention—6 wks, wash out—7 wk. c9, t11-CLA enriched or normal milk, cheese, and butter (1) High c9, t11-CLA—1.421 g/d (n = 26–30) (2) Low c9, t11-CLA0.151 g/d (n = 26–30) Intervention—12 wks, 500 mL milk with CLA mix or placebo, 3 g/d

Did not report plasma insulin values ↑ Muscle ceramide is a potential mechanism for CLA-induced IR Increased lipid peroxidation is a risk factor for developing future IR

Insulin AUC ↑ 20%, glucose AUC ↑ 39%, muscle ceramide ↑ Fasting plasma glucose and insulin NC, prostaglandin F2 ↑ 83%

NC may be due to c9, t11-CLA, normally not known to cause IR

Fasting plasma insulin and glucose NC in both groups.

Fasting plasma glucose and HOMA NC. Placebo NC.

Comments

Results

AUC, area under curve; AST, aspartate aminotransferase; CLA mix, conjugated linoleic acid isomer mix; CRP, C-reactive protein; CVD, cardiovascular disease; FFA, free fatty acid; HOMA, homeostasis model assessment; HDL, high-density lipoproteins; ISI, insulin sensitivity index; IR, insulin resistance; NC, no change; NS, nonsignificant; OGTT, oral glucose tolerance test; QUICKI, quantitative insulin sensitivity check index; RDPC, randomized double-blind placebo controlled; SF oil, sunflower oil; TG, triglycerides; LDL, low-density lipoproteins; WBC, white blood cells; d, day; wks, weeks; yrs, years.

Raff et al. [42]

Thrush et al. [30]

32 healthy middle aged men, 34–60 yrs, RDPC crossover

Tricon et al. [36]

Table 9.1 (continued) Authors Subjects and design

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to impaired insulin sensitivity independent of changes in insulin. In the second study, these investigators compared the effects of purified c9, t11-CLA with those of a placebo (olive oil); both supplemented at 3 g/day for 3 months to men with abdominal obesity. They found that c9, t11CLA also reduced insulin sensitivity compared with the placebo. This is the only study that we found in which c9, t-11-CLA was found to reduce insulin sensitivity [33]. These findings are at variance with those reported with animal models where c9, t11-CLA did not cause IR. In a long-term study supplementing mixture of CLA isomers as triglycerides (3 g/day for 2 years), Gaullier et al. reported a significant (20%) increase in fasting insulin without any changes in glucose [35]. All studies (except one) that did not find any effect of CLA on markers of IR were conducted with a mixture of CLA isomers, ranging from 3 to 6 g/day, for durations of 8 weeks–1 year. The one study conducted with purified CLA, supplemented c9, t11-CLA (1.4 g/day, 6 weeks) to healthy men and found no change in insulin sensitivity [36]. These findings are consistent with those from the animal studies in which c9, t11-CLA did not alter insulin sensitivity. Smedman et al. [15] supplemented 4.2 g/day of CLA mixture to healthy men and women for 12 weeks; they did not find any change in fasting glucose or insulin when comparing the pre- and postsupplement values. The lack of an effect in this study could be due to the health status of the subjects and low sensitivity of the methods used to assess IR. Whigham et al. [12] supplemented 6 g/day of CLA mixture to overweight subjects for 1 year. Even if these authors did not find a change in circulating insulin, they found significant increase in plasma glucose after 2 weeks of CLA supplementation, but not at any of the later time points. The study subjects were on a weight-loss liquid diet for the first 12 weeks and on weight-maintenance diet for the rest of the year. Results may have been impacted by the weight loss. We conducted a study with healthy women at the metabolic research unit under strictly controlled diet and activity level. After 30 days of consuming stabilization diets, subjects took a supplement of either a mixture of CLA isomers (3 g/day, 64 days) or the same amount of placebo oil (sunflower oil). Plasma insulin increased more than 10% after 4, 7, and 9 weeks of CLA supplementation (nonsignificant), but not in the placebo group [37]. The lack of significant difference in insulin concentration was most likely due to the small number of subjects (n = 10) and that the subjects were healthy. Plasma leptin concentration, however, decreased significantly after 4 and 7 weeks of CLA supplementation. Gaullier et al. [38] found no effect of supplementing 3.4 g/day of CLA mixture for 6 or 12 months on plasma insulin, insulin-like growth factor, glucose, and HbA1c in overweight or obese men and women. Similarly, supplementing a mixture of CLA isomers (3.4 g/day, 1 year) to moderately obese subjects did not affect IR, but significantly increased the number of circulating white blood cells [39]. Three other studies with overweight or obese subjects also did not find a change in circulating insulin while supplementing a mixture of CLA isomers (3–5.5 g/day, 3–6 months) [40–42], but one of the studies reported a significant increase (83%) in lipid peroxidation as determined by the urinary F2 isoprostane concentration [42]. In some of these studies with mixtures of CLA isomers, circulating insulin was increased but did not attain statistical significance. The lack of an effect of CLA in these studies could be due to a number of confounding variables, which will be discussed in the next section. Coincidentally, several of these authors also reported a conflict of interest either because they have patents on CLA or because they are associated with the manufacturers of CLA supplements. In contrast to the results from the above studies which showed either adverse effects of CLA on insulin sensitivity or no effect, two studies reported an improvement in insulin sensitivity after

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CLA supplementation. One of these studies provided supplements of a mixture of CLA isomers (3.9 g/day, 8 weeks) to young overweight sedentary human subjects [43]. Fasting plasma insulin decreased and calculated insulin sensitivity index improved after 8 weeks of CLA treatment, while glucose and insulin response to OGTT did not change. Thus, there is an inconsistency between the results calculated by two different approaches. The authors also agree that the data on ISI had large variability, 4 out of 10 CLA-supplemented subjects showed reduced ISI or no change. The other study [44] was conducted in nonobese regularly exercising women, who took either supplements of a mixture of CLA isomers or high oleic acid sunflower oil (3.9 g/day, 12 weeks). Glucose concentrations at 0, 30, 60, 90, and 120 min or the AUC for glucose did not change from the start to the end of study in both groups. Nor did the insulin concentrations differ at 0, 30, and 120 min in men and at 0 and 30 min in women. However, the insulin concentration at 120 min following OGTT was significantly decreased in the women participants in the CLA but not in the placebo group. Authors concluded that CLA improved insulin sensitivity in the women but not in men; however, the results are not very convincing and need to be confirmed in future studies. Thus, there is only scant and weak data supporting the favorable effects of CLA on insulin sensitivity. Overall, most studies showing no effect of CLA on insulin sensitivity were done with mixtures of CLA isomers, which are known to have opposing effects, while studies with pure isomers, especially t10, c12-CLA did show the adverse effects of CLA on IR. On the other hand, data showing improved insulin sensitivity with CLA are quite weak.

4 CLA and Nonalcoholic Fatty Liver Disease NAFLD is a condition in which liver histology resembles alcohol-induced liver injury, but occurs in patients with little or no history of alcohol consumption. It encompasses a histological spectrum that ranges from fat accumulation in hepatocytes, but without inflammation (hepatic steatosis), to fat accumulation with inflammation, which may or may not be associated with fibrosis (nonalcoholic steatohepatitis or NASH). NAFLD is the most common liver disease in the United States and also worldwide. Its prevalence in the United States is estimated to be 30% in the adults, 75–92% in morbidly obese, and 13–14% in pediatric patients [45, 46]. Thus, it is a major health problem. There are dozens of animal studies in which mixtures of CLA isomers or purified t10, c12CLA caused lipodystrophy, which included the loss of adipose tissue fat and its deposition in the liver, spleen, or muscle [23]. While these effects have been observed in several species (mice, rats, hamsters, chicken, pigs, and fish), mice seem to be the most sensitive species in which CLA caused several fold increase in liver fat [47]. Very few human studies examined the effects of CLA supplementation on markers of NAFLD; to the best of our knowledge only three studies have reported that CLA supplementation induced NAFLD. The complexity of techniques (ultrasound, CT or MRI scans, liver biopsies) needed to evaluate NAFLD in human subjects have contributed to the scarcity of this information. Though some CLA studies have reported increased serum concentrations of hepatic enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) which are known to increase during NAFLD, however, because of the wide range of their normal values, such determinations lack sensitivity in the early stages of NAFLD.

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Recently, first case report about the hepatotoxic effects of CLA has been reported in a 46year-old woman [48]. The patient was reported presenting symptoms of asthenia, jaundice, and pruritus. There was no medical history or clinical evidence of viral hepatitis, autoimmune hepatitis, hemochromatosis, or Wilson’s disease. The patient revealed that 14 days prior to admission she had begun self-medicating with CLA to reduce body fat; she was suspected of having CLA hepatotoxicity, which was subsequently confirmed by a liver biopsy. At the time of admission, the plasma concentrations of ALT and AST were elevated by 60- and 40-folds, respectively, of their normal ranges. Also there was a greater than 10-fold increase in plasma concentrations of total and conjugated bilirubin. After the patient ceased to ingest CLA, plasma concentrations of liver enzymes and bilirubin returned to normal levels within 60 days. In another study with overweight Japanese men, the concentration of liver enzymes AST and ALT in the serum increased after supplementing their diets with 6.8 g/day of CLA isomer mixture for 12 weeks; elevated values were still within the normal range [49]. On the other hand, only serum AST but not ALT significantly increased after long-term CLA supplementation (3.4 g/day, 2 years) in overweight men and women [35]. The inconsistency in results between these two studies may be due to the differences in isomer mixtures of CLA and the duration of supplementation. Overall, there is very convincing evidence that CLA induces NAFLD in animal models, but data from human studies are limited.

5 Reasons for Discrepancies A number of factors including characteristics of the study participants, composition of CLA supplements, diet, exercise, and methods used to assess the effects of CLA may contribute to the diagnosis or failure to detect adverse effects of CLA in human subjects. Results in animal studies showed that the effects of CLA varied with the age and BMI of the animals used, we anticipate the same in humans. Amount, duration, and type of the CLA supplement were also reported to impact the CLA effects on IR and NAFLD in animal studies. The major isomers c9, t11-CLA and t10, c12-CLA were found to have opposing effects on fatty acid and lipid metabolism in mice and humans [31, 47]. Most of the studies have been conducted with variable mixtures of CLA isomers. Varying ratios between the concentrations of the two major isomers as well as the concentrations of some of the minor isomers could be a major factor causing the inconsistency of the results among different studies. It is therefore important to conduct studies with purified isomers. The total fat content of the diets and its fatty acid composition are critical in determining the adverse effects of CLA. Diets high in saturated and trans-fatty acids, and sucrose aggravate the effects of CLA on IR and NAFLD. On the other hand, diets rich in polyunsaturated fatty acids, particularly the n–3 PUFA protect from the adverse effects of CLA (see Section 6 below). Source of dietary protein is another factor that impacts IR and NAFLD; casein promoted the NAFLD induced by high sucrose and high-fat diets in rats, while fish, rapeseed, or soy proteins prevented the development of NAFLD by the same diets [50–54]. It remains to be determined if it is the amino acid composition or the residual n–3 fatty acids that provided the protective effects of fish and rapeseed proteins. Similarly it is not known if the protective effect of soy proteins is due to the isoflavones or the amino acid composition or both. Diets low in choline

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or those containing hepatotoxins can also lead to the development of NAFLD. Exercise plays a critical role in determining insulin sensitivity and lipid metabolism. Differences in the amount and type of exercise among different studies could significantly impact the effects of CLA on IR and NAFLD. The sensitivity and reproducibility of the assay methods used are important in determining the health effects of CLA. Methods with low sensitivity and large errors of estimation will not detect small changes in markers of IR and NAFLD. Among the methods used to determine IR, fasting glucose seems to be the least sensitive; some studies used glucometers to determine fasting glucose which has greater than 20% error of estimation. OGTT and IGTT have higher sensitivity than fasting glucose and are not too difficult to perform. Insulin and glucose clamp methods are most sensitive, but are not easy to conduct. Similarly there are differences in the sensitivity and reproducibility of the methods used to evaluate NAFLD. Methods need to be standardized for comparison of the results among different studies.

6 Potential Mechanisms for CLA Action NAFLD and IR are associated with deranged fatty acid metabolism resulting in decreased concentrations of hepatic and circulating arachidonic acid (20:4 n–6; AA), EPA and DHA, increased trans-fatty acid concentration, and an increased ratio between total n–6 and n–3 PUFA [55, 56]. While both the major CLA isomers alter hepatic fatty acid metabolism, it is only the t10, c12CLA isomer that lead to the development of NAFLD [24, 47]. Effects of the two CLA isomers on fatty acid composition varied in different tissues [57]. The most striking effect of c9, t11-CLA was a decrease in the concentration of monounsaturated fatty acids (MUFA) in several tissues including liver, adipose tissue, and spleen with a concomitant increase in the concentration of n–6 PUFA. In contrast, t10, c12-CLA increased concentrations of MUFA and decreased n–6 PUFA in several tissues. t10, c12-CLA supplementation also decreased total n–3 PUFA in several tissues, particularly heart and liver while c9, t11-CLA had no effect. Thus, t10, c12-CLA decreased total n–3 PUFA and increased the ratio of n–6:n–3 PUFA in different tissues. One exception was the spleen, where t10, c12-CLA increased the n–3 PUFA concentration by 700% and c9, t11-CLA decreased it by 90%. These changes in fatty acid composition may be due to the changes in synthesis, elongation, desaturation, and fatty acid transport between the tissues. It appears that deficiency of n–3 PUFA induced by t10, c12-CLA may be a major factor in the development of NAFLD. This notion is supported by the fact that most published reports with CLA, IR, and NAFLD used basal diets with high amounts of linoleic acid (LA) and inadequate amounts of α-linoleic acid (ALA) [47, 57–63]. t10, c12-CLA-induced NAFLD resulted from both increased hepatic fatty acid synthesis and decreased fatty acid oxidation [64]. Increased apoptosis of adipocytes and/or restricted transport of hepatic triglycerides both contributed to the development of CLA-induced NAFLD, but the relative contribution of these and other possible factors in the development of NAFLD are not fully understood. Fish oils, that contain a mixture of EPA/DHA and purified DHA prevented the development of IR and NAFLD induced by diets high in fat [65–68] or sucrose [69–71], deficient in n–3 PUFA [72], or containing CLA [63, 73–75]. Like the long-chain n–3 PUFA, α-linolenic acid (18:3n–3, ALA) supplementation of diets also prevented the development of NAFLD and IR in obese rats

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and mice [76, 77] and the CLA-induced IR in normal mice [78]. Both ALA and DHA prevented the CLA-induced increase in plasma insulin concentration but EPA did not [74]. Results from two studies that investigated the effects of all three n–3 PUFA (ALA, EPA, and DHA) suggest that ALA may be more effective than EPA and DHA in reducing blood glucose [74, 78]. In one study with obese mice, only ALA decreased the AUC for glucose following an insulin tolerance test [77]. In the second study with normal mice fed CLA-containing diet, only ALA decreased the fasting glucose while DHA and EPA did not [74, 78]; the concentration of ALA used was only 20% of that for DHA and EPA (0.3 vs 1.5%). PPAR-γ, a member of PPAR family of transcription factors, is a master adipogenic regulator and is important for adipocyte differentiation and insulin sensitivity by transcriptionally activating genes involved in insulin signaling, glucose and fatty acid uptake, and storage. t10, c12-CLA has been shown to dramatically decrease PPAR-γ expression in preadipocytes through NFkB and ERK-mediated phosphorylation. It activates NFkB and ERK 1/2, which in turn initiate the transcription of inflammatory cytokines like IL-6 and IL-8. The activated NFkB translocates to the nucleus where it activates NFkB p65 and other transcription factors leading to the suppression of PPARγ activity and the expression of PPARγ-dependent genes including ap2, stearoyl CoA desaturase, lipoprotein lipase, fatty acid synthase, GLUT-4, and perilipin; together these changes lead to adipocyte delipidation and insulin resistance [79]. Effects of CLA on gene expression may vary on different insulin-sensitive tissues (liver, adipose tissue, and muscle). CLA supplementation in mice has also been shown to cause pancreatic β-cell hyperplasia, which may contribute to hyperinsulinemia seen with CLA supplementation [80]. The pancreatic β-cell hyperplasia may be because of targeted disruption of PPAR-γ in the pancreas as seen in adipose or a compensatory response to insulin resistance caused by CLA [23]. CLA-induced insulin resistance may also be mediated by adipokines like leptin and adiponectin. Priorie et al. [80] showed that plasma levels of leptin and adiponectin sharply decreased within 2 days of CLA feeding, in mice although adipose tissue mass decreased only after day 6. Hyperinsulinemia developed at day 6 and consistently worsened in parallel with increases in hepatic lipid content. Purushotam et al. [81] reported a decrease in only adiponectin but not leptinafter 4 weeks of CLA supplementation in mice, which was accompanied by hepatic steatosis and insulin resistance. However, insulin resistance and liver steatosis were attenuated by maintaining plasma adiponectin. We reported that concomitant supplementation of CLAcontaining mice diets with EPA or DHA partially restored plasma concentrations of leptin, but only DHA partially restored plasma adiponectin and reduced insulin concentrations, suggesting that DHA may improve insulin sensitivity by increasing adiponectin concentration [74]. Thus, CLA may alter insulin sensitivity and NAFLD by altering the expression and/or activity of PPARg, NFKB, adipokines, and other genes. An understanding of these mechanisms of CLA actions may help plan interventions to prevent its adverse effects.

7 Conclusions Here we have discussed some of the adverse effects of one of the modern day fats, conjugated linoleic acid, on insulin resistance and NAFLD. Adverse effects of CLA isomers are isomer specific; it is only the t10, c12-CLA that caused IR and NAFLD with the exception of one human study in which c9, t11-CLA also induced IR. Although both c9, t11-CLA and t10, c12-CLA

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altered the tissue fatty acid composition in mice, only t10, c12-CLA caused IR and NAFLD. Varying ratios of the isomers in the CLA supplements could be a major factor for the inconsistency of results between different studies, because the two major CLA isomers had opposing effects on lipid metabolism and tissue fatty acid composition. Further studies are needed with individual isomers to determine if there are any health benefits of any of the CLA isomers. Considering the adverse health effects of t10, c12-CLA and of mixtures of CLA isomers, human use of CLA supplements should not be recommended.

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21. Li C, Ford ES, McGuire LC, Mokdad AH, Little RR, Reaven GM. Trends in hyperinsulinemia among nondiabetic adults in the US. Diabetes Care 2006; 29: 2396–2402. 22. Smith SC Jr. Multiple risk factors for cardiovascular disease and diabetes mellitus. Am J Med 2007; 120: S3–S11. 23. Poirier H, Niot I, Clement L, Guerre-Millo M, Besnard P. Development of conjugated linoleic acid (CLA)mediated lipoatrophic syndrome in the mouse. Biochimie 2005; 87: 73–79. 24. Warren JM, Simon VA, Bartolini G, Erickson KL, Mackey BE, Kelley DS. Trans-10,cis-12 CLA increases liver and decreases adipose tissue lipids in mice: possible roles of specific lipid metabolism genes. Lipids 2003; 38: 497–504. 25. Kelley DS, Erickson KL. Modulation of body composition and immune cell functions by conjugated linoleic acid in humans and animal models: benefits vs risks. Lipids 2003; 38: 377–386. 26. Noto A, Zahradka P, Ryz NR, Yurkova N, Xie X, Taylor CG. Dietary conjugated linoleic acid preserves pancreatic function and reduces inflammatory markers in obese, insulin-resistant rats. Metabolism 2007; 56: 142–151. 27. Wendel AA, Belury MA. Effects of conjugated linoleic acid and troglitazone on lipid accumulation and composition in lean and Zucker diabetic fatty (fa/fa) rats. Lipids 2006; 41: 241–247. 28. Nagao K, Inoue N, Wang YM, Yanagita T. Conjugated linoleic acid enhances plasma adiponectin level and alleviates hyperinsulinemia and hypertension in Zucker diabetic fatty (fa/fa) rats. Biochem Biophys Res Commun 2003; 310: 562–566. 29. Moloney F, Yeow TP, Mullen A, Nolan JJ, Roche HM. Conjugated linoleic acid supplementation, insulin sensitivity, and lipoprotein metabolism in patients with type 2 diabetes mellitus. Am J Clin Nutr 2004; 80: 887–895. 30. Thrush AB, Chabowski A, Heigenhauser GJ, McBride BW, Or-Rashid M, Dyck DJ. Conjugated linoleic acid increases skeletal muscle ceramide content and decreases insulin sensitivity in overweight, non-diabetic humans. Appl Physiol Nutr Metab 2007; 32: 372–382. 31. Tricon S, Burdge GC, Kew S et al. Opposing effects of cis-9,trans-11 and trans-10,cis-12 conjugated linoleic acid on blood lipids in healthy humans. Am J Clin Nutr 2004; 80: 614–620. 32. Riserus U, Arner P, Brismar K, Vessby B. Treatment with dietary trans10cis12 conjugated linoleic acid causes isomer-specific insulin resistance in obese men with the metabolic syndrome. Diabetes Care 2002; 25: 1516–1521. 33. Riserus U, Vessby B, Arnlov J, Basu S. Effects of cis-9,trans-11 conjugated linoleic acid supplementation on insulin sensitivity, lipid peroxidation, and proinflammatory markers in obese men. Am J Clin Nutr 2004; 80: 279–283. 34. Riserus U, Vessby B, Arner P, Zethelius B. Supplementation with trans10cis12-conjugated linoleic acid induces hyperproinsulinaemia in obese men: close association with impaired insulin sensitivity. Diabetologia 2004; 47: 1016–1019. 35. Gaullier JM, Halse J, Hoye K et al. Supplementation with conjugated linoleic acid for 24 months is well tolerated by and reduces body fat mass in healthy, overweight humans. J Nutr 2005; 135: 778–784. 36. Tricon S, Burdge GC, Jones EL et al. Effects of dairy products naturally enriched with cis-9,trans-11 conjugated linoleic acid on the blood lipid profile in healthy middle-aged men. Am J Clin Nutr 2006; 83: 744–753. 37. Medina EA, Horn WF, Keim NL et al. Conjugated linoleic acid supplementation in humans: effects on circulating leptin concentrations and appetite. Lipids 2000; 35: 783–788. 38. Gaullier JM, Halse J, Hoye K et al. Conjugated linoleic acid supplementation for 1 y reduces body fat mass in healthy overweight humans. Am J Clin Nutr 2004; 79: 1118–1125. 39. Larsen TM, Toubro S, Gudmundsen O, Astrup A. Conjugated linoleic acid supplementation for 1 year does not prevent weight or body fat regain. Am J Clin Nutr 2006; 83: 606–612. 40. Syvertsen C, Halse J, Hoivik HO et al. The effect of 6 months supplementation with conjugated linoleic acid on insulin resistance in overweight and obese. Int J Obes (Lond) 2007; 31: 1148–1154. 41. Laso N, Brugue E, Vidal J et al. Effects of milk supplementation with conjugated linoleic acid (isomers cis-9, trans-11 and trans-10, cis-12) on body composition and metabolic syndrome components. Br J Nutr 2007; 98: 860–867. 42. Raff M, Tholstrup T, Basu S, Nonboe P, Sorensen MT, Straarup EM. A diet rich in conjugated linoleic acid and butter increases lipid peroxidation but does not affect atherosclerotic, inflammatory, or diabetic risk markers in healthy young men. J Nutr 2008; 138: 509–514. 43. Eyjolfson V, Spriet LL, Dyck DJ. Conjugated linoleic acid improves insulin sensitivity in young, sedentary humans. Med Sci Sports Exerc 2004; 36: 814–820.

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44. Lambert EV, Goedecke JH, Bluett K et al. Conjugated linoleic acid versus high-oleic acid sunflower oil: effects on energy metabolism, glucose tolerance, blood lipids, appetite and body composition in regularly exercising individuals. Br J Nutr 2007; 97: 1001–1011. 45. Erickson SK. Nonalcoholic fatty liver disease (NAFLD). J Lipid Res 2009 Apr; 50(Suppl): S412–6. 46. Erickson SK. Nonalcoholic fatty liver disease. J Lipid Res 2009; 50(Suppl): S412–S416. 47. Kelley DS, Bartolini GL, Warren JM, Simon VA, Mackey BE, Erickson KL. Contrasting effects of t10, c12and c9,t11-conjugated linoleic acid isomers on the fatty acid profiles of mouse liver lipids. Lipids 2004; 39: 135–141. 48. Ramos R, Mascarenhas J, Duarte P, Vicente C, Casteleiro C. Conjugated linoleic acid-induced toxic hepatitis: first case report. Dig Dis Sci 2008; 54(5): 1141–1143. 49. Iwata T, Kamegai T, Yamauchi-Sato Y et al. Safety of dietary conjugated linoleic acid (CLA) in a 12-weeks trial in healthy overweight Japanese male volunteers. J Oleo Sci 2007; 56: 517–525. 50. Mariotti F, Hermier D, Sarrat C et al. Rapeseed protein inhibits the initiation of insulin resistance by a high-saturated fat, high-sucrose diet in rats. Br J Nutr 2008; 100: 984–991. 51. Ascencio C, Torres N, Isoard-Acosta F, Gomez-Perez FJ, Hernandez-Pando R, Tovar AR. Soy protein affects serum insulin and hepatic SREBP-1 mRNA and reduces fatty liver in rats. J Nutr 2004; 134: 522–529. 52. Badger TM, Ronis MJ, Wolff G et al. Soy protein isolate reduces hepatosteatosis in yellow Avy/a mice without altering coat color phenotype. Exp Biol Med (Maywood) 2008; 233: 1242–1254. 53. Shukla A, Brandsch C, Bettzieche A, Hirche F, Stangl GI, Eder K. Isoflavone-poor soy protein alters the lipid metabolism of rats by SREBP-mediated down-regulation of hepatic genes. J Nutr Biochem 2007; 18: 313–321. 54. Gudbrandsen OA, Wergedahl H, Liaset B, Espe M, Berge RK. Dietary proteins with high isoflavone content or low methionine–glycine and lysine–arginine ratios are hypocholesterolaemic and lower the plasma homocysteine level in male Zucker fa/fa rats. Br J Nutr 2005; 94: 321–330. 55. Araya J, Rodrigo R, Videla LA et al. Increase in long-chain polyunsaturated fatty acid n-6/n-3 ratio in relation to hepatic steatosis in patients with non-alcoholic fatty liver disease. Clin Sci (Lond) 2004; 106: 635–643. 56. El-Badry AM, Graf R, Clavien PA. Omega 3—Omega 6: What is right for the liver? J Hepatol 2007; 47: 718–725. 57. Kelley DS, Bartolini GL, Newman JW, Vemuri M, Mackey BE. Fatty acid composition of liver, adipose tissue, spleen, and heart of mice fed diets containing t10, c12-, and c9, t11-conjugated linoleic acid. Prostaglandins Leukot Essent Fatty Acids 2006; 74: 331–338. 58. Clement L, Poirier H, Niot I et al. Dietary trans-10,cis-12 conjugated linoleic acid induces hyperinsulinemia and fatty liver in the mouse. J Lipid Res 2002; 43: 1400–1409. 59. Javadi M, Beynen AC, Hovenier R et al. Prolonged feeding of mice with conjugated linoleic acid increases hepatic fatty acid synthesis relative to oxidation. J Nutr Biochem 2004; 15: 680–687. 60. Roche HM, Noone E, Sewter C et al. Isomer-dependent metabolic effects of conjugated linoleic acid: insights from molecular markers sterol regulatory element-binding protein-1c and LXRalpha. Diabetes 2002; 51: 2037–2044. 61. Takahashi Y, Kushiro M, Shinohara K, Ide T. Activity and mRNA levels of enzymes involved in hepatic fatty acid synthesis and oxidation in mice fed conjugated linoleic acid. Biochim Biophys Acta 2003; 1631: 265–273. 62. Tsuboyama-Kasaoka N, Takahashi M, Tanemura K et al. Conjugated linoleic acid supplementation reduces adipose tissue by apoptosis and develops lipodystrophy in mice. Diabetes 2000; 49: 1534–1542. 63. Winzell MS, Pacini G, Ahren B. Insulin secretion after dietary supplementation with conjugated linoleic acids and n-3 polyunsaturated fatty acids in normal and insulin-resistant mice. Am J Physiol Endocrinol Metab 2006; 290: E347–E354. 64. Rasooly R, Kelley DS, Greg J, Mackey BE. Dietary trans 10, cis 12-conjugated linoleic acid reduces the expression of fatty acid oxidation and drug detoxification enzymes in mouse liver. Br J Nutr 2007; 97: 58–66. 65. Capanni M, Calella F, Biagini MR et al. Prolonged n-3 polyunsaturated fatty acid supplementation ameliorates hepatic steatosis in patients with non-alcoholic fatty liver disease: a pilot study. Aliment Pharmacol Ther 2006; 23: 1143–1151. 66. Delarue J, LeFoll C, Corporeau C, Lucas DN-. n-3 long chain polyunsaturated fatty acids: a nutritional tool to prevent insulin resistance associated to type 2 diabetes and obesity? Reprod Nutr Dev 2004; 44: 289–299.

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67. Flachs P, Mohamed-Ali V, Horakova O et al. Polyunsaturated fatty acids of marine origin induce adiponectin in mice fed a high-fat diet. Diabetologia 2006; 49: 394–397. 68. Le Foll C, Corporeau C, Le Guen V, Gouygou JP, Berge JP, Delarue J. Long-chain n-3 polyunsaturated fatty acids dissociate phosphorylation of Akt from phosphatidylinositol 3 -kinase activity in rats. Am J Physiol Endocrinol Metab 2007; 292: E1223–E1230. 69. Ghafoorunissa IA, Rajkumar L, Acharya V. Dietary (n-3) long chain polyunsaturated fatty acids prevent sucrose-induced insulin resistance in rats. J Nutr 2005; 135: 2634–2638. 70. Rossi AS, Lombardo YB, Lacorte JM et al. Dietary fish oil positively regulates plasma leptin and adiponectin levels in sucrose-fed, insulin-resistant rats. Am J Physiol Regul Integr Comp Physiol 2005; 289: R486–R494. 71. Alwayn IP, Gura K, Nose V et al. Omega-3 fatty acid supplementation prevents hepatic steatosis in a murine model of nonalcoholic fatty liver disease. Pediatr Res 2005; 57: 445–452. 72. Gonzalez-Periz A, Horrillo R, Ferre N et al. Obesity-induced insulin resistance and hepatic steatosis are alleviated by {omega}-3 fatty acids: a role for resolvins and protectins. FASEBb J 2009; 23: 1946–1957. 73. Ide T. Interaction of fish oil and conjugated linoleic acid in affecting hepatic activity of lipogenic enzymes and gene expression in liver and adipose tissue. Diabetes 2005; 54: 412–423. 74. Vemuri M, Kelley DS, Mackey BE, Rasooly R, Bartolini G. Docosahexaenoic acid (DHA) but not eicosapentaenoic acid (EPA) prevents trans-10, cis-12 conjugated linoleic acid (CLA)-induced insulin resistance in mice. Metabol Syndr Relat Dis 2007; 5: 315–322. 75. Yanagita T, Wang YM, Nagao K, Ujino Y, Inoue N. Conjugated linoleic acid-induced fatty liver can be attenuated by combination with docosahexaenoic acid in C57BL/6 N mice. J Agric Food Chem 2005; 53: 9629–9633. 76. Murase T, Aoki M, Tokimitsu I. Supplementation with alpha-linolenic acid-rich diacylglycerol suppresses fatty liver formation accompanied by an up-regulation of beta-oxidation in Zucker fatty rats. Biochim Biophys Acta 2005; 1733: 224–231. 77. Mustad VA, Demichele S, Huang YS et al. Differential effects of n-3 polyunsaturated fatty acids on metabolic control and vascular reactivity in the type 2 diabetic ob/ob mouse. Metabolism 2006; 55: 1365–1374. 78. Kelley DS, Vemuri M, Adkins Y, Gill SH, Fedor D, Mackey BE. Flaxseed oil prevents trans-10, cis-12conjugated linoleic acid-induced insulin resistance in mice. Br J Nutr 2009; 101: 701–708. 79. Chung S, Brown JM, Provo JN, Hopkins R, McIntosh MK. Conjugated linoleic acid promotes human adipocyte insulin resistance through NFkappaB-dependent cytokine production. J Biol Chem 2005; 280: 38445–38456. 80. Poirier H, Rouault C, Clement L et al. Hyperinsulinaemia triggered by dietary conjugated linoleic acid is associated with a decrease in leptin and adiponectin plasma levels and pancreatic beta cell hyperplasia in the mouse. Diabetologia 2005; 48: 1059–1065. 81. Purushotham A, Wendel AA, Liu LF, Belury MA. Maintenance of adiponectin attenuates insulin resistance induced by dietary conjugated linoleic acid in mice. J Lipid Res 2007; 48: 444–452.

Part III

Fats and Cardiovascular Disease

Chapter 10

Dietary Fat Intake: Promotion of Disease in Carotid Artery Disease: Lipid Lowering Versus Side Effects of Statins Rakesh Sharma, Ram B. Singh, Robert J. Moffatt, and Jose Katz

Key Points • Carotid artery disease is the outcome of elevated blood lipids and “cardiovascular incapability” to detect initial stages of atherosclerosis such as integration of endothelial dysfunction, smooth muscle cell dysfunction, and metabolic abnormality of the carotid artery wall. Initially, dyslipidemia is developed to cause elevated blood lipids due to lipid disorder. Later it leads to the “cardiovascular incapability” common in atherosclerosis, systemic inflammatory disorders, and vascular atrophy. • The dyslipidemia is improved by dietary intervention and recommended in adolescents. The responsible biochemical mechanisms of oxidative injury, inflammatory changes and eventual therapeutic interventions are highlighted. • The elevated blood lipids are treated by statins to target “cardiovascular incapability” in the early stage of atherosclerosis to lower the lipids when carotid artery vascular abnormalities are not apparent. • Statins are safe and reduce the cardiovascular events and improve the patient’s survival if prescribed with care, with possible life-threatening side effects of rhabdomyolysis by fibrates. • The present chapter focuses on dyslipidemia management, lipid lowering vs side effects of statin therapy. Lipid lowering vs side effects of statin therapy with analysis is suggesting that there are predisposing factors or specific properties of any statin compounds causing the development of side effects of hepatic and renal function, muscular impairment, and other side effects. • Lipid screening and dietary intervention is important to lower lipids. The highly elevated lipids are treated with statins and severe side effects can completely be minimized by careful statin selection without changing the lipid-lowering effect of statins. Keywords Carotid artery disease · Dietary fat · Statin · Cardiovascular protection · Heart

R. Sharma () Department of Medicine, Columbia University, New York 10033, USA; Center of Nanomagnetics and Biotechnology, Florida State University, Tallahassee, FL 32304, USA e-mail: [email protected] F. De Meester et al. (eds.), Modern Dietary Fat Intakes in Disease Promotion, Nutrition and Health, DOI 10.1007/978-1-60327-571-2_10, © Springer Science+Business Media, LLC 2010

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1 Introduction Dietary lipids are considered as risk of dyslipidemia and development of atherosclerosis. Dyslipidemia is defined if one or more of these lipid, lipoprotein, or apolipoprotein levels are abnormal in the blood or body. The elevated cholesterol and lipoproteins are the main lipids to cause dyslipidemia. The elevated lipids are known as triglycerides (TC), lipoproteins (LDL-C), apolipoproteins (apo-B), non-HDL-C, TG, and low HDL-C and apo A-I in the blood. The lipid disorders are classified into seven dyslipidemia profiles [1]. • • • • • •

elevated LDL-C (type IIa) elevated LDL-C combined with high triglyceride (TG) (type IIb) elevated TG (type IV) low HDL-C (hypo-α) elevated LDL-C type IIa, type IIb, or type IV accompanied by low HDL-C hyper-apobetalipoproteinemia (hyper-apoB), i.e., elevated apolipoprotein B (apoB) but normal LDL-C • Inherited lipoprotein disorders that often present in youth at high risk of future CVD include familial hypercholesterolemia (FH), familial combined hyperlipidemia (FCHL), hyper-apoB, familial hypoalphalipoproteinemia, apolipoprotein A-I mutations, common and rare variants in ABCA1 including Tangier disease, lecithin cholesterol acyl transferase (LCAT) deficiency, and hyper-TG associated with lipoprotein lipase deficiency and defective apoC-II. The disorder of cholesteryl ester transfer protein deficiency often presents as high HDL-C, but its increased or reduced risk of CVD is not resolved.

1.1 What Is Lipid Lowering? The elevated blood lipids are the result of lipid disorder(s) in the body mainly due to metabolic changes in liver, intestine, and adipose tissue at the cellular level of membrane, mitochondria, and macrophages as shown in Fig. 10.1. The central regulatory pathway is cholesterol biosynthesis and its breakdown into bile acids. The first regulatory enzyme segment includes 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (for cholesterol synthesis) and cholesterol-7α hydroxylase (CHOL-H for cholesterol breakdown) to precursors. The ratio of HMG-CoAR:CHOL-H plays significant role in control of lipids in the body. The “lipid lowering” is the measure of bring back the elevated blood lipids to normal lipid levels in the body by using the choice of HMG-CoAR inhibitors (mainly statins) or CHOL-H stimulators (mainly bile acid sequestrants). The lipid lowering may also include dietary low-fat intake or synthetic diets to keep low supply of lipids by utilizing the stored lipids and fats (step I and step II diets). However, broadly success in lipid lowering by use of diets or drugs also depends on several other body constitutional, age, heredity, socio-economic, and environmental factors.

1.2 How Severe Is Dyslipidemia to Cause Lipid Disorders? The elevated lipids, lipoprotein, and apoB levels are common in primary dyslipidemias associated with premature CVD. FH is an autosomal-dominant disorder due to defects in the LDL

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improved endothelial function with no side effects.

Fig. 10.1 Three major physiological pathways of plasma lipoprotein metabolism are shown: (1) transport of dietary (exogenous) fat (left), (2) transport of hepatic (endogenous) fat (center), and (3) reverse cholesterol transport (bottom). Sites of action of the six major lipid-altering drugs on exogenous and endogenous pathways of lipoprotein metabolism are (1) inhibition of HMG-CoA reductase by statins and dependence on HMGCoAR:cholesterol hydroxylase; (2) binding of bile acids by sequestrants, interfering with their reabsorption by the ileal bile acid transporter (IBAT); (3) binding of a cholesterol absorption inhibitor to the Niemann Pick C1L1, decreasing the absorption of dietary and biliary cholesterol; (4) Decreased mobilization of free fatty acids (FFA) by niacin, leading to decreased uptake of FFA by liver and reduced VLDL, IDL, and LDL production; (5) inhibition of TG synthesis by ω-3 fatty acids; (6) up-regulation of lipoprotein lipase (LPL) and decreased production of apoC-III, an inhibitor of LPL, by a fibric acid derivative, leading to decreased VLDL-TG. The hepatic cholesterol pool is decreased by the agents at steps I, II, and III, each leading to an up-regulation of the LDLR. In tissues, the lipid synthesis and oxidation at different cellular organelle play role shown with dots. LCAT, lecithin cholesterol acyl transferase; ABCA-I, ATP-binding cassette protein A-I; ABCG, ATP-binding cassette protein G; BA, bile acids; CE, cholesteryl esters; CM, chylomicrons; CMR, chylomicron remnants; SR-A, class A scavenger receptor; SRB1, class B scavenger receptor [1]

receptor (LDLR) gene (Fig. 10.1). FCHL and hyper-apoB result from overproduction of VLDL, IDL, and LDL (Fig. 10.1). The expression of FCHL can be delayed or associated with type IIa, IIb, or IV lipoprotein profiles or isolated high apoB with premature CAD. The apoB and apoA-I apolipoprotein levels were stronger predictors of parental CVD than LDL-C and HDL-C. National Health and Nutrition Education Survey (NHANES) in collaboration with NCEP and AHA has set guidelines on use of lipid profiles in evaluation of dyslipidemia. The lipid profile includes the following lipids including TC, TG, LDL-C, HDL-C, and non-HDL-C. Each lipid is measured by following calculations:

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LDL-C = TC – (HDL-C + TG/5) TG = (VLDL)-C. For TG = 400 mg/dl, a direct LDL-C is measured TC, HDL-C, and non-HDL-C are measured by clinical chemistry on nonfasting condition apoB and apoA-I are measured by immunochemical methods non-HDL-C = TC – HDL-C. It includes apoB-containing lipoproteins [VLDL, intermediatedensity lipoprotein (IDL), LDL, and lipoprotein(a)] • VLDL, LDL, and HDL subclasses by nuclear magnetic resonance spectroscopy or verticalspin density-gradient ultracentrifugation

• • • • •

Statins are considered to preserve the endothelial function. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are statin compounds. They are drugs to reduce serum cholesterol levels. All statins have one characteristic in common. Statins inhibit the conversion of HMG-CoA to mevalonic acid and reduce the biosynthesis of cholesterol to cause low cholesterol content in hepatocytes. Hepatocytes send signal of sterol depletion by activating nuclear sterol regulatory element- binding protein-2 that upregulates the transcription of mRNA (from genes) involved in HMG-CoA reductase and the low-density lipoprotein (LDL) receptor synthesis. As a result, the cholesterol-lowering effect of statins is the upregulation of LDL receptor activity. The LDL receptor elevates hepatic uptake of atherogenic apoB-containing lipoproteins. These lipoproteins may be very low-density lipoprotein (VLDL), VLDL remnant, intermediate density lipoprotein (IDL), and LDL. In the last decade, several success stories have been reported of statins to reduce carotid artery disease in hypercholesterolemia patients in both primary prevention and secondary prevention. The striking benefit of statin cholesterol-lowering effect seems multifactorial in that statins exert pleiotropic effects on blood vessels. The pleiotropic effects are derived from suppression of the small GTP-binding protein Rho and Rho-kinase signaling. These effects improve the vascular endothelial function; inhibit the vascular smooth muscle cell proliferation and migration, antiinflammatory actions, antioxidative effects; and stabilize the vulnerable plaques.

1.3 Endothelial dysfunction and need of statin therapy Atherosclerosis is a progressive disease characterized by increased lipids and blood lipids. In general, it is a carotid artery multifactorial injury and leads to the formation of atheromatous or fibrous plaques. The atherosclerosis plaques are wall regions of thickened intima growing inside lumen and are composed of various mixtures of fibrous tissues, cells, and lipid. Carotid artery wall injury promotes the endothelial dysfunction, loss of immunity, and increased adhesion of leukocytes and platelets to endothelium, leading to release of various inflammatory mediators that cause vascular smooth muscle proliferation, accumulate peroxidized lipid, and finally form plaque. In plaque development, endothelial dysfunction is an initial stage of atherosclerosis. Other players are smooth muscle cell dysfunction, metabolic abnormality of the carotid artery wall including inflammation, oxidative stress, and breakdown of neurohormonal balance occurring in the early stage of atherosclerosis process. Patients with dyslipidemia, hypertension, diabetes mellitus, smoking, or others are known to have endothelial dysfunction, smooth muscle cell dysfunction, and abnormalities of the carotid wall lipid metabolism. These factors

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contribute as atherogenic risk factors to prevent disease progression. We believe these cardiovascular functions should be intact and capable to minimize atherogenesis. Now, we propose a new concept called “cardiovascular incapability” to detect early stages of atherosclerosis: endothelial dysfunction, smooth muscle cell dysfunction, and metabolic abnormality of the carotid artery wall. Statins should be prescribed targeting atherosclerosis to minimize “cardiovascular incapability.” However, there are concerns of statin side effects and internal toxicity to liver, muscle as described in following section.

2 Dietary Fat Intake and Lipid Lowering In the past two decades the major focus was to identify the nutrition factors to promote cardiovascular disease, mainly higher dietary fat intake exceeding >13% fat energy among almost all socioeconomic groups.1 However, saturated fat and cholesterol-rich dietary intake were considered as the major contributory factors among effluent societies in Western and European world, with increased prevalence of heart attack, myocardial infarction, hypertension, and atherosclerosis. Continued efforts showed that the lipid lowering was very effective by dietary intake of polyunsaturated fatty acids and omega-3 and omega-6 fatty acids in cardiovascular prevention in general to keep normal serum lipid profile in both carotid artery and coronary artery diseases.1 The current trend is to identify endothelial dysfunction of cardiovascular tissue and decrease the inability of heart, coronary, and carotid arteries (cardiovascular incapability) to fight against lipid deposition leading to vascular occlusion, stroke, and plaque formation by using statins. In this direction, two major suspects of endothelial dysfunction are (1) dietary fat intake and blood lipids and (2) dysfunction of endothelial cascade and statin side effects. We have focused in this chapter on the association of endothelial dysfunction with cardiovascular disease and its prevention by statins.

2.1 Dietary Therapy and Lipid Lowering Initially dyslipidemia are treated with a diet reduced in total fat, saturated fat, and cholesterol. The intake of complex carbohydrates is increased with minimum simple sugars and no change in total proteins keeping calories sufficient to maintain normal growth and development. The NCEP recommended diet treatment after 2 years of age [2]. The STRIP trial recommended low-fat diet at 6 months of age under medical supervisión [3].

2.2 Who Needs Treatment with Diet? • If TC, LDL-C, non-HDL-C, or TG is elevated or HDL-C is low followed by repeat profile 3 week later to confirm the first profile.

1 Sharma

R. The dietary lipids: The effect of antihypertensive therapy on serum lipid profile. MSc Applied Nutrition dissertation, submitted to National Institute of Nutrition (ICMR), India. 1988; pp. 17–33.

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• If one or more of the lipid or lipoprotein values remain above the elevated cutoff point or HDL-C is low, secondary causes of dyslipidemia—need of dietary treatment step I diet. • If repeat lipoprotein profile in 6–8 week shows dyslipidemia—step II diet is initiated [2].

2.3 Safety and Efficacy of Dietary Therapy in Infants, Children, and Adolescents Human milk remains the gold standard for infant feeding. A low-fat diet is safe in age of 7 months–11 year in STRIP [3] and from the ages of 8–10 year throughout adolescence in the Dietary Intervention Study in Children (DISC) [4]. However, efficacy and safety of low-fat diet is based on epidemiological reports and insulin resistance; endothelial function in adolescents interferes with lipid lowering.

2.4 Current View of Nutraceuticals and Bioactive Foods in Lipid Lowering The authors believe that lipid lowering effect based on the mixed reports of verbal testimonies or epidemiological surveys is insufficient claim in favor of lipid lowering by foods. However, scientific evidences exist in favor. The use of margarines (three servings daily) high in either plant stanol esters or plant sterol esters can reduce LDL-C 10–15% when added to a low-fat diet. Water-soluble fibers such as psyllium may lower LDL-C (5–10%). Soy protein lowers VLDLC and TG and increases HDL-C without effect on LDL-C. Supplementation of a low-fat diet with an ω-3 fatty acid (docosahexaenoic acid 1.2 g/d) increased the large-sized LDL 91% and reduced the small-sized LDL 48% [1]. However, the prescription of ω-3 fatty acids is not yet approved by the FDA. Garlic does not lower LDL-C in hyperlipidemic children [1]. Niacin is a choice in FH homozygotes (55–87 mg/kg·d in divided doses), due to the significant reduction of VLDL and LDL production (see Fig. 10.1). Use of a fibrate (48, 96, or 145 mg/d) is limited to that adolescent with TG over 500 mg/dl, who may be at increased risk of pancreatitis. Fish oils (1–2 g/d) lower TG by decreasing TG biosynthesis (Fig. 10.1). A recent report on bioactive foods reviewed the significance of plant sterols, fibers, flavones, antioxidants, and polyunsaturated fatty acids in lipid lowering with biochemical basis of cardiovascular prevention [5]. Overall, a diet low in fat in children with dyslipidemias appears safe and efficacious when performed under supervision. Medical and nutritional support is necessary to reinforce good dietary behaviors and ensure nutritional adequacy.

2.5 Drug Therapy in Lipid Lowering The drug therapy is aimed to lower significantly elevated LDL-C during Tanner stage II in males and post-menstrual stage in girls if the LDL-C is > 190 mg/dl and no history of CVD; or LDL-C > 160 mg/dl with family history of premature CVD or the metabolic syndrome is present. In this direction, two major classes of effective drugs, stains and bile acid sequestrants (BAS) have surfaced to combat with elevated LDL-C (Fig. 10.1). The main mechanism of lipid lowering is

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the release of the sterol regulatory element binding protein (SREBP) from the cytoplasm into the nucleus, where SREBP binds to the SRE of the promoter of the LDL receptor gene and increases the number of LDL receptor to decrease LDL-C. SREBP also up-regulates the gene for hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase to inhibit this enzyme. • HMG-CoA reductase inhibitors: Statins reduce hepatic cholesterol by inhibiting HMGCoA reductase and decreasing cholesterol biosynthesis. It improves endothelial function. Atorvastatin, lovastatin, pravastatin, and simvastatin are approved by the FDA for use in adolescents with FH. • Bile acid sequestrants: BAS are safe drug recommended by NCEP for lipid lowering. Colestipol, Colesevelam (625 mg tablets, three or six per day), cholestyramine drugs reduce lipids by 15%. • Cholesterol absorption inhibitors: Ezetimibe blocks the absorption of cholesterol and plant sterols and reduces hepatic cholesterol (Fig. 10.1).

3 Prevention of Carotid Artery Disease by Lipid Lowering: Statins in Clinical Trials Several clinical trials were reported in the recent past including European WOSCOPS [6], US AFCAPS/TexCAPS [7], Scandinavian Simvastatin Survival Study [8], LIPID (Long-term Intervention with Pravastatin in Ischemic Disease Study) [9], CARE (Cholesterol and Recurrent Events) [10]. The AVERT (Atorvastatin Versus Revascularization Treatment) [11], MIRACL (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering) [12], and LIPS (Lescol Intervention Prevention Study) [13] trials clearly showed the association of dietary lipid intake as carotid artery disease development. Statins were cited as drugs of choice to prevent further carotid artery atherosclerosis. Four major epidemiological studies from Muscatine, Bogalusa, Coronary Artery Risk Development in Young Adults (CARDIA) [14], and Special Turku Coronary Risk Factor Intervention Project (STRIP)[3] have set guidelines on use of drugs and prevention by lipid lowering. HMG-CoA reductase inhibitors have been advocated in favor of lipid lowering to treat dyslipidemia. A number of randomized controlled trials [15–17] and a meta-analysis [18] showed high efficacy of statins for LDL-C and apo-B- lowering and tolerable side effects, compared with placebo.

4 Statins for Cardiovascular Incapability 4.1 Statins’ Actions for Carotid Artery Endothelial Dysfunction Endothelium is a monolayer of cells covering vascular lumina throughout the body. Endothelial cells in the wall play biological roles of maintaining vascular tone and structure, intravascular hemostasis and permeability, protecting from oxidative stress, and inhibiting cell adhesion and migration, i.e., anti-inflammatory properties [19]. The endothelium releases several vasoactive

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substances: endothelium-derived relaxing factors (EDRFs) and endothelium-derived contracting factors (EDCFs). The EDRFs such as nitric oxide (NO), endothelium-derived hyperpolarizing factors (EDHF), or prostacyclin (PGI2) protect the vasculature from atherogenic insult. The EDCFs such as endothelin-1 (ET-1) or thromboxane A2 (TXA2) display opposite effects and actively participate in the atherogenesis. Endothelial dysfunction is characterized as reduced bioavailability of EDRFs such as NO, whereas EDCFs increase the NO production or improve endothelial dysfunction [20]. This imbalance of EDRFs and EDCFs leads to impaired endothelium-dependent vasodilation, a kind of endothelial dysfunction. However, another contributory factor is “endothelial activation” characterized by a pro-inflammatory, proliferative, and procoagulatory milieu that favors all stages of atherogenesis (Fig. 10.2) [21]. Thus, the status of endothelial function may reflect the “cardiovascular incapability” of an individual to develop atherosclerotic disease. The initial evaluation of endothelial dysfunction may detect the initial step of “cardiovascular incapability” and possibility of atherogenesis.

Fig. 10.2 Production of nitric oxide (NO) by endothelial cells. NO is produced by the action of endothelial nitric oxide synthase (eNOS) on L-arginine. This reaction requires a number of cofactors, including tetrahydrobiopterin (BH4) and nicotinamide adenine dinucleotide phosphate (NADPH). Increased intercellular Ca in response to vasodilator agonists or shear stress displaces the inhibitor caveolin from calmodulin (CaM), activating eNOS. NO diffuses to vascular smooth muscle and causes relaxation by activating guanylate cyclase (GC), thereby increasing intracellular cyclic guanosine monophosphate (cGMP) [21]

Statins are documented to minimize the “cardiovascular incapability” to arrest the vascular failure associated with endothelial dysfunction. Hypercholesterolemia reduces NO production and enhances NO degradation in vascular endothelial cells. Statins’ lipid-lowering effects increase the endothelial nitric oxide synthase (eNOS) gene expression via the reduction of degradation of mRNA and decrease of the ET-1 production [22]. However, statins may show lipid-independent effects on endothelial function. Simvastatin preserved the endothelial function in experimental porcine hypercholesterolemia in the absence of any lipid-lowering effects [23, 24]. Pravastatin was shown to improve endothelial function in cynomolgus monkeys, independent of serum lipoprotein concentrations [25]. Since endothelial dysfunction is characterized by an imbalance between vasodilating and vasoconstricting substances, viz., impairment of EDRFs and a predominance of EDCFs, both of these factors contribute to statin-induced

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endothelial function improvement. Thus, both enhancement of vasodilator and attenuation of vasoconstrictor activity in the carotid artery wall are the major players.

4.2 Vascular Endothelial Function Evaluation and Effect of Statins There are several physiological methods of cardiovascular endothelial function of arteries (Table 10.1). The first description of endothelial dysfunction in atherosclerotic epicardial arteries appears in 1986 by Ludmer and colleagues [26], invasive assessment of endothelial function by quantitative MR angiography along with acetylcholine (ACh), as the “golden standard” for endothelial function testing. ACh displays both actions of vasodilation by promoting endothelial NO release and vasoconstriction by direct action to vascular smooth muscles. ACh dilates the normal blood vessels that have intact endothelium but constricts the vessels if their endothelium is damaged [26–30]. Carotid artery vasospasm is a feature of endothelial dysfunction [31] and can be caused by hyperconstriction of vascular smooth muscle [32]. Presently, injection of ACh is routine to diagnose vasospasm angina supported with Doppler flow measurements to get an information of endothelial function of artery resistance [33, 34].

Table 10.1 Vasoregulatory endothelial functions and cardiovascular incapability parameters

• Endothelium function and factors Endothelium-derived contracting factors (EDCFs) Endothelium-derived relaxing factors (EDRFs) Endothelium-derived contracting factors: nitric oxide (NO) Endothelium-derived hyperpolarizing factors (EDHF) Prostacyclin (PGI2), fatty acids, antioxidants, L-arginine, folic acid • Cardiovascular incapability parameters Hypercholesterolemia and hypertriglyceridemia Intima pathology Cardiac output Left ascending artery angiography Left ventricular mechanics and blood flow

Recently noninvasive techniques of blood flow measurement (FBF) or flow-mediated vasodilation (FMD) by high-resolution ultrasonography have become common to assess endotheliumdependent vascular function of the carotid artery and peripheral vascular endothelial function [35]. Using strain gauge plethysmography, endothelial function can be evaluated by an AChinduced blood flow increase or post- ischemic reactive hyperemia [36]. On the other hand, post-ischemic reactive hyperemia is also mediated by endothelial NO [37]. In contrast, since reactive hyperemia increases the vessel wall shear stress in the proximal artery with subsequent blood flow-dependent vasodilation, FMD of the brachial artery is nowadays the most frequently used as a noninvasive surrogate of endothelial function. The noninvasive nature of this technique allows repeated measurements over time to study the effectiveness of various interventions that may affect vascular health. Uehara et al. [38] observed brachial artery FMD by noninvasive assessment compared with coronary endothelial function testing by assessing the conduit vessel

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vasomotor response to ACh as a part of coronary angiography in the same patients and demonstrated that both were correlated. This result suggests that noninvasively measured peripheral arterial endothelial function can be a simple surrogate for carotid artery endothelial function. Using the above-mentioned techniques, statins’ effects for vascular endothelial function of the carotid artery as well as peripheral arteries were extensively assessed in various clinical settings. The administration of 20 mg/day fluvastatin but not 10 mg/day pravastatin for 16 weeks improved the endothelial function [39]. Thus, statin’s effects on the reduction of coronary events may be in part derived from the improvement in endothelial function as shown in Fig. 10.3. Endothelial dysfunction is considered an important early marker of atherosclerosis and cardiovascular risk and is currently used as a surrogate end point for cardiovascular risk in clinical trials [40–42]. Recent evidence suggests that some benefit from the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors may also occur independent of lipid lowering. However, simvastatin preserved the coronary endothelial function, endothelial NO synthase (eNOS) expression, and oxidative stress in experimental hypercholesterolemia (HC) in the absence of cholesterol lowering [43–47].

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4.3 Vascular Smooth Muscle Dysfunction and Statin Carotid artery vascular smooth muscle dysfunction can be as impaired smooth muscle relaxation and smooth muscle cell proliferation. Endothelium-dependent vasodilation, i.e., endothelium improvement, and smooth muscle cell relaxing are interrelated characteristics of vascular smooth muscle cell function. On the other hand, vasodilatory capacity after administration of NO donor such as sodium nitroprusside or nitroglycerin can assess the endothelium-independent

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vasodilation. The endothelial impairment is accompanied with smooth muscle cell proliferation [48]. Statins also have direct action of endothelium-independent vasodilation by inhibiting inward L-type Ca++ current in smooth muscle cells [49]. At this point, physicians check if statin improves the smooth muscle function in a clinical setting. In the process of arteriosclerosis development, medial smooth muscle cell proliferates and migrates into the intima, accompanied with atherosclerosis plaque formation. Thus, vascular smooth muscle cell proliferation leads to neointimal thickening toward progression of atherosclerosis. It has been known that statins inhibit proliferation and migration of smooth muscle cells by inducing apoptosis. Statins suppress the c-fos gene expression by impairing insulin-like growth factor (IGF)/ insulin signaling and lead to inhibiting smooth muscle cell proliferation and migration. Intimal–medial thickness (IMT) of carotid artery observed by ultrasonogram is widely used routinely to evaluate the stage of “cardiovascular incapability.” Several reports demonstrated a relationship between the severity of carotid artery IMT and carotid artery disease evaluated by MR angiography or myocardial perfusion scintigraphy [50–53]. There are several evidences showing that progression of carotid artery IMT could predict outcomes of cardiovascular events including stroke and stenosis. In addition, intravascular ultrasound (IVUS) imaging directly provides us information regarding intimal thickening in the carotid artery with luminal narrowing. Statins showed the regression of the carotid IMT in various clinical trials [54, 55]. Nishioka et al. [56] investigated the effects of statins on intimal thickness of the carotid artery using the IVUS imaging in patients undergoing stenting, focusing on the plaques of nontreated segments, and observed statins’ effect on regression of plaques without positive vessel remodeling.

4.4 Inflammation in the Process of Atherosclerosis Recently, atherosclerosis has been widely recognized as an inflammatory disease. Recent advances in basic science have established a fundamental role for inflammation in mediating all stages of atherosclerosis from initiation through progression to the plaque formation and ultimately plaque rupture and subsequent thrombotic complications in acute coronary syndrome (ACS) [57–59]. Initiation and progression of atherosclerosis are characterized by recruitment of monocytes and T-lymphocytes to the artery wall, which is promoted by interaction between leukocytes and vascular endothelial cells. Increased leukocyte–endothelial adhesion is present in hypercholesterolemia. A triggering event for this process is accumulation of oxidized lowdensity lipoprotein (LDL), which stimulates the overlying endothelial cells to produce a number of pro-inflammatory molecules, including adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), P-selectin, or E-selectin; chemotactic protein such as monocyte chemotactic protein-1 (MCP-1); and growth factors such as macrophage colony-stimulating factor (M- CSF), resulting in the recruitment of monocytes to the vessel wall. Oxidized LDL has other effects, such as inhibiting the production of NO, an important mediator of vasodilation and expression of E-selectin. Among endothelial cell adhesion molecules likely to be important in the recruitment of leukocytes are ICAM-1, VCAM-1, P-selectin, E-selectin, and platelet/endothelial cell adhesion molecule (PECAM)-1. Important adhesion molecules on monocytes include beta 2- integrin lymphocyte functional antigen (LFA)1 (CD11a/CD18) or Mac-1 (CD11b/CD18), beta 1-integrin vary late antigen (VLA)-4, and PECAM-1. Monocytes recruited into the vessel wall are differentiated into macrophages by

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M-CSF stimulation and express scavenger receptors that take up highly oxidized LDL, leading to cell formation. Recent studies have shown that the interaction of CD40 and its ligand CD40L (CD154) makes an important contribution to the development of advanced lesions [60, 61]. Vulnerable plaques have rich lipid, thin fibrous cap, and abundant infiltration of inflammatory cells, monocytes/macrophages, and T- lymphocytes. Activated macrophages produce matrix metalloproteinases (MMPs) that result in matrix degradation, leading to plaque rupture [62]. Once plaques rupture, in the process of thrombus formation, tissue factor activates coagulation cascade and subsequently platelets and leukocytes; neutrophils as well as monocytes are activated and interacted [63, 64]. Thus, the process of plaque rupture is characterized as acute inflammatory reaction. On the other hand, restenosis after percutaneous coronary intervention (PCI) is also triggered by inflammation in the PCI site injured vessel wall [65]. In the post-PCI inflammatory process, cross talk between platelet surface P-selectin and leukocyte Mac-1 has a crucial role [66, 67]. Clinical studies have shown that this emerging biology of inflammation in the process of atherosclerosis from its onset to plaque vulnerability applies directly to human patients by the measurement of various inflammatory markers including cytokines such as interleukin (IL)-6 or tumor necrosis factor (TNF)-alpha; , adhesion molecules such as ICAM-1, VCAM-1, P-selectin, or E-selectin; and acute phase reactant proteins existing downstream of them such as C-reactive protein (CRP) or serum amyloid A (SAA). Among these inflammatory markers, the most useful marker for clinical use seems to be CRP [68]. Recent development of highly sensitive measurement method of CRP (hs-CRP) enables us to assess low-grade inflammation, and the CRP has been established as an independent predictor of cardiovascular events in healthy individuals. On the other hand, elevated circulating CRP accompanies ACS, reflecting a primary inflammatory instigator of vulnerable plaque [69]. In patients with ACS, elevated CRP is associated with an adverse in- hospital and short-term prognosis that includes death, recurrent episodes of ACS, or myocardial infarction [70]. Recent research on CRP has focused on its localization and production in various inflammatory lesions, especially in atherosclerotic plaques, in addition to its production in the liver. We measured CRP values in patients with coronary artery disease in both blood samples just distal and just proximal to the lesion and observed that CRP was higher in the distal blood samples than in the proximal samples. The translesional gradient of CRP (distal CRP minus proximal CRP) as well as the proximal CRP was higher in unstable angina patients than in stable angina patients. The translesional CRP gradient correlated with the proximal CRP, namely systemic CRP. Thus, we observe in part CRP derived from atherosclerotic plaque in peripheral blood measurement [71]. CRP is also increased after PCI with the maximum increase at 48 h after the procedure, and the CRP at 72 h can predict restenosis [72].

4.5 Anti- inflammatory Actions of Statins Among the statins’ pleiotropic effects, anti-inflammatory properties might represent one of the most important actions. It was demonstrated that fluvastatin attenuates the leukocyte– endothelial cell adhesion responses in hypercholesterolemic rat model independently of any lipid-lowering effect [73]. Recently, these findings were extended by demonstrating a significant reduction of leukocyte–endothelial cell interactions with simvastatin in a normocholesterolemic rat model in

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vivo, which was at least partly mediated by attenuated upregulation of P-selectin on endothelial cells [74]. Moreover, it has been shown that Rho is essential for integrin-mediated leukocyte adhesion to endothelial cells [75]. Because geranylgeranylation is required for Rho activation, it can be speculated that statins modulate leukocyte–endothelial cell interactions in part by inhibition of geranylgeranylation of this protein [76]. Besides these anti- inflammatory effects on endothelial cell adhesion molecules, statins seem to exert similar effects on leukocyte adhesion molecules. Fluvastatin inhibits adhesive interaction between monocytes and human umbilical vein endothelial cells (HUVECs) by lowering the expression of LFA-1 on monocyte and ICAM-1 on HUVECs [77]. Addition of lovastatin to isolated human monocytes led to a significant reduction of surface expression of CD11b, which in turn was associated with decreased CD11b-dependent adhesion of monocytes to HUVECs [78]. Co- incubation with mevalonate, but not with LDL, reversed the lovastatin’s effect, suggesting a crucial role for early cholesterol precursors of the mevalonate pathway for the inhibitory effect of statins on integrin expression and leukocyte–endothelial cell interactions. Furthermore, it has been demonstrated that treatment with simvastatin is associated with attenuation of CD18 upregulation in neutrophils in response to stimulation with leukotriene B4 (LTB4) in normocholesterolemic rats [79]. Recently, cerivastatin was shown to reduce monocyte adhesion to endothelium under physiological flow condition via downregulation of integrin adhesion molecules, CD11a, CD18, and VLA-4, and inhibition of actin polymerization via prevention of Rho translocation to the membrane [80]. Thus, statins may affect leukocyte–endothelial cell interactions by various mechanisms, which depend on their ability to inhibit HMG-CoA reductase but are independent of cellular cholesterol biosynthesis. Lovastatin blocks LFA-1-mediated adhesion and co-stimulation of lymphocytes via direct binding to a specific site within LFA-1 [81], suggesting a novel mechanism of action, which is unrelated to statin-mediated inhibition of HMG-CoA reductase as found to contribute to the anti-inflammatory potential of statins. Another anti-inflammatory action demonstrated for several statins is the reduction of the production of pro-inflammatory cytokines. In one study [82] fluvastatin and pravastatin were found to significantly inhibit angiotensin II-induced secretion of interleukin (IL)-6 in cultured human smooth muscle cells, whereas in another study [83] fluvastatin and simvastatin but not pravastatin reduced production of IL-6 and IL-1 beta in HUVECs. Moreover, it was found that the reduction of the expression of several pro- inflammatory mediators, such as IL-6 and MCP-1, exerted by lovastatin in an in vivo model of local acute inflammation is dependent on the impairment of the biosynthesis of non-sterol derivatives arising from the mevalonate pathway [84]. The observation that similar dose of atorvastatin and pravastatin produced a similar reduction of MCP-1 expression in different arterial vascular beds despite significant differences in their plasma lipid-lowering potential in hypercholesterolemic pigs further supports the existence of such lipid-independent anti-inflammatory effects of statins in vivo [85]. Atorvastatin, lovastatin, and pravastatin were shown to suppress T-cell responses, repressing interferon (IFN)-gamma-induced expression of major histocompatibility complex class II (MHCII) molecules on various cell types [86]. This effect, suggesting an immunomodulatory role for statins, was limited to antigen-presenting cells requiring co-stimulation by IFN-gamma, whereas antigen-presenting cells constitutively expressing MHC-II, such as B cells and dendritic cells, were not affected. Further evidence for an immunomodulatory role for statins stems from a study demonstrating that pravastatin may exert a synergistic effect with cyclosporine regarding the inhibition of cytotoxic T-cell activity in vitro [87].

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Statins’ anti-inflammatory qualities may also contribute to stability of the vulnerable plaques. Simvastatin was demonstrated to dose-dependently inhibit migration and MMP-9 secretion of the human monocytic cell line THP-1, an effect that was reversed by the simultaneous addition of mevalonate and its derivates, farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP) [88]. Also, fluvastatin and simvastatin decrease secretion of MMP-9 by human and mouse macrophages in culture by their inhibitory action on the mevalonate pathway [89]. These statins’ inhibiting actions on MMPs may lead to prevention of plaque rupture and suggest a potential therapeutic paradigm of acute coronary syndrome. Statins’ anti-inflammatory actions are also demonstrated in a large clinical trial by the measurement of CRP. The MIRACL trial [12], evaluated the effects of aggressive lipid lowering by 80 mg/day of atorvastatin within 24–96 h from the onset in 3,086 ACS patients. In this trial, CRP was measured as a surrogate marker and the result indicated that CRP was 34% lower with atorvastatin than with placebo. Effects on CRP levels in humans are investigated for various statins. Jialal et al. [90] tested the effects of three statins, simvastatin (20 mg/day), pravastatin (40 mg/day), and atorvastatin (10 mg/day), on levels of CRP in a randomized, double-blind, crossover trial of 22 patients with combined hyperlipidemia. The three statins similarly reduced CRP levels without significant effects on either plasma interleukin-6 or interleukin-6 soluble receptor levels. There was no relationship between reductions in CRP and LDL cholesterol. Figure 10.4 shows the case of a 65-year-old male patient with unstable angina. He was admitted to our hospital after 3 non-onset angina attacks. After admission, his angina attack repeatedly appeared despite the intensive treatment with heparin, aspirin, and nitrates. As serum LDL cholesterol showed high level as 152 mg/dL, atorvastatin 10 mg/dL was prescribed, and then his angina disappeared. The LDL cholesterol level decreased to 124 mg/dL. During his course, CRP level was monitored. The CRP level showed over 0.5 mg/dL at the beginning but gradually decreased under 0.1 mg/dL, in association with stabilization of the symptom. On the seventh hospital day, coronary angiography showed a stenotic lesion in the right coronary artery, and an intravascular ultrasound imaging showed a plaque with lipid core in this lesion (Fig. 10.4). As a result, this patient could be avoided to undergo PCI because ischemic evidence was absent symptomatically or in exercise stress electrocardiography. In this patient, atorvastatin’s pleiotropic effect, especially anti-inflammatory effect, in addition to lipid lowering might result in plaque stabilization and favorable outcome.

Fig. 10.4 Coronary angiography showed a stenotic lesion in right coronary artery, and an intravascular MR imaging showed a plaque with lipid core in this lesion (right, arrow) [50]

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4.6 Oxidative Stress in Atherogenesis Increasing numbers of studies have demonstrated that oxidative stress, i.e., dysregulation of cellular redox state, plays a pivotal role in the pathogenesis of atherosclerosis, especially vascular endothelial dysfunction [91]. Superoxide anion is formed by univalent reduction of molecular oxygen. Although several enzymes are involved in the generation of superoxide anion, including xanthine oxidase, NADH/NADPH oxidase, lipoxygenase, and nitric oxide synthase, one of the largest factories producing superoxide anion in vivo is the mitochondrion [92]. Via spontaneous or enzymatically catalyzed dismutation, superoxide anion is reduced to hydrogen peroxide. Transition metal, such as iron or copper, -catalyzed interaction with hydrogen peroxide produces highly toxic hydroxyl radicals. Reactive oxygen species (ROS) have detrimental effects on vascular function through several mechanisms. First, as their direct effect, reactive oxygen species, especially hydroxyl radicals, injure cell membrane and nuclei. Second, by interacting with endogenous vasoactive mediators formed in endothelial cells, reactive oxygen species modulate vasomotion and atherogenic process. Third, reactive oxygen species peroxide lipid components leading to formation of oxidized LDL, which is one of the key mediators of atherosclerosis [93]. Whereas native LDL does not cause cholesterol ester accumulation in macrophages, modified LDL by oxidation does [94]. Oxidized LDL has also been implicated in other mechanisms potentially involved in the development of atherosclerosis, i.e., cytotoxic or chemotactic actions on monocytes and inhibition of macrophage motility [95]. There are a number of clinical markers suggested to assess oxidative stress status (Table 10.2). Thiobarbituric acid reactive substance (TBARS) is the lipid peroxide derived from unsaturated fatty acids. Isoprostanes such as 8-iso-prostaglandin (PG) F2 alpha or 8-epi-PGF2 alpha are compounds formed in vivo by nonenzymatic free radical-catalyzed peroxidation of arachidonic acid. TBARS and isoprostanes are both markers for nonspecific lipid peroxidation. Elevated urinary 8-iso-PGF2 alpha levels are found in patients with elevated postprandial remnant lipoproteins or in smokers, even in passive smokers. 8-Hydroxy-2 -deoxyguanosine (8-OHdG) is a degradation product of DNA oxidation and its measurement provides information on various degrees of oxidative stress in the DNA level. Serum 8-OHdG levels are elevated in smokers and the smoking abstension reduced the levels [96]. Among various lipids peroxidized, oxidatively modified LDL directly involves in the atherosclerosis process. Thus, the direct measurement of oxidized LDL (Ox-LDL) provides important information regarding oxidative stress in atherosclerosis. On the other hand, specific immunological epitopes expressed on Ox-LDL were found in atherosclerotic lesions both in animals with experimental atherosclerosis and in humans. Expression of such epitopes in vitro can be generated by various procedures, including incubation with endothelial Table 10.2 Oxidative stress markers are shown active in atherogenesis

Thiobarbituric acid reactive substance (TBARS) Oxidized low-density lipoprotein (LDL) Malondialdehyde-modified LDL (MDA-LDL) Oxidized LDL receptor (LOX-1) 8-Hydroxy-2 -deoxyguanosine (8-OHdG) 8-Iso-prostaglandin F2alpha Antioxidized LDL antibody Oxidized α1-antitrypsin Tetrahydrobiopterin (BH4) Asymmetric dimethylarginine (ADMA)

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cells and macrophages, oxidation in the presence of copper ions, and treatment with malondialdehyde [97]. Ox-LDL can interact with scavenger receptors of monocyte-derived macrophages. It is suggested that these interactions can induce formation of anti-Ox-LDL. Therefore, anti-OxLDL can be considered to be a marker of LDL oxidation at the level of tissues or cells. Since anti-Ox-LDL titer in serum of the patients with hypercholesterolemia is not correlated with LDL cholesterol level but with 8-OHdG, the anti-Ox-LDL also seems to be a marker of oxidative DNA damage in dyslipidemic patients [98]. The titer of anti-Ox-LDL is associated with shortterm lesion progression or regression of atherosclerotic coronary artery disease [99] as well as peripheral artery disease [100, 101] or higher in patients with ACS than in patients with stable angina [102].

4.7 Antioxidative Effects of Statins Some kinds of statins have been considered to have antioxidative effects. Wilson et al. [103] demonstrated that simvastatin decreased plasma levels of 8-epi-PGF2 alpha and malondialdehyde, both markers of which indicate increased oxidative stress in vivo, in a model of experimental hypercholesterolemia, independently of lipid-lowering effect. In addition, atorvastatin, pravastatin, and cerivastatin may inhibit the NADPH oxidase-dependent superoxide anion formation in endothelial cells by preventing isoprenylation of the small GTP-binding protein Rac, which is essential for NADPH activation [104–106]. Atorvastatin increases catalase expression both in rat VSMCs in vitro and in normocholesterolemic spontaneously hypertensive rats in vivo [106]. A dose-dependent inhibitory effect on LDL oxidation was demonstrated for simvastatin [107]. Similarly, chronic administration of fluvastatin or lovastatin in hypercholesterolemic patients was shown to reduce the ex vivo susceptibility of LDL to oxidation, which was thought to be partly mediated by direct binding of the drugs to the phospholipids fraction of LDL [108]. Among various statins, fluvastatin is thought to be the most powerful antioxidant. Differently from other statins, fluvastatin has lipid-independent strong radical scavenging action and reduces superoxide anion formation both in vitro and in vivo [109–111]. Fluvastatin has an indole ring in its structure, which is believed to be important for manifestation of this action. We demonstrated that fluvastatin 20 mg/day reduced anti-Ox-LDL titer and serum 8-OHdG levels in hypercholesterolemic patients (Fig. 10.5) and the reduction of anti-Ox-LDL titer by fluvastatin was associated with that of serum 8-OHdG levels [112]. In addition, we also demonstrated that antioxidative effect of fluvastatin attenuated nitrate tolerance, which is considered in part to occur in association with oxidative stress, in patients with coronary artery disease and dyslipidemia who had been receiving organic nitrates over a long period [113]. It is noteworthy that because NO and superoxide anion interact chemically to neutralize each other, an increase in the local concentration of superoxide anion is associated with a decrease in the concentration of biologically active NO [104]. Thus, the antioxidant properties of statins may potentiate their effect on NO bioavailability.

4.8 Effects of Statins on Platelets Activation and Thrombogenesis Platelet activation and thrombogenesis in the process of plaque disruption is a key event in acute coronary syndrome. Since the endothelial cells of the coronary plaques are eroded or

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Fig. 10.5 Antioxidative effect of fluvastatin. Fluvastatin decreased anti-Ox-LDL titer and 8-OHdG levels in hypercholesterolemic patients. anti-Ox-LDL = antibody against oxidized low-density lipoprotein; 8-OHdG = 8-hydroxy-2 -deoxyguanosine [125]

denuded, blood is directly exposed to procoagulant elements on subendothelial tissues, triggering the coagulation cascade, platelet aggregation, and fibrin deposition, which may lead to occlusive or semiocclusive thrombus formation. This thrombogenic process determines clinical outcome, which may vary from event-free to myocardial infarction or even sudden death. Statins inhibit platelet aggregation in part by lipid lowering because changes in the cholesterol content of platelet membranes alter membrane fluidity [114]. Statins’ effects on endothelial NO production may also inhibit platelet aggregation independently of lipid lowering. Atorvastatin has been shown to upregulate eNOs in platelets and to decrease platelet activation in vivo without lowering cholesterol levels [115]. Moreover, statins’ effect on decreasing isoprostanes, such as 8-iso-PGF2 alpha or 8-epi-PGF2 alpha, which are potent platelet activators as well as oxidative stress markers, may also lead to inhibiting platelet aggregation [116]. In addition to antiplatelet actions, statins may also enhance antithrombic activities mediated by inhibiting coagulation system. For example, simvastatin, fluvastatin, and cerivastatin were shown to reduce expression of tissue factor (TF) in cultured human monocytes/macrophages. This effect was reversed by co-incubation with mevalonate or all-trans-geranylgeraniol but not cholesterol, indicating its dependence on statin-induced reduction of intracellular GGPP biosynthesis independently of lipid lowering [117]. Therefore, statins may shift the fibrinolytic balance within the vessel wall toward increased fibrinolytic activity. Simvastatin also inhibits the expression of plasminogen activator inhibitor-1 (PAI-1) from human VSMCs and

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endothelial cells, while it increases the expression of tissue-type plasminogen activator (tPA) from endothelial cells [118]. The upregulation of the fibrinolytic potential of endothelial cells is demonstrated in a study showing that lovastatin increases t-PA activity and decreases PAI-1 activity in a rat endothelial cell line in a time- and concentration-dependent manner. In this study, the lovastatin-induced modification of the endothelial fibrinolytic activity was found to be caused by inhibition of Rho geranylgeranylation and disruption of cellular actin filaments [119]. The antiplatelet, anticoagulatory, and pro-fibrinolytic effects of statins observed in vitro suggest an important role for statins in the therapy of acute coronary syndrome associated with an increased thrombogenesis.

4.9 Effects of Statins on Neovascularization Angiogenesis is the formation of new blood vessels by germination from the preexisting vessels, which is a favorable mechanism to restore the blood flow in ischemic diseases such as coronary artery disease and peripheral artery occlusive diseases. On the other hand, excessive vascularization is also considered to be associated with atherosclerotic plaque formation [120]. Angiogenesis shows very complex process that depends on the interaction of both pro- and anti-angiogenic molecules to form functional vessels [121]. Statins are considered to have both pro-and anti-angiogenic actions. Statins’ anti-angiogenic actions are represented by inhibition of endothelial cell migration, possibly through inhibiting Rho geranylgeranylation [122]. Simvastatin prevents vasa vasorum neovascularization, indicating the inhibitory effects of statins on angiogenesis [123], but this seems to act to inhibit atherosclerotic plaque progression. Vascular endothelial growth factor (VEGF) is one of the key growth factors involved in angiogenesis [124]. Statins’ actions on VEGF are controversial. Fluvastatin results in a significant reduction of VEGF levels that are elevated in patients with hyperlipidemia in both lipid-dependent and lipid-independent fashions [125]. Since elevated level of VEGF is associated with enhanced atherosclerotic plaque progression and increased plaque macrophage, the VEGF reduction by fluvastatin possibly leads to the prevention of plaque progression. Conversely, statins are also reported to enhance VEGF secretion from cultured VSMCs, leading to proangiogenic actions [126]. On the other hand, atorvastatin therapy is demonstrated to lead to an early increase in the number and the functional activity of circulating endothelial progenitor cells (EPCs) in patients with stable coronary artery disease [127]. EPCs are bone marrow-derived cells that home to neovascularization sites and differentiate into endothelial cells in situ. Recently, statins have been shown to induce EPC mobilization from the bone marrow and EPC differentiation into endothelial cells via the serine/threonine kinase Akt signaling pathway [128, 129]. Since enhancement of eNOS and NO production by activating the Akt in endothelial cells is associated with the induction of angiogenesis, statins may also promote angiogenesis through NO production. Although statins have the potential to both inhibit and promote neovascularization, both inhibiting and promoting actions seem to protect ischemia. A different angiogenic response to statins may depend on the difference of vascular beds for their affected sites and different pathological state.

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4.10 Effects of Statins on Myocardial Protection Early and effective reperfusion is a key factor minimizing myocardial injury after an acute coronary event. However, reperfusion itself may promote an inflammatory response and enhance myocardial injury [130, 131]. During reperfusion, activated leukocytes infiltrate the myocardium, releasing proteases, pro-inflammatory cytokines, and oxygen-derived free radicals, thereby increasing vascular endothelium and cardiomyocyte damage [132, 133]. In an animal model, pretreatment of statins is shown to reduce reperfusion injury and ventricular dysfunction. In addition, statin-treated rats showed lower adherence of neutrophils to vascular endothelium and lower infiltration in the ischemic myocardium. This attenuation in neutrophil–endothelial interaction seems to be the consequence of a reduction in the expression of adhesion molecules from endothelial cells and an inhibition of neutrophil activation after statin treatment. The myocardial protective effects of statins are also detectable in the absence of neutrophils. The addition of the active form of simvastatin to the perfusion medium of isolated rat hearts reduces ischemia/reperfusion injury [134]. In addition, statin treatment partially prevents endothelial NO synthase reduction induced by ischemia/reperfusion injury; this cardioprotective effect of statins is completely abolished by simultaneous treatment with an NOS inhibitor. These findings in animal models suggest that acute treatment with statins could potentially attenuate ischemia/reperfusion injury in a lipidindependent mechanism. Despite the relevance of these findings, further studies are awaited to clarify the lipid-independent mechanism for cardioprotection. Myocardial hypertrophy, fibrosis, and left ventricular remodeling after myocardial infarction are key determinants of deterioration of long-term prognosis. Statins inhibit intracellular signaling pathways involved in cardiac hypertrophy and fibrosis including downregulation of the activity of small GTP-binding proteins of the Rho family [135, 136]. In addition, statins may modulate the remodeling process. Recently, it has been demonstrated that statin therapy improves cardiac function and symptoms in patients even with non-ischemic cardiomyopathy [137]. Myocardial MMPs are increased during the development of dilated cardiomyopathy. Since statins suppress growth of macrophages expressing MMPs, it is possible that statins suppress ventricular remodeling through inhibitory effects on MMPs in addition to the reduction of inflammatory cytokines [138].

5 Guidelines to Physician, Nurses, and Health The following section is a guide to medical and healthcare workers who are involved in cardiovascular care and cardioprevention actively. The awareness of both dietary fat intake along with side effects of statins and their safe use is important while practicing them to perform lipid lowering in prospective patient population. The lipid dysfunction includes mainly hypercholesterolemia, hypertriglyceridemia, low HDL cholesterol, and apolipoprotein changes. The target lipid levels (LDL-C <2.5 mmol/L, <3.5 mmol/L, <4.5 mmol/L, and total cholesterol/HDL-C ratio <6.0, <5.0, <4.0) indicate the high risk, moderate risk and low risk of dyslipidemia. The triglycerides >1.7 mmol/L with HDL-C <1.0-1.3 mmol/L indicate metabolic syndrome. Dietary fat intake to improve serum lipid profile includes mainly intake of unsaturated omega3 and omega-6 fatty acids, antioxidants, L-arginine, and folic acid. Of specific mention,

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eicosapentaenoic and docosahexaenoic fatty acids and HMG-CoA reductase inhibitors have shown promise in lipid lowering in low risk and moderate risk catagories. Whole foods such as garlic, spirulina, fenugreek, ginkgo, soy, and genistein have been on nonprescription counters as cardioprotective food supplements. The high risk category (LDL-C <2.5 mmol/L and TC/HDL-C ratio <4.0) needs immediate attention for lipid lowering medication preferably statins. Other choices are BSA, fibrates (benzo-, phenol-), gemfibrozil (400-1200 mg/day) and niacin (1-3 gm). However, health workers need to be aware of the limits of beneficial effects of these supplements and risk of persistent uncontrolled hyperlipidemia. On the other hand, statins have gained popularity in acute hyperlipidemia and acute cardiovascular diseases to combat within time. However, statin therapy is free from side effects and it needs a right prescription www.cmaj.ca/cgi/content/full/169/9/921/DC1/ and its safe use [1].

5.1 Safe Use of Statins Statins are the number one family of drugs for the treatment of hyperlipidemia. They act via inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), the rate-limiting enzyme of cholesterol biosynthesis inducing LDL receptor upregulation and consequently enhancing cholesterol clearance from blood. The statins have been proven remarkably safe in clinical routine (Table 10.3). In general, statins improve patient survival and reduce vascular events with only minimal toxicity, most likely via lipid and non-lipid actions. Statins showed side effects and wide range of non-lipid (pleiotropic) effects, most of which are still not yet well understood. In general, this family of compounds is well tolerated with mild adverse events. The incidence of more serious side effects was reported to range between 1 and 7% [139]. A review [140] of the available statins in the UK (pravastatin, simvastatin, atorvastatin, and rosuvastatin) revealed a comparable rate of adverse events for the four compounds resulting in drug withdrawal of about 3% (2.5–3.2). Wong et al. [78] confirmed the occurrence of myopathy with normal CK in association with statin therapy in muscle biopsy samples. Fatal rhabdomyolysis was extremely rare (31 cases after 9.8 million prescriptions) as reported in the United States [104]. Meanwhile, after withdrawal of cerivastatin and due to more careful prescriptions, this figure improved. Elevation of CK to more than 10 times of normal occurs in 1 out of 10,000 patients/year on statin use only. While the incidence of serious muscle problems is very low, the rate of mild side effects has been heavily underestimated so far.

Table 10.3 Comparison of different statins on blood lipid lowering and endothelium dysfunction Efficacy on Recommended Statins Lipid lowering Endothelium daily dose (mg) Reference Atorvastatin L A 10–80 [11], [144] Fluvastatin A 20–80 [13] Pravastatin L E A 10–40 [25] Rosuvastatin A 10–40 [140], [146] Simvastatin L E A 10–80 [23], [24] L: Lipid lowering or LDL oxidation resistance; A: Smooth cell proliferation; E: Endothelial dilatation. The arrows indicate increase by; ↑ decrease by; ↓ and no change by ↔.

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5.2 How to Remain Safe Statins help in prevention of vascular disease. Care is needed by physicians on safe selection of individual, drug dosage, and monitoring. In order to minimize adverse events five golden rules of statin therapy [1, 141] for patients have been reported: 1. Start always with the lowest available dose for at least 4 weeks. 2. Avoid combination with fibrates. 3. At the onset of muscular symptoms, stop statin treatment immediately even before contacting your physician. 4. When taking a new drug ask your physician whether this combination is compatible. If this is not possible and the new drug is important, the statin treatment should be discontinued until clarification. 5. If (macrolid-)antibiotics or antimycotics have to be taken, statin therapy has to be discontinued for the entire duration of the antibiotic/antimycotic treatment. 6. Keep your lipid profile low in normal range and restrict dietary fat intake to <10% energy fat content.

5.3 Adverse Events of Statin Therapy 1. Liver Function. Studies in humans revealed hepatotoxicity, mainly minor elevation of alanine aminotransferase (ALT). ALT levels more than three times the upper normal level were reported at 2.6% at low (20 mg/d) and 5.0% at high (80 mg/d) doses of lovastatin [142]. The recent study “Treating to New Targets” (TNT) showed an increase in transaminases after atorvastatin 10 mg dose of 0.2% and 80 mg dose of 1.2%, eventually indicating dose dependency. There was no difference in liver enzyme elevations when patients were grouped according to LDL estimated (PROVE-IT). Acute hepatic failure (<1 in 1 million patient treatment years) was close to the background rate. Discontinuation of statin therapy resulted in rapid normalization of hepatic enzymes. Interestingly, for unknown reasons, in some patients enzymes may normalize despite ongoing therapy at unchanged statin dose. In combination therapy with fenofibrate ALT increase more than three times the upper limit of normal was same as without fibrate therapy [143]. 2. Renal Function. Statin-induced effect on hyperlipidemia is related to progression of renal disease. Statins have been reported to partially restore renal function. Atorvastatin improved creatinine clearance as well as microalbuminuria (MAU) in hypercholesterolemic patients [144]. The maximum benefit was achieved at 3 months but reached a plateau thereafter. At high doses of simvastatin ≥80 mg, atorvastatin ≥80 mg, rosuvastatin ≥40 mg, MAU exhibited a significant increase. The basis of this J-shaped response was unknown. A change in endocytosis has been claimed for the tubular proteinemia [145]. The mild proteinuria occurring on all statins was generally transient and reversible and not associated with deterioration in renal function [146]. It makes it uncertain to continue statins in atherosclerosis. 3. Erectile Dysfunction. Dyslipidemia-induced development and progression of atherosclerotic vascular disease is linked with erectile dysfunction (ED) [147–149]. Statins improved both

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lipid lowering and ED [150]. The earlier view was that the intake of hypolipidemic drugs is associated with an increased rate of ED. A literature review in 2002 revealed the suggestion to regulatory agencies that statins cause ED [82]. Spontaneous reporting severely underestimates ED. Using a standardized validated questionnaire [151], a clear statin dose-dependent increase in ED was evident on atorvastatin at 20 mg and even more at a 40-mg daily dose [152]. The pathomechanism is not understood. 4. Muscular Complaints. In middle-aged people bone, joint, and muscle symptoms have been reported in clinical trials of statins. Muscular complaints are quite common among patients on statin therapy, in the great majority with normal creatine kinase enzyme levels. Usually clinical symptoms disappear almost immediately after statin withdrawal. No significant difference for the statins currently in use has been shown so far concerning prevalence or any special type of muscular side effects. Patients may tolerate one statin, but not another one, for unknown reasons [153]. Therefore, switching should be considered first rather than discontinuing [154]. Only very rarely patients do not tolerate any of the available statins. Nowadays, muscular adverse events due to statins usually are classified into the following: 1. Myalgia – muscle pains; CK normal or elevated 2. Myopathy – muscle pains plus CK elevation; positive EMG 3. Myositis – inflammatory component; CK – normal or elevated; CRP – normal or elevated 4. Rhabdomyolysis – muscle destruction, myoglobin release, muscle pain; dose dependent 5. Muscle ache-like symptoms – usually appearing immediately after exercise, rather promptly disappearing 6. Muscle cramp-like symptoms – the onset in the majority of patients appears on the day after exercise 7. Muscle burning sensation – mainly after exercise, onset immediately 8. Flu-like symptoms – with acute heavy muscle pain [155] and oppressive pain are the most severe and acute forms. They are accompanied by an increase in inflammatory markers (CRP, interleukin-6, etc.), fever, and often arthralgia 9. Muscle weakness – tonometrically proven, usually appears rather late, even months or years after initiation of statin therapy 10. Myositis migrans – muscle symptoms, mainly ache like moving over certain muscles in a characteristic individual sequence [156]. CK enzyme is always increased. It may cause renal failure. All the described events are reversible if diagnosed in time (e.g., rhabdomyolysis). Up to a dose of 0.4 mg, CK increase on cerivastatin does not appear to be different from other statins. The majority of cases of rhabdomyolysis with cerivastatin were seen at a dose of 0.8 mg, particularly in combination with fibrates (gemfibrozil). Statin was reported to cause chronic low-grade myopathy [157] and statin-associated myopathy with cramps and 59% weakness, rhabdomyolysis patients [158]. Statin-associated muscular problems are considered severe side effects of this class of drugs [159, 160]. There is no doubt that in daily clinical routine the prevalence of muscular complaints is substantially higher. Mechanisms: Rate of myotoxicity due to statins depends whether statins metabolize by cytochrome system or lipophilic statins due to the higher penetration of the myocyte [161]. It has dose dependency and various forms of myotoxicity.

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The interruption of glycoprotein synthesis in the myocyte membrane [162], chloride channel activation deficiency [161], impaired sodium– potassium channel function [163], increased intracellular calcium concentration [164], and altered membrane fluidity due to reduced cholesterol [165] have been speculated for muscle toxicity by statins. Statin-induced apoptosis mediated via depletion of geranylgeranylated proteins may be the cause of substantial apoptosis. The statinassociated muscle problems might result from impaired fatty acid oxidation [166] and prevalence of hypertriglyceridemia [167]. It has been stated that myopathy in association with statins is dose related concerning CK increase. In atorvastatin and rosuvastatin, the dose relationship is unclear. Muscle biopsies identified the mitochondrial dysfunction. The IMPOSTER trial, a doubleblind, randomized, crossover designed study showed the statin therapy patients with muscle symptoms and signs of mitochondrial dysfunction. The role of exercise: If regular exercise is performed, these symptoms on statins become more prevalent and severe. Top athletes have been shown to tolerate only rarely statins [168]. Lipid Oxidation and oxidative injury: LDL cholesterol is major player in oxidation. Cholesterol oxidation to different products is other factor. Cholesterol esters, bile salts, vitamin D and hormones are main products. (a) LDL oxidation: In fact, most data have shown a decreased susceptibility of LDL to oxidation in vitro as well as ex vivo [169–171] using a variety of different tests. One of the few studies showing increased LDL susceptibility to oxidation during statin administration found only partial restoration of antioxidant capacity of LDL when CoQ10 was supplemented [172]. (b) Isoprostanes: Oxidation injury is one major concern in patients on statins. The isoprostane 8-epi-PGF2 alpha is a reliable marker for in vivo oxidation injury [173]. The statins are associated with a decrease in oxidation injury (decrease in isoprostane 8-epi-PGF2 alpha [174]) and reduced oxidizability of lipoproteins (LDL, HDL, VLDL). A decrease in 8-epi-PGF2 alpha has been shown for various statins [174, 175]. Rhabdomyolysis has been shown to be linked to increased lipid peroxidation [165]. Oxidation injury at the mitochondrial level may be the underlying biomechanism. 5. Arthritis. Pleiotropic actions of statins may interfere with acute inflammatory processes [176]. Statins, atorvastatins, have been found to be of clinical benefit in rheumatoid arthritis patients in acute phase [177–179]. Some patients may develop arthritis symptoms affecting mainly small finger joints, and symptoms disappear upon withdrawal of statins. Sometimes, arthralgia is associated with the flu-like response as a secondary event. Controlled, prospective studies to assess the effect of statins on the disease activity in chronic inflammatory disease and rheumatoid arthritis are not available. 6. Lupus-Like Syndrome. Statins may induce a systemic autoimmune reaction. The statininduced lupus-like syndrome was associated with skin eruption, antinuclear antibodies, and severe autoimmune hepatitis with atorvastatin [180]. Simvastatin-induced diffuse interstitial pneumonia [181] and lupus-like syndrome with interstitial lung disorders have been reported [181, 182]. 7. Tendinopathy. Tendinopathy in patients receiving statin therapy was reported (two Achilles, one tibialis anterior, one hand), two of them being on simvastatin and two on atorvastatin

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[183]. Prospective sonographic monitoring of the Achilles tendon from initiation of statin treatment could help to clarify this issue. 8. Polyneuropathy. Statin use and polyneuropathy suggested that a risk may exist, prevalence and intensity being low and being small as compared to the benefits [32]. Guillain–Barre syndrome by statin therapy was reported [184]. The symptoms disappeared within 1 year after statin withdrawal [185]. A higher incidence in peripheral neuropathy (1/14,000 on statins a year) effecting thick and thin nerve fibers was reported dependent on statin dose, type of statin, duration of treatment, and pathomechanism. Statin-associated exacerbation of myasthenia was reported [186]. Severe central nervous system anomalies have been reported in first pregnancy in trimester statin exposure [185]. 9. Cognitive Function. Some statins were reviewed on statin-associated memory loss, depression, sleeping disorders and global amnesia supported that claim [186]. In a double-blind, randomized, placebo- controlled study (n = 209; duration 6 months) with lovastatin, detrimental effects on cognitive performance (attention, working memory, mental efficiency) were described [187]. A retrospective cohort study found that statins are ameliorating cognitive decline in older people [188]. Impaired cognitive function, dementia, or depression may result in a very low adherence to medication regimen [189, 190]. 10. Depression. The long-term statin therapy and depression were associated with a lower risk of abnormal depression scores (OR 0.63), anxiety (OR 0.69), and hostility (OR 0.77) [178, 191].

6 Therapeutic Intervention 6.1 Coenzyme Q10 CoQ10 (ubiquinone) is an important redox component [192]. It is reported that CoQ10 is lowered during lovastatin and pravastatin therapy in a dose-dependent manner [193–196]. Ubiquinone is used by mitochondria for electron transport. In statin-induced myopathy, the resulting defective ATP synthesis at the mitochondrial level might contribute eventually to cellular instability and decreased CoQ10 between 10 and 15% lower accompanied with LDL decrease of more than 20% at lowest available statin dose used. Vitamin E and CoQ10, important antioxidants for LDL [197, 198], are carried among others (VLDL, HDL) by LDL lipoprotein. The LDL is lowered by statin therapy similar to CoQ10 and vitamin E. The statins increase the CoQ10/LDL ratio and vitamin E/LDL ratio in almost all patients. The lovastatin administration enhanced the ubiquinol oxidation [73]. Ubiquinone supplementation also was not associated with a significant improvement in antioxidant capacity [74]. Although no data are available to support this conclusion, the ACCC/AHA NHLBI clinical advisory claims a coenzyme Q10 deficiency as a possible mechanism [199].

6.2 L-Carnitine L -carnitine might exert a favorable action on lovastatin-induced myotoxicity [7, 112]. Preliminary data on carnitine administration in patients for muscular side effects of various

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statins revealed no benefit on either symptoms of elevated CK or elevation of 8-epi-PGF2 alpha. No benefit has been proven on any of the known statin-induced adverse events. Statins have been in use since decades and recommended by the US Statin Advisory. The main complaint is toxicity of muscle. The creatine kinase enzyme elevated levels over normal enzyme levels exclude the muscle toxicity of statins but it is not the final answer. Muscle toxicity may occur despite normal CK and patients with CK elevation may not show symptoms. A prospective blinded study focused to assess the exact rate of adverse events with even only one statin would require an extremely high number of patients (above 10,000) because of the difficulty to differentiate mild side effects from the background. Otherwise, adverse event rate might be underestimated again. The first attempt in this direction with about 1,000 patients is currently performed [200]. The serum aldolase to identify CK-negative statin myopathy [172] cannot be proven. Another parameter myoglobin does not identify patients with either symptoms and/or CK elevation. In nutshell, statins have good efficacy in lipid lowering in hypercholesterolemia to keep control on LDL-C within recommended limits. On other side, the statins have shown noticeable side effects as a public concern. It has become necessary to be aware of its pros and cons before patient gets worse after statin overload. Our attempt in this chapter is to bring the both issues of dyslipidemia control by statins and alarming side effects in case of statin therapy. Such side effects can be minimized or avoided if statins are used carefully under strict guidelines as recommended by national bodies under supervision of regulatory bodies at federal and state level. In this direction, diagnosis of dyslipidemia, followup of lipid screening with intermittent monitoring of dietary fat intake, lipid profile and therapeutic intervention under supervision are necessary recommendations.

7 Future Aspects of Lipid Lowering Versus Statin Therapy in Carotid Artery Disease Nowadays we can see the success of low-fat dietary lifestyle from a large number of clinical trials. Statins have become established drugs for preventing coronary events. Considering their favorable direct effects on blood vessels independently of lipid-lowering effects, opinion before year 2008 was that statins should be aggressively applied for treatment of coronary artery disease even in patients without dyslipidemia. In year 2008, several clinical trials ENHANCE, JUPITER, SEAS and GISSI-HF did not support the benefits of drugs to decrease carotid-intima-media thickness and cardiac prevention [5]. These studies emphasized the measurement of clinical endpoints such as cardiac death and myocardial infarction. The current view is that among multiple actions, the most unique one may be stabilization of vulnerable plaques. Since statins have recently been recognized to have acute pharmacological actions, we should start to prescribe them soon after dyslipidemia in patients with acute coronary syndrome is established, prior to PCI, if possible, to improve long-term prognosis after PCI. Statins should also be used in patients with effort angina to target inhibition of coronary artery lesion progression or to expect the improvement of nitrate tolerance. Furthermore, statins’ improvement of vascular endothelial function or vascular smooth muscle relaxation make them a possible drug in the application for vasospastic angina. Statins’ inhibition of SMCs and anti-inflammatory actions may prevent post-PCI restenosis, and statincoating stents are now under investigation. However, the most hopeful end point may be primary

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prevention of coronary artery disease onset by the use of statins in patients independent of their cholesterol levels. To apply statin therapies for these settings, we must take several efforts. First, we must establish and standardize diagnostic methods for clinically detecting “cardiovascular incapability” to assess the effectiveness of statin therapies. The degree of “cardiovascular incapability” will be a surrogate end point to evaluate the vascular pleiotropic effects of statins. Next, we must re-evaluate pleiotropic effects of each statin to know how to use it properly. In addition, development of new statins that have less unfavorable adverse effects such as rhabdomyolysis and renal dysfunction would be needed so that we can use them more readily. In future, statin therapy would be more extensively applied even in normolipidemic patients if they have conventional risk factors such as hypertension, diabetes mellitus, or others. Furthermore, we may need to use statins to intervene in earlier stage risk factors such as postprandial hyperlipidemia or hyperglycemia, insulin-resistant state, masked hypertension, or metabolic syndrome to further reduce mortality or morbidity of coronary artery disease. Acknowledgements The authors are thankful to Dr. Soonjo Kwon, Ph.D., at Utah State University to suggest new ideas on endothelial functions in carotid artery and manuscript corrections made in time.

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Chapter 11

Recent Cholesterol-Lowering Drug Trials: New Data, New Questions Michel de Lorgeril

Key Points • The cholesterol-lowering drug trials recently published were either negative (ENHANCE, SEAS, GISSI-HF) or obviously biased and therefore not credible (JUPITER). • New data strongly suggest that the results of previous, highly positive trials with statins in the secondary prevention of coronary heart disease published between 1994 and 2004 and that were used to issue guidelines for medical practitioners should be reviewed carefully and considered somewhat suspect. Keywords Cholesterol-lowering drugs · Heart disease · Cholesterol · Drug trials

1 Introduction The year 2008 has been very disappointing for cholesterol experts and the cholesterol drug industry. Today, marketing is primarily based on the publication of results of randomized trials. However, the year 2008 has been a sad year because trials results obviously do not support the theory according to which cholesterol-lowering results in significant benefits in the prevention of coronary heart disease (CHD), including the so-called the lower the better theory. The results of the ENHANCE study conducted in patients with familial hypercholesterolemia [1] were published in March 2008—and were disappointing. In ENHANCE, an association of ezetimibe, a cholesterol-lowering drug acting by decreasing the absorption of cholesterol in the digestive tract, and simvastin, a statin that acts by decreasing the endogenous synthesis of cholesterol, was tested. Actually, the association of the two drugs in the same patient results in a drastic reduction of cholesterol levels, in particular LDL levels. The test was not performed by measuring hard clinical endpoints such as cardiac death or myocardial infarction, but by repeated

M. de Lorgeril () Laboratoire TIMC-IMAG, UMR 5525, Cœur and Nutrition, Faculté de Médecine, Université Joseph Fourier – Grenoble 1, CNRS, Grenoble, France; Domaine de la Merci, 38706 La Tronche, France e-mail: [email protected] F. De Meester et al. (eds.), Modern Dietary Fat Intakes in Disease Promotion, Nutrition and Health, DOI 10.1007/978-1-60327-571-2_11, © Springer Science+Business Media, LLC 2010

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measurements of carotid intima–media thickness (IMT), a supposed marker of atherosclerosis progress. Unexpectedly, the combination of the two drugs failed to provide incremental benefits over simvastatin alone, despite a drastic reduction of cholesterol [1]. In addition, both treatments did not result in significant effects on the primary endpoints: not only did the change in IMT not differ over time, from baseline to 24 months, between the two study groups, but there was a slight increase in IMT in both groups: at 2 years, the estimates were of +0.0095 ± 0.0040 mm in the simvastatin-only group (P = 0.02 vs. baseline) and +0.0121 ± 0.0038 mm in the combined therapy group (P < 0.01 vs. baseline), which suggests that the lower the cholesterol, the greater was the increase in IMT [1]. These surprising and very disappointing data might explain why the results of ENHANCE were hidden from the medical community for nearly 2 years, while the drug was being used by millions of patients over the world, hoping that it was protecting their hearts [2–5]. It is noteworthy that until ENHANCE, IMT was used as a surrogate of CHD complications [6, 7]. This was supported by several studies showing that intensive cholesterol-lowering ineluctably resulted in IMT regression [8, 9]. If ENHANCE had been positive, IMT would have been celebrated again as an effective marker of the risk of CHD complication. Because ENHANCE was negative, cholesterol experts immediately claimed that IMT cannot be a marker of atherosclerosis progress or a surrogate of CHD [10, 11]. The data of ENHANCE led an ACC panel to urge physicians to only prescribe cholesterollowering medications with proven clinical effectiveness, i.e., proven effects on hard clinical CHD endpoints such as cardiac death, myocardial infarction, and stroke [4]. As a matter of fact, ezetimibe was approved and marketed in 2002 based solely upon a 20% reduction of cholesterol, but not on data related to its effectiveness on any clinical endpoint [12]. In addition, the effectiveness of the ezetimibe+simvastatin combination against hard clinical endpoints has never been demonstrated. In November 2008, a press release announced the premature termination of JUPITER, a trial testing rosuvastatin, presumably the most effective statin in terms of cholesterol lowering, against a placebo in the primary prevention of CHD [13, 14]. With this announcement, the pharmaceutical company probably wanted to communicate that rosuvastatin, contrary to ezetimibe+simvastatin, resulted in an “unequivocal evidence of reduction in cardiovascular morbidity and mortality” as written in the press release [13, 14]. This was quite strategic for cholesterol experts at that particular time, because several trials testing cholesterol lowering had been published during the previous years in various clinical circumstances (ASPEN, 4D, PREVENT IT, IDEAL, ILLUMINATE [15–19] and also ENHANCE [1], and all of them reported no convincing protective effect against CHD complications [1, 15–19]. The failure of ENHANCE, in particular, generated unprecedented media coverage, patient and physician concerns, and the involvement of the US Congress over the use of cholesterol-lowering drugs to reduce CHD risk [2–5, 10, 11]. Following the publication of ENHANCE, two studies of cholesterol-lowering treatments were either not published or abruptly terminated [20, 21]. CASHMERE tested atorvastatin in postmenopausal women. ACHIEVE tested a novel combination tablet associating niacin and laropiprant (a prostaglandin D2 blocker) [21]. This indicated that even in 2008, trials that were obviously negative or tended in the wrong direction were still not publicly discussed by investigators and sponsors and sometimes were halted before completion. This gives an idea of what was being done before the new clinical research regulation came into force in 2005–2006, after the Vioxx affair [22], with the obligation of declaring all the clinical trials and of publishing the results even when they are not favorable to the tested drug [23, 24].

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During summer 2008, the results of two important trials were reported: SEAS and GISSI-HF [25, 26]. The Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial was a randomized, placebo-controlled study evaluating ezetimibe+simvastatin, like ENHANCE [1]. This time, however, cholesterol lowering was tested (against a placebo) by evaluating its effects on hard clinical endpoints, including aortic valve replacement and CHD complications in patients with aortic stenosis [25]. The main assumption was that disease progression in aortic stenosis is strongly influenced by hypercholesterolemia [27, 28] and often associated with CHD complications [29, 30]. Thus, double benefits were expected in these patients: first, by preventing CHD complication and, second, by preventing aortic valve complications. To summarize SEAS results, drastic cholesterol lowering had no significant effect on the primary endpoint [25]. SEAS actually confirmed the negative results of ENHANCE, but this time for of hard clinical endpoints [25]. SEAS is a critical study for several reasons. First, SEAS confirmed previous recent trials [15–19], including ENHANCE [1], and the inability of cholesterol lowering to reduce the risk of CHD complications in certain populations. In fact, some experts have claimed that previous positive trials were not the result of cholesterol lowering but of other properties of statins, the so-called pleiotropic effects [31]. At this point in the controversy, cholesterol experts appeared to be divided into two groups: those who were claiming that cholesterol lowering is still important whatever the results of ENHANCE and SEAS and those claiming that cholesterol lowering is not important as long as patients receive intensive statin treatment in order to induce pleiotropic protection [2–5, 32]. Second, the control group in SEAS received a placebo, whereas in ENHANCE the comparison group received simvastatin alone. This means that the difference in LDL cholesterol between the experimental and the control group was huge in SEAS, close to 50%, but still did not provide any protection. Thus, ENHANCE and SEAS taken together should have logically led to reject the “the lower the better” theory that states that the lower the cholesterol, the better the protection [33, 34]. Third, it is noteworthy that in SEAS, patients with low cholesterol levels in the experimental group had more cancers and died more frequently from cancers than those receiving the placebo [25]. Although it can be speculated that the increased cancer rate was a chance effect [35, 36], this raises another critical question: May intensive cholesterol lowering increase the risk of cancers in certain patients? The results of another important statin trial were reported during summer 2008. GISSI-HF was a double-blind randomized trial testing whether 10 mg rosuvastatin compared with a placebo could reduce mortality and cardiac complications in patients with chronic heart failure (CHF) [26]. Large observational studies, small prospective studies, and post hoc analyses (including meta-analyses) of large randomized trials have indeed suggested that cholesterol lowering could be beneficial in CHF patients. Despite a 36% reduction of LDL cholesterol in the statin group compared with placebo, there was no difference between groups for total mortality (657 deaths versus 644 in the placebo group) and for other cardiovascular endpoints in GISSI-HF [26]. GISSI-HF thus confirmed the results of a previous trial published less than 1 year before, the CORONA trial [37]. In CORONA, 10 mg rosuvastatin also was tested against placebo in patients with CHF aged 60 and more. Contrary to GISSI-HF, all patients in CORONA were CHD patients who had survived a previous myocardial infarction and presented left ventricular dysfunction. In other words, CORONA was a secondary prevention trial in high-risk patients because left ventricular dysfunction significantly increases the risk of CHD complications and cardiac death. Before CORONA, statin experts claimed that the higher the risk of cardiac death was, the higher the benefits of intensive cholesterol lowering would be [38, 39].

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Official and international guidelines state that a statin should be given to all patients (whatever their cholesterol level) in high-risk secondary prevention, whereas in primary prevention, when the risk of cardiac death is lower, prescription should depend on the cholesterol level [34, 40, 41]. In CORONA, the primary composite outcome was cardiac death, nonfatal infarction, and nonfatal stroke [37]. LDL cholesterol was reduced by 45% and CRP (an inflammatory marker) by 37% in the rosuvastatin group compared with placebo. CORONA was therefore designed not to fail. However, no significant difference was recorded for the primary composite outcome. Moreover, there were 488 and 487 cardiovascular deaths in the rosuvastatin and placebo groups, respectively. The numbers of deaths due to worsening heart failure were 191 and 193 in the placebo and statin groups, respectively. Thus, the unequivocal lessons of CORONA were that both drastic cholesterol lowering and the supposed pleiotropic (anti-inflammatory) effect of the statin had no effect at all in the secondary prevention of CHD in high-risk patients. CORONA and GISSIHF therefore provided exactly the same information in two different populations, namely that cholesterol lowering does not improve the prognosis for high-risk CHD patients. The theory that the higher the risk (notably in secondary prevention of CHD), the higher the benefit [34, 38–41] should logically be rejected. Also, the theory according to which statin pleiotropy could have a significant clinical impact appears to be very elusive after GISSI-HF and CORONA. JUPITER tested the effects of 20 mg rosuvastatin in subjects without cardiovascular disease, normal cholesterol levels but relatively high CRP [42]. The authors report a 50% decrease in LDL cholesterol, a 37% decrease in CRP, and a decrease by about 50% in cardiovascular complications. However, there are methodological problems and major clinical inconsistencies in JUPITER. The main methodological problem in JUPITER regards the premature trial termination [42]. Investigators made the awkward decision to stop the trial after 393 cases of complications, before the calculated number of at least 520 events calculated in their analysis plan was reached [42]. Taking only the hard complications of fatal and non-fatal myocardial infarction and stroke into account, they actually stopped the trial after only 240 events. The ethical argument according to which patients in the placebo group could no longer be left untreated is not relevant, and even the opposite, as many scientific articles constantly stress [43, 44]. The results of JUPITER look dramatic. The primary endpoint is a mix of diverse complications, although some of them such as revascularization are irrelevant because they are not complications but medical decisions. This being said, we actually observe an impressive difference between the two groups in terms of hard clinical complications, myocardial infarction, and stroke (157 against 83). However, there are no clear data on cardiovascular mortality in the text of the article. One may infer that fatal myocardial infarction is the difference between “any myocardial infarction” and “nonfatal myocardial infarction,” giving total numbers of 9 (31 less 22) in the rosuvastatin group and 6 (68 less 62) in the placebo group. We can make the same calculation for fatal stroke (the difference between “any stroke” and “nonfatal stroke”), resulting in total numbers of 3 (33 less 30) in the rosuvastatin group and 6 (64 less 58) in the placebo group. Cardiovascular mortality (fatal stroke+fatal myocardial infarction) is therefore identical in the two groups (12 against 12). The lack of effect on cardiovascular mortality associated with a miraculous effect on nonfatal complications is puzzling and should have led to suspect a bias and to the continuation of the trial instead of a premature ending. We are clearly facing a major clinical inconsistency. Mortality from myocardial infarction is known to be very high. In fact, the “case fatality rate” in epidemiological reports has been reported in many populations with very different risks

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[45]. Out of 100 patients who have a myocardial infarction, an average of 50 die immediately or within the 3–4 weeks that follow, and almost never less than 40 out of 100 even in populations with low cardiovascular mortality [37]. In JUPITER, mortality during infarction (6 divided by 68 multiplied by 100) is 8.8% in the placebo group. This is extremely low, and here we have another major clinical inconsistency! Pending confirmation of JUPITER by a new trial that will—hopefully—follow traditional and validated clinical trial methods, the obvious conclusion is that JUPITER results are not clinically consistent and therefore not credible. We must bear in mind that two previous trials with rosuvastatin (CORONA and GISSI-HF) were negative for CHD prevention [26, 37]. Thus, no clinical trial so far has been published showing an unequivocal clinical benefit of rosuvastatin. And this right at the time where other anti-cholesterol drugs (tested in ENHANCE and SEAS, for instance) showed totally ineffective whatever the type of hard or surrogate endpoints used to test the effects of cholesterol lowering [1, 25].

2 Conclusion For cholesterol experts and the cholesterol industry, 2008 has definitely been a very disappointing year. The trial results reported at the three world cardiology meetings (ACC, ESC, and AHA) were either negative (ENHANCE, SEAS, GISSI-HF) or not clinically consistent and probably biased (JUPITER) because of premature termination. Taken together, in the light of other recent negative trials (CORONA, ASPEN, 4D, PREVEND IT, IDEAL, ILLUMINATE) published after the Vioxx affair in 2005 and the following new clinical research regulations, the 2008 trials are puzzling. They suggest that the positive trials published before 2005 and the Vioxx affair should be urgently re-examined. A minimum would be that experts independent from the industry and free of conflict of interest should be committed to carefully checking all the raw data recorded in the data sets and redo the statistical analyses. The next question would then be: Is it not time for a full reappraisal of the cholesterol theory?

References 1. Kastelein JJ, Akdim F, Stroes ES, for ENHANCE investigators. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008; 358: 1431–1443. 2. Mitka M. Controversies surround heart drug study. Questions about Vytorin and trial sponsors’ conduct. JAMA 2008; 299: 885–887. 3. Greenland P, Lloyd-Jones D. Critical lessons from the ENHANCE trial. JAMA 2008; 299: 953–955. 4. O’Riordan M. Congress continues to probe Merck and Shering-Plough: angry emails highlight ENHANCE controversy. http:www.medscape.com/viewarticle/572392. 5. Stevermer J. ENHANCE study: ezetimibe lowers LDL, but does it matter? J Fam Pract 2008; 57: 436–437. 6. Bots ML, Hoes AW, Koudstaal PJ, Hofman A, Grobbee DE. Common carotid intima-media thickness and risk of stroke and myocardial infarction. The Rotterdam Study. Circulation 1997; 96: 1432–1437. 7. O’Leary DH, Polak JF, Kronmal RA et al. Carotid intima-media thickness as a risk factor of myocardial infarction and stroke in older adults. N Engl J Med 1999; 340: 14–22. 8. Smilde TJ, van Wissen S, Wollersheim H et al. Effect of aggressive versus conventional lipid-lowering on Atherosclerosis Progression in Familial Hypercholesterolemia (ASAP): a prospective, randomized, doubleblind trial. Lancet 2001; 357: 577–581. 9. Taylor AJ, Kent SM, Flaherty PJ et al. ARBITER: Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol: a randomized trial comparing the effects of atorvastatin and pravastatin on carotid intima media thickness. Circulation 2002; 106: 2055–2060.

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10. Toutouzas P, Richter D. Carotid intima-media thickness (cIMT): a useful clinic tool or research luxury? Another view of the ENHANCE trial. Angiology 2008; 59: 77S–79S. 11. Stein EA. Additional lipid lowering trials using surrogate measurements of atherosclerosis by carotid intimamedia thickness: more clarity or confusion? J Am Coll Cardiol 2008; 52: 2206–2209. 12. Sudhop T, von Bergmann K. Cholesterol absorption inhibitors for the treatment of hypercholesterolemia. Drugs 2002; 62: 2333–2347. 13. O’Riordan M. JUPITER halted: rosuvastatin significantly reduces cardiovascular morbidity and mortality. From Heartwire, a professional news service available at: http://medscapemobile.com/viewarticle/572270. 14. AstraZeneca. Crestor outcomes study JUPITER closes early due to unequivocal evidence of benefit. http://www.astrazeneca.com/pressrelease/5385.aspx. 15. Knopp RH. d‘Emden M, Smilde JG, Pocock SJ. Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes: the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in non-insulin-dependent diabetes mellitus (ASPEN). Diabetes Care 2006; 29: 1478–1485. 16. Wanner C, Krane V, März W et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005; 353: 238–248. 17. Asselbergs FW, Diercks GFH, Hillege HL et al., for the Prevention of Renal and Vascular Endstage Disease Intervention Trial (PREVEND IT) investigators. Effect of fosinopril and pravastatin on cardiovascular events in subjects with microalbuminuria. Circulation 2004; 110: 2809–2816. 18. Pedersen TR, Faergeman O, Kastelein JJ et al. High-dose atorvastatin vs. usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study, a randomized controlled trial. JAMA 2005; 294: 2437–2445. 19. Barter PJ, Caulfield M, Eriksson M et al., for the ILLUMINATE investigators. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007; 357: 2109–2122. 20. O’Riordan M. CASHMERE: no IMT effect with atorvastatin over 12 months. http:www.medscape.com/viewarticle/577309. 21. O’Riordan M. ACHIEVE stopped: IMT study with Niacin/Laropiprant halted by Merck & Co. http: www.medscape.com/viewarticle/574978. 22. Topol EJ. Failing the public health. Rofecoxib, Merck and the FDA. N Engl J Med 2004; 315: 1707–1709. 23. Bollapragada S, Norrie J, Norman J. Review of new regulations for the conduct of clinical trials of investigational medicinal products. BJOG 2007; 114: 917–921. 24. Chalmers I. Proposal to outlaw the term “negative trial”. BMJ 1985 ; 290: 1002. 25. Rossebø AB, Pedersen TR, Boman K et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med 2008; 359: 1343–1356. 26. Tavazzi L, Maggioni AP, Marchioli R et al., GISSI-HF Investigators. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomized, double-blind, placebo-controlled trial. Lancet 2008; 372: 1231–1239. 27. Palta S, Pai AM, Gill SK, Pai RG. New insights into the progression of aortic stenosis: implication for secondary prevention. Circulation 2000; 101: 2497–2502. 28. Nassimiha D, Arronow WS, Ahn C, Goldman ME. Association of coronary risk factors with progression of valvular aortic stenosis in older persons. Am J Cardiol 2001; 87: 1313–1314. 29. Mautner GC, Roberts WC. Reported frequency of coronary arterial narrowing by angiogram in patients with valvular aortic stenosis. Am J Cardiol 1992; 70: 539–540. 30. Peltier M, Trojette F, Sarano ME et al. Relation between cardiovascular risk factors and non rheumatic severe calcific aortic stenosis among patients with a three-cuspid aortic valve. Am J Cardiol 2003; 91: 97–99. 31. Davidson MH. Clinical significance of statin pleiotropic effects: hypotheses versus evidence. Circulation 2005; 111: 2280–2281. 32. Nissen JE. Courage under fire: what is the optimal approach to initial treatment of stable angina? Curr Cardiol Rep 2008; 10: 79–80. 33. Nissen SE, Tuzcu EM, Schoenhagen P et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004; 291: 1071–1080. 34. Cannon CB, Braunwald E, McCabe CH et al. Intensive versus moderate lipid-lowering with statins after acute coronary syndromes. N Engl J Med 2004; 350: 1495–1504. 35. Peto R, Emberson J, Landray M et al. Analyses of cancer data from three ezetimibe trials. N Engl J Med 2008; 359: 1357–1366.

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36. Collins R, Peto R. Analyses of cancer data from three ezetimibe trials: the authors reply. N Engl J Med 2009; 360: 86–87. 37. Kjekshus J, Apetrei E, Barrios V et al. Rosuvastatin in older patients with systolic heart failure. N Engl J Med 2007; 357: 2248–2261. 38. Khush KK, Waters D. Lessons from the PROVE-IT trial. Higher dose of potent statin better for high-risk patients. Cleve Clin J Med 2004; 71: 609–616. 39. Scirica BM, Morrow DA, Cannon CP et al. Intensive statin therapy and the risk of hospitalization for heart failure after an acute coronary syndrome in the PROVE IT-TIMI 22 study. J Am Coll Cardiol 2006; 47: 2326–2331. 40. Schwartz GG, Olsson AG, Ezekowitz MD et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA 2001; 285: 1711–1718. 41. Fonarow GC, French WJ, Parsons LS, Sun H, Malmgren JA. Use of lipid-lowering medications at discharge in patients with acute myocardial infarction: data from the National Registry of Myocardial Infarction 3. Circulation 2001; 103: 38–44. 42. Ridker PM, Danielson E, Fonseca FA et al., for the JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-Reactive protein. N Engl J Med 2008; 359: 2195–2207. 43. Mueller PS, Montori VM, Bassler D, Koenig BA, Guyatt GH. Ethical issues in stopping randomized trials early because of apparent benefit. Ann Intern Med 2007; 146: 878–881. 44. Montori VM, Devereaux PJ, Adhikari NK et al. Randomized trials stopped early for benefit: a systematic review. JAMA 2005; 294: 2203–2209. 45. Tunstall-Pedoe H, Kuulasmaa K, Mähönen M, Tolonen H, Ruokokoski E, Amouyel P. Contribution of trends in survival and coronary-event rates to changes in coronary heart disease mortality: 10-year results from 37 WHO MONICA project populations. Monitoring trends and determinants in cardiovascular disease. Lancet 1999; 353: 1547–1557.

Chapter 12

Leptin and Obesity: Role in Cardiac Structure and Dysfunction Sherma Zibadi, Douglas F. Larson, and Ronald Ross Watson

Key Points • Obesity, a growing health problem worldwide, contributes to the onset and/or development of heart disease. Even when uncomplicated by hypertension or diabetes, obesity triggers cardiac maladaptive remodeling, which plays a major role in the progression of various heart diseases to heart failure. • Major contributors to the obesity-induced maladaptive remodeling include alterations in myocyte shape and number, and extracellular matrix, resulting in cardiac hypertrophy and fibrosis. • Leptin, an adipokine over-produced in obesity, is emerging as a novel mechanistic link between obesity and cardiovascular disease by directly attenuating systolic contraction, inducing or preventing hypertrophy, and inducing mitogenesis in primary cardiomyocytes. • Once the role of leptin in development of cardiac interstitial fibrosis and diastolic dysfunction is defined, leptin modulation may provide an avenue for treating obesity- and other hyperleptinemic-related cardiac dysfunction. Keywords Leptin · Obesity · Heart · Remodeling

1 Introduction Obesity contributes to cardiovascular diseases and associated comorbid conditions such as type 2 diabetes, hypertension, and dyslipidemia [1]. The latter are leading risk factors for coronary artery disease, aggravating the cardiovascular outcome associated with obesity. However, obesity has been identified as an independent risk factor for coronary heart disease and congestive heart

S. Zibadi () College of Medicine, Sarver Heart Center, The University of Arizona, Tucson, AZ 85724, USA; College of Public Health, The University of Arizona, Tucson, AZ 85724, USA e-mail: [email protected] F. De Meester et al. (eds.), Modern Dietary Fat Intakes in Disease Promotion, Nutrition and Health, DOI 10.1007/978-1-60327-571-2_12, © Springer Science+Business Media, LLC 2010

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failure. Obesity alone is the cause of 11% of cases of cardiac failure in men and 14% of cases in women in the United States [2]. As the prevalence of obesity continues to rise, it is expected that obesity will become an important cause of cardiac failure in the coming years. After correction for other risk factors, the Framingham study showed that for every point increase in body mass index, the increased risk of developing cardiac failure was 5% in men and 7% in women [3].

2 Obesity-Induced Cardiac Remodeling Even when uncomplicated by hypertension or diabetes, obesity is associated with volume overload, which induces changes in ventricular cardiomyocytes and interstitium. Initially, cardiac remodeling is activated as an adaptive response to normalize wall stress, resulting in eccentric hypertrophy and altered extra cellular matrix (ECM) composition. This maladaptive cardiac ECM remodeling has been linked to disproportionate ECM fibrillar collagen synthesis/degradation rate and the degree of collagen cross-linking. In obesity, disruption of the collagen network leads to myocardial fibrosis, resulting in cardiac stiffness, decreased left ventricular compliance, and diastolic dysfunction [4]. In addition, increased collagen cross-linking contributes further to increased ventricular stiffness by increasing fibrillar strength and stability [5]. Consequently, the accumulated collagens contribute to the development of systolic dysfunction and heart failure [6]. Since adverse cardiac remodeling contributes notably to cardiac functional and structural abnormalities, causing progressive cardiac dysfunction, it is critically important to investigate the potential mediators of obesity-induced cardiac ECM remodeling as a therapeutic target.

3 Leptin: A Possible Link Between Obesity and Cardiovascular Diseases With the growing prevalence of obesity, interest in the biology of adipose tissue has been extended to the secretory products of adipocytes. These adipokines influence several aspects in the pathogenesis of obesity-related diseases. A key element is leptin, a 16-kDa non-glycosylated polypeptide, encoded by the obese gene. Leptin has long been recognized as one of the most important central signals for maintaining energy homeostasis [7]. As a cytokine-like hormone with pleiotropic actions, leptin affects neuroendocrine function, angiogenesis, and immune function [8, 9]. Although a clear mechanistic basis for increased cardiovascular risk in obese individuals is uncertain, leptin is a potential causative or at least a contributing factor for hypertension as well as other cardiovascular conditions [10]. Even in the absence of obesity, which is primary stimulus to elevated plasma leptin concentrations, heart disease such as ischemic heart disease [11] and heart failure [12] can be associated with hyperleptinemia, although to a markedly lowered degree.

4 Expression of Leptin and Its Receptors in the Heart Leptin circulates at a level of 5–15 ng/mL in lean humans and can be up to four times higher in obese subjects [13]. Once considered to be solely derived from adipose tissue, which accounts

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for the greatly increased levels observed in obese subjects, leptin can be produced by many tissues, including the heart, where it appears to function in an autocrine and paracrine manner. Increased leptin expression is seen in the heart following reperfusion after ischemia [14, 15]. Leptin concentration in cardiomyocyte culture serum is increased with endothelin-1 and angiotensin-II treatment [16], suggesting the heart as a site of leptin production. Six isoforms of leptin receptors, Ob-Rs (a–f), have been identified in murine model. Ob-Ra and Ob-Rb represent the dominant isoforms in the heart, whereas the others are expressed at low levels [17]. These isoforms have identical extracellular domains and ligand-binding affinity, although differing in their intracellular domains. The long isoform (Ob-Rb) appears to be of prime importance in signal transduction [18]. The major signaling pathway activated by leptin binding to Ob-Rb is the JAK/STAT pathway [18, 19]. This system appears to be important in the heart as leptininduced hypertrophy is associated with increased STAT3 phosphorylation, and pharmacologic inhibition of JAK2 can prevent the hypertrophic response [20]. Whereas JAK/STAT activation represents the classical primary pathway, recent studies suggest the potential role of MAP kinase and RhoA/Rho kinase pathways [21–23]. Ob-Ra activation initiates cell signaling through the MAP kinase pathway both dependently and independently of JAK phosphorylation [19, 23].

5 Leptin’s Effect on Cardiac Remodeling Evidence for leptin as a hypertrophic factor stems primarily from (A) in vitro studies examining the direct effect of leptin on cardiomyocyte and (B) clinical studies that have demonstrated a significant association between plasma leptin level and the degree of left ventricular hypertrophy [24, 25]. Leptin has been shown to induce hypertrophy in cultured neonatal rat ventricular myocytes [20, 26, 27], as well as the proliferation of human pediatric cardiomyocytes and a murine-cultured HL-1 cell line [22]. Leptin can mediate hypertrophic effects of both endothelin1 and angiotensin-II in vitro [16]. As a post-infarction modulatory factor, leptin treatment in myocardial of infracted-mice resulted in eccentric dilation associated with increased systolic function [20]. However, leptin administration to leptin-deficient ob/ob mice reversed left ventricular hypertrophy [28], which may not reflect a direct effect of leptin on cardiomyocytes, but instead correction of whole body physiological parameters that influence cardiac structure. Although various aspects of leptin-mediated remodeling of cardiomyocytes have been extensively investigated in vitro and in vivo, the effects of leptin on ECM remodeling have not been completely described. One in vitro study on human pediatric cardiomyocytes has shown that leptin increases the expression of matrix metalloproteinase(MMP)-2, enhances collagen type III and IV mRNA, and decreases collagen type I mRNA without affecting total collagen synthesis [29], suggesting that leptin selectively regulates different forms of collagen. However, this experiment was done with cardiomyocytes and not cardiac fibroblasts. A recent study by our laboratory (in preparation for publication) has shown that leptin-deficient ob/ob mice demonstrated eccentric hypertrophy, associated with significant increase of pro-MMP-2 and MMP-8 and TIMP-1 and TIMP-3 mRNA level, all implicated in collagen degradation, marked increase in pro-MMP-2 activity, and a reduction in cardiac collagen, compared to C57BL/6 control. Upon treatment with leptin, ob/ob mice displayed diastolic dysfunction and partial reversal of eccentric hypertrophy, coincided with significant increase in pro-collagen Iα1 and IIIα1 , suppression of pro-MMP8, TIMP-1, and TIMP-3 gene expressions, and increase in myocardial collagen, compared to

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ob/ob controls. These data indicate the profibrotic effects of leptin in the heart through increased collagen synthesis/degradation rate. However, these results need to be confirmed in other rodent fibrotic models.

6 Conclusion These epidemiologic and experimental animal studies lead us to the conclusion that leptin initiates or attenuates the adverse cardiac remodeling associated with obesity and other hyperleptinemic conditions, which may in turn contribute to the clinical syndrome of heart failure. Although the effects of leptin on cardiomyocytes have been extensively investigated, it is critically important to further investigate the effect of leptin as a profibrotic chemokine on the heart. Such studies may provide a novel mechanistic link between obesity and the associated myocardial fibrosis. This will likely provide the basis for future development of leptin-modulator therapeutics to prevent/lessen adverse cardiac remodeling and diastolic dysfunction in obese and other hyperleptinemic populations.

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16. Rajapurohitam V, Javadov S, Purdham DM, Kirshenbaum LA, Karmazyn M. An autocrine role for leptin in mediating the cardiomyocyte hypertrophic effects of angiotensin II and endothelin-1. J Mol Cell Cardiol 2006; 41: 265–274. 17. Fei H, Okano HJ, Li C, Lee GH, Zhao C, Darnell R, Friedman JM. Anatomic localization of alternatively spliced leptin receptors (Ob-R) in mouse brain and other tissues. Proc Natl Acad Sci USA 1997; 94: 7001–7005. 18. Purdham DM, Zou MX, Rajapurohitam V, Karmazyn M. Rat heart is a site of leptin production and action. Am J Physiol Heart Circ Physiol 2004; 287: H2877–H2884. 19. Bjorbaek C, Uotani S, da Silva B, Flier JS. Divergent signaling capacities of the long and short isoforms of the leptin receptor. J Biol Chem 1997; 272: 32686–32695. 20. Abe Y, Ono K, Kawamura T, Abe Y, Ono K, Kawamura T, Wada H, Kita T, Shimatsu A, Hasegawa K. Leptin induces elongation of cardiac myocytes and causes eccentric left ventricular dilatation with compensation. Am J Physiol Heart Circ Physiol 2007; 292: H2387–H2396. 21. Loirand G, Guerin P, Pacaud P. Rho kinases in cardiovascular physiology and pathophysiology. Circ Res 2006; 98: 322–334. 22. Tajmir P, Ceddia RB, Li RK, Coe IR, Sweeney G. Leptin increases cardiomyocyte hyperplasia via extracellular signal-regulated kinase- and phosphatidylinositol 3-kinase-dependent signaling pathways. Endocrinology 2004; 145: 1550–1555. 23. Banks AS, Davis SM, Bates SH, Myers MG. Activation of downstream signals by the long form of the leptin receptor. J Biol Chem 2000; 275: 14563–14572. 24. Iacobellis G, Ribaudo MC, Zappaterreno A, Vecci E, Tiberti C, Di Mario U, Leonetti F. Relationship of insulin sensitivity and left ventricular mass in uncomplicated obesity. Obes Res 2003; 11: 518–524. 25. Paolisso G, Tagliamonte MR, Galderisi M, Zito GA, Petrocelli A, Carella C, de Divitiis O, Varricchio M. Plasma leptin level is associated with myocardial wall thickness in hypertensive insulin-resistant men. Hypertension 1999; 34: 1047–1052. 26. Rajapurohitam V, Gan XHT, Kirshenbaum LA, Karmazyn M. The obesity-associated peptide leptin induces hypertrophy in neonatal rat ventricular myocytes. Circ Res 2003; 93: 277–279. 27. Xu FP, Chen MS, Wang YZ, Yi Q, Lin SB, Chen AF, Luo JD. Leptin induces hypertrophy via endothelin-1reactive oxygen species pathway in cultured neonatal rat cardiomyocytes. Circulation 2004; 110: 1269–1275. 28. Barouch LA, Berkowitz DE, Harrison RW, O‘Donnell CP, Hare JM. Disruption of leptin signaling contributes to cardiac hypertrophy independently of body weight in mice. Circulation 2003; 108: 754–759. 29. Madani S, De Girolamo S, Munoz DM, Li RK, Sweeney G. Direct effects of leptin on size and extracellular matrix components of human pediatric ventricular myocytes. Cardiovasc Res 2006; 69: 716–725.

Chapter 13

Cardiac Structural and Functional Changes in Genetically Modified Models of Obesity Felina Cordova, Sherma Zibadi, Douglas F. Larson, and Ronald Ross Watson

Key Points • There are many factors that influence the propensity to become obese with the genetics behind how individuals gain weight and become obese less understood than diet and exercise. • Animal models including mice and rats have been successful at illustrating some of the genetics of obesity and from these genetic animal models the effects of obesity have been shown to be very adverse on the cardiac system. Keywords Obesity · Heart · Genetic

1 Introduction Obesity affects more than 72 million people in the United States [1]. It is defined as having a body mass index [BMI: weight (kg)/height (m2 )] higher than 30 for adults [2]. As for children/teens in the age range of 2–19, the exact marker for obesity in regard to BMI varies by their age and those with a BMI above the 95th percentile for their age are considered obese [2]. Being obese is a major public health problem which can lead to life-threatening diseases and adverse heart conditions such as coronary heart disease and congestive heart failure [3]. Hospitalization records show the degree to which obesity and heart-related issues are a problem. Cardiac concerns are the number one reason for staying in the hospital in the United States and obesity is one of the top 10 comorbidities for hospitalizations [4]. The outcomes of malnutrition on weight gain have been well researched with consensus that a high-fat diet can result in obesity. To look at how inherited obesity can alter the human heart in the absence of dietary influences, several genetic mechanisms have been proposed through various animal models with various heart-related outcomes (Table 13.1).

F. Cordova () Mel and Enid Zuckerman College of Public Health, University of Arizona, 1295 N. Martin, Tucson, AZ 85724-5155, USA e-mail: [email protected] F. De Meester et al. (eds.), Modern Dietary Fat Intakes in Disease Promotion, Nutrition and Health, DOI 10.1007/978-1-60327-571-2_13, © Springer Science+Business Media, LLC 2010

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Table 13.1 Genes involved in animal model obesity Animal strain

Gene(s) involved

Cardiac structure effects

Zucker fatty rat

Leptin receptor

Obese mouse

Leptin gene

Diabetes mouse

Leptin receptor

↑ Cardiac mass (2×) ↑ Mass of left ventricle ↑ Myocytes death ↑ Triglycerides ↓ Cardiac contractility/fibrosis ↑ LV wall thickness ↑ Triglycerides ↓ Cardiac mass index ↓ Cardiac contractility/fibrosis ↑ LV wall thickness ↑ Triglycerides ↓ Cardiac contractility/fibrosis

Yellow/agouti mouse

Agouti gene

Cardiac dysfunction effects ↓ Heart rate

↑ Systolic pressure ↓ Mean arterial pressure

Diastolic dysfunction ↓ Heart rate ↑ Heart rate ↑ Elevated systolic pressure, ↑ elevated mean arterial pressure

2 Genes Animals. Many animal models have been used to illustrate the effects of inherited weight gain and though they do not all share the same genetic mutation, they all induce obesity. The yellow/agouti mouse model of genetic obesity is the result of a mutation in agouti gene, leading to abnormal increase in the amount of the agouti protein [5]. The agouti protein promotes feeding (or appetite) by blocking the inhibitory effect of the melanocyte-stimulating hormone and its receptors on hunger [5]. One of the most common pathways that induce obesity is alteration of the leptin gene or the leptin receptor. By a single mutation in the leptin gene or the leptin receptor, animals can be genetically engineered to have induced weight gain without increasing the consumption of dietary fat. Leptin works through melanocortin in the hypothalamus through the hunger/satiety pathway and lack of leptin suppresses the signal of being full during feeding which leads to overconsumption [6]. In addition to creating feelings of being full, leptin also increases the amount of energy that is spent through the sympathetic nervous system [6, 7]. The obese mouse (ob/ob) has mutation in its leptin gene causing the animal to be deficient of leptin [5]. The ob/ob mouse is able to create the obese condition in as few as 18 days [8]. Both the diabetes mouse (db/db) and the Zucker rat (fa/fa) are models with mutations in their leptin receptor. Both models are due to a single mutation in the leptin receptor that is autosomal recessive, resulting in reduced metabolism and increased triglyceride concentration [9]. In addition, obesity in ob/ob, db/db mice, and Zucker fatty rats can lead to diabetes. Humans. Human obesity gene map is an ongoing project with published results in 2005. Based on this analysis there are about 22 genes associated with obesity. Those that have been able to be confirmed by multiple research teams/studies include PPAR-γ (peroxisome proliferator-activated receptor gamma), ADRβ3 (beta-3 adrenergic receptor), ADRβ2 (beta-2 adrenergic receptor),

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LEPR (leptin receptor), GNB3 (guanine nucleotide-binding protein), UCP (uncoupling protein)1, -2, and -3, ADIPOQ (adiponectin), LEP (leptin), HTR2C (5-hydroxytryptamine receptor 2C), and NR3C1 (glucocorticoid receptor) [10]. In humans the FTO (fat mass and obesity associated) gene has been recently discovered (results published 2007) to be associated with increasing the propensity to develop obesity. The FTO gene resides on chromosome 16 and produces increased weight gain for those whose gene has undergone a single-nucleotide polymorphism [11]. The mechanism of how this gene works has not been fully elucidated at this point but it is known that the gene produces obesity in all age groups [11]. The findings on this gene’s relation to increased chances of obesity among people that are not family related have been confirmed by multiple research teams. In a case–control study of adult diabetics by Field et al., the FTO gene was positively associated with obesity as it was in children and teens in a case–control study of children hospitalized for obesity-related problems [12, 13].

3 Alternations in Cardiac Structure and Function Abnormal changes in cardiac structure have been observed in many studies involving genetically modified obese animals, with no dietary intervention. There are divergent findings about the effect of genetic obesity on heart weight varying by the animal studied. Looking at the entire mass of the heart, ob/ob mice have cardiac mass index (measured as milligram per gram body weight) that is half that of the controls [5], whereas other models of genetic obesity such as the Zucker rat have a heart mass two times that of a control heart [14]. Accordingly when compared to controls, higher weight of the left ventricle is characteristic in Zucker rats as early as 4 weeks [14, 15]. Diabetes mice (db/db) on the other hand do not show an elevated left ventricle weight in comparison to their controls [16]. Disregarding left ventricle weight, hypertrophic conditions can also be characterized by measuring left ventricular (LV) wall thickness. Echocardiograms of ob/ob and db/db mice hearts have produced statistically significant data that show increased LV thickness of approximately 1.18 mm for ob/ob, 1.16 mm for db/db in comparison to 0.75 mm seen in controls [17]. Increase in LV wall thickness was observed only in ob/ob and db/db mice at more advanced age (12–14 months) and not in their younger counterparts (2–3 months) [17]. In addition, in the Zucker rat and the diabetic mouse, a lowered heart rate in comparison to controls is also characteristic [18, 19], whereas the opposite is observed in the agouti mice [5]. As seen in obese humans, hypertension is prevalent in genetically obese animals as measured by tail cuff method. The systolic blood pressure of obese Zucker fatty rats, obese mice (ob/ob), and agouti mice was significantly higher in comparison to their control counterparts [5, 20]. Agouti mice also have higher mean arterial pressure than do both controls and ob/ob mice [5].

4 Conclusions Through echocardiogram, diastolic function can be assessed by looking at E (peak early mitral flow velocity) and A (peak late mitral flow velocity) and the E-to-A ratio. In db/db mice (6 week old) with echo in Doppler flow measurement, peak A velocity value is not statistically

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significant, but in older mice (12 weeks old), it is shown to be elevated [19]. Db/db mice also show a significant higher E peak velocity value (at 6 weeks old) and a lower E-to-A ratio at 12 weeks, suggestive of diastolic dysfunction [19]. Using echocardiograms with Doppler flow for ob/ob reveals different results for the E-to-A ratio (lower value) and the same results for the A peak (increased) [18]. Increased levels of triglycerides in the myocardium are prevalent in db/db mice, ob/ob mice, and the Zucker fatty rat, which may at least in part also contribute to induction of diastolic dysfunction [15, 16, 21]. In addition, cardiac interstitial fibrosis is also related to abnormal diastolic performance. Fibrosis causes less contractile ability of the myocardium, which has been proven to be the case in the Zucker rat, the ob/ob mouse, and the db/db mouse [22]. Myocardial fibrosis has been reported in ob/ob mice at the age of 7 month [23]. In addition, increased levels of myocyte death are associated with reparative fibrosis in the Zucker fatty rat (fa/fa) [24]. The levels of cardiac cell death are also increased as the animal ages for Zucker rats [24].

References 1. Ogden CL, Carroll MD, McDowell MA, Flegal KM. Obesity Among Adults in the United States-No Significant Change Since 2003–2004. NCHS Data Brief no 1. Hyattsville, MD: National Center for Health Statistics, 2007. 2. Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak CJ, Flegal KM. Prevalence of overweight and obesity in the United States 1999–2004. JAMA 2006; 295: 1549–1555. 3. Eckel H. Obesity and heart disease: a statement for healthcare professionals from the nutrition committee, American Heart Association. Circulation 1997; 96: 3248–3250. 4. Merrill CT, Elixhauser A. Hospitalizations in the United States 2002. Rockville, MD: Agency for Healthcare Research and Quality, 2005, HCUP Fact Book No. 6. AHRQ Publication No. 05–0056. 5. Mark AL, Shaffer RA, Corrella MLG, Morgan DA, Sigmund CD, Haynes WG. Contrasting blood pressure effects of obesity in leptin-deficient ob/ob mice and agouti yellow obese mice. J Hypertens 1999; 17(2): 1949–1953. 6. Aizawa-Abe M, Ogawa Y, Masuzaki H, Ebihara K, Satoh N, Iwai H et al. Pathophysiological role of leptin in obesity-related hypertension. J Clin Invest 2000; 105: 1243–1252. 7. Tartaglia LA. The leptin receptor. J Biol Chem 1997; 272(10): 6093–6096. 8. Coleman DL, Eicher EM. Fat (fat) and Tubby (tub): two autosomal recessive mutations causing obesity syndromes in the mouse. J Hered 1990; 81(6): 424–427. 9. Phillips MS, Liu Q, Hammond HA, Dugan V, Hey PJ, Caskey CJ et al. Leptin receptor missense mutation in the fatty Zucker rat. Nat Genet 1996; 13: 18–19. 10. Rankinen T, Zuberi A, Chagnon YC, Weisnagel SJ, Argyropoulos G, Perusse L et al. The human obesity gene map: the 2005 update. Obesity 2006; 14: 529–644. 11. Frayling TM, Timpson NJ, Weedon NM, Zegginni E, Freathy RM, Lindgren CM et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 2007; 316: 889–894. 12. Field SF, Howson JMM, Walker NM, Dunger DB, Todd JA. Analysis of the obesity gene FTO in 14,803 type I diabetes cases and controls. Diabetologia 2007; 50: 2218–2220. 13. Hinney A, Nguyen TT, Scherag A, Friedel S, Bronner G, Muller TD et al. Genome wide association (GWA) study for early onset extreme obesity supports the role of fat mass and obesity associated gene (FTO) variants. PLoS One 2007; 2(12): 1–5. 14. McGavock JM, Victor RG, Unger RH, Szczepaniak LS. Adiposity of the heart revisited. Physiol Med 2006; 144: 517–524. 15. Zhou YT, Grayburn P, Karim A, Shimabukuro M, Higa M, Baetens D, Orci L et al. Lipotoxic heart disease in obese rats: Implications for human obesity. PNAS 2000; 97(4): 1784–1789. 16. Belke DD, Larsen TJ, Gibbs ME, Severson DL. Altered metabolism causes cardiac dysfunction in perfused hearts from diabetic (db/db) mice. Am J Physiol Endocrinol Metab 2000; 279: E1104–E1113.

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17. Barouch LA, Gao D, Chen L, Miller KL, Xu W, Phan AC et al. Cardiac myocytes apoptosis is associated with increased DNA damage and decreased survival in murine models of obesity. Circ Res 2006; 98: 119–124. 18. Christoffersen C, Bollano E, Lindegaard ML, Bartels ED, Goetze JP, Andersen CB, Nielsen LB. Cardiac lipid accumulation associated with diastolic dysfunction in obese mouse. Endocrinology 2003; 144(8): 3483–3490. 19. Semeniuk LM, Kryski AJ, Severson DL. Echocardiographic assessment of cardiac function in diabetic db/db and transgenic db/db-HGLUT4 mice. Am J Physiol Heart Circ Physiol 2002; 283: H976–H982. 20. Ren J, Sowers JR, Walsh MF, Brown RA. Reduced contractile response to insulin and IGF-1 in ventricular myocytes from genetically obese Zucker RATS. Am J Physiol Heart Circ Physiol 2000; 279: H1708–H1714. 21. Mazumder PK, O’Neill BT, Roberts MW, Buchanan J, Yun UJ, Cooksey RC et al. Impaired cardiac efficiency and increased fatty acid oxidation in insulin-resistant ob/ob mouse hearts. Diabetes 2004; 53: 2366–2374. 22. Unger RH, Orci L. Diseases of liporegulation: new perspective on obesity and related disorders. FASEB J 2001; 15: 312–321. 23. Zibadi S, Cordova F, Larson D, Watson RR. Leptin regulation of cardiac remodeling due to obesity. 100th AOCS Annual Meeting & Expo Abstracts. 63–64, 2009. 24. Abel ED, Litwin SE, Sweeney G. Cardiac Remodeling in Obesity. Physiol Rev 2008; 88: 389–419.

Chapter 14

Fat-Modified Dairy Products and Blood Lipids in Humans Gerhard Jahreis and Christin Hengst

Key Points • Fat-modified dairy products provide beneficial effects on human health in comparison to regular milk products. • Consumption of fat-modified dairy products lowers the risk factors of the metabolic syndrome, playing a central role in the prevention of cardiovascular disease. • Ruminant milk lipids have beneficial as well as unfavourable properties so that nutritional intervention with fat-modified dairy products for patients at high risk for metabolic disorders or cardiovascular events is recommended. Keywords Dairy products · Fat-modified milk · Blood lipids · Metabolic disorders · Cardiovascular diseases

1 Introduction Particularly in the last years, several studies have reported an inverse relationship between the intake of dairy products and the risk of diseases which are common in the Western world, such as hypertension [1, 2], dyslipidemia [3], obesity [4, 5] and type 2 diabetes [6]. The metabolic syndrome, also known as syndrome X, insulin resistance syndrome, or the deadly quartet, is a cluster of these medical disorders. Since the metabolic syndrome affects vascular metabolism adversely, it is strongly associated with the risk of developing cardiovascular diseases (CVD) [7, 8]. Due to the fact that the prevalence of the metabolic disorders increases with age, the demographic changes, taking place in the following years, will contribute to increased financial

C. Hengst () Department of Nutritional Physiology, Institute of Nutrition, Friedrich Schiller University, Dornburger Str. 24, D-07743 Jena, Germany e-mail: [email protected] F. De Meester et al. (eds.), Modern Dietary Fat Intakes in Disease Promotion, Nutrition and Health, DOI 10.1007/978-1-60327-571-2_14, © Springer Science+Business Media, LLC 2010

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burdens for the health-care systems. Consequently, the primary prevention especially through nutritional intervention has come into the focus of research.

2 Dairy Products Dairy products like milk, yoghurt, or cheese are an important component of the human diet and contribute to the nutrient uptake (Fig. 14.1). Milk and dairy products contain significant amounts of fat, protein, vitamins and minerals. Additionally, they are a source of various bioactive compounds like immunoglobulins, lactoferrin or glycomacropeptides [9]. Men

Intake of milk and milk products [g/day]

400

Women

350 Recommendation of German Society of Nutrition

300 250 200 150 100 50 0 14-18

19-24

25-34

35-50

51-64

65-80 Age [years]

Fig. 14.1 Intake of milk and milk products by different age groups in comparison with the recommendation of the German Society of Nutrition (modified according to the Second National Diet Study of Germany: 15,371 persons, aged between 14 and 80, diet history interviews, November 2005 to 2006 [73])

Ruminant milk fat consists of diverse classes of lipids including mono-, di- and triacylglycerides as well as free fatty acids, phospholipids, glycolipids and steroids. The fat content and the fat composition of ruminant milk vary widely and depend on different factors (e.g. feeding, breed of cows, season). Besides high amounts of saturated fatty acids (SFA), smaller amounts of unsaturated fatty acids (UFA) are present in ruminant milk. Special feeding with fat-rich linseed and rapeseed cakes can improve the ratio of SFA to monounsaturated fatty acids (MUFA) of ruminant milk fat compared to conventional milk fat (Table 14.1). Generally, SFA are associated with an increase of serum cholesterol [10, 11] or a higher risk of CVD [12]. Especially, myristic acid (C14:0) and palmitic acid (C16:0) cause the LDL-raising effects of ruminant milk fat [13]. Due to its high content of serum cholesterol-raising SFA, milk is linked with hypercholesterolemia and an increased insulin resistance [14–16]. In contrast, UFA are predominantly associated with health benefits. The most abundant MUFA present in ruminant milk is oleic acid (C18:1n9). For diets high in oleic acid, antiatherogenic effects are reported [17]. However, oleic acid is also discussed to correlate positively with the breast cancer risk [18]. Polyunsaturated fatty acids (PUFA) belong to the class of essential fatty acids and since they cannot be synthesised de novo within the human organism, they must be provided through the diet. Dairyproducts contain

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Table 14.1 Variation of fatty acid distribution and SFA/MUFA ratio in conventional and special cow’s milk (% FAME) Milk Fatty acids

Conventional milk

SFAb 69.8 27.2 MUFAc PUFAd 3.0 CLAe 0.6 SFA/MUFA 2.6 a Linseed and rapeseed cake feeding. b Saturated fatty acids. c Monounsaturated fatty acids. d Polyunsaturated fatty acids. e Conjugated linoleic acids.

Special milka

Milk from Alps

61.3 34.9 3.8 1.1 1.7

61.5 31.5 7.0 2.7 2.0

mainly linoleic acid (C18:2n6) and α-linolenic acid (C18:3n3), which are necessary precursors for the endogenous synthesis of the eicosanoids. Hence, they play a decisive role in physiological and pathological processes, especially in inflammation. Studies suggest that n–3 PUFA reduce the incidence of CVD [19]. In the recent past, research has focused on trans fatty acids (TFA) and on conjugated linoleic acids (CLA). The latter are conjugated derivates of linoleic acid occurring primarily in ruminant milk fat since they are formed by the rumen bacteria. Recent findings suggest that the abundant isomer cis-9,trans-11-CLA is related to a modulated immune function [20, 21] and to a reduced risk of cancer [22, 23], atherosclerosis [24] and diabetes [25]. TFA are products of incomplete biohydrogenation of PUFA in ruminants. The predominant TFA in dairy products is vaccenic acid (trans-11 C18:1). Since this rumen-derived fatty acid is endogenously converted into cis-9,trans11-CLA [26], milk can contribute to increase the tissue level of CLA. In contrast to natural ruminant TFA, those mainly found in industrially processed foods containing hydrogenated oil are considered to be detrimental with respect to CVD [27]. TFA elevate the requirements of essential fatty acids since both compete for the same enzyme system. The phospholipids present in milk are characterised by a high concentration of sphingomyelin which is linked to the cholesterol metabolism and a decreased risk of bowel cancer [28]. Finally, ruminant milk is a unique source of substances which may provide beneficial effects on human physiology.

3 Blood Lipids Blood lipids belong to several classes of lipids circulating in the blood whose concentrations depend on the nutrient intake and the intestinal absorption. The most abundant components are cholesterol and triacylglycerides. Cholesterol is an ubiquitously occurring steroid which is an important component of cell membranes and subcellular compartments like mitochondria. Furthermore, it is the precursor of steroid hormones and bile acids. Despite its complex chemical structure, cholesterol is not essential for the human organism. The biosynthesis takes place in the liver, the skin, and the intestinal tract. Approximately 60–75% of the circulating cholesterol result from endogenous synthesis and about 25–40% are of dietary origin.

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The intestinal absorption of lipids is a complex process based on hydrolysis and emulsification. Hydrolysis products of lipid digestion are fatty acids, monoacylglycerides, phospholipids like phosphatidylcholine (lecithin) and unesterified cholesterol. Bile acids promote the complexation and solubilisation of the lipolytic products by the formation of mixed micelles. These aggregates enable diffusion through the unstirred water layer which separates the brush border membrane of the enterocytes from the lumen. Currently, the mechanisms by which micelles mediate the translocation of lipolytic products across the enterocyte membrane remain speculative. Besides disaggregation of the micelle and a simple diffusion across the plasma membrane of the enterocytes, active carrier-mediated transport mechanisms are discussed. After transfer from the intestinal lumen to the lymph, special structures are needed to transport lipids in the aqueous medium of lymph and blood. While long-chain fatty acids are bound to albumin and short-chain fatty acids are dissolved in the plasma, lipoprotein particles are responsible for the transport of the remaining lipids like triacylglycerides, cholesterol and phospholipids. Lipoproteins are aggregates consisting of lipids and apoproteins (e.g. ApoA, ApoB48 , ApoB100 , ApoC, ApoE). There are five categories of lipoproteins present in the blood which are classified according to their density: chylomicrons, VLDL, IDL, LDL and HDL. Chylomicrons are released from the enterocytes into the lymph by exocytosis. In the bloodstream, chylomicrons acquire apoproteins from HDL and undergo a hydrolysis catalysed by epithelial-bound lipoprotein lipase. While the released fatty acids are absorbed by the peripheral cells, the chylomicron remnants are lipolysed in the hepatocytes. For the transport of endogenous lipids, VLDL is originated and secreted by the liver and then converted to LDL in the bloodstream. LDL particles are the primary carriers of cholesterol in the blood, transporting it to peripheral tissues. LDL is taken up by the cells via receptor-mediated endocytosis. HDL, also synthesised and excreted by the liver, collects cholesterol from peripheral tissues and carries it back to the liver. Elevated LDL cholesterol levels are involved in the pathogenesis of CVD, whereas high levels of HDL play a protective role. Hence, an efficient homeostatic regulation of the cholesterol level is necessary for the prevention of CVD. The LDL/HDL ratio is widely used to assess the individual risk; a ratio below 3 is associated with a lower CVD risk [29].

4 Modification of Blood Lipid Composition via Dairy Products The conception persists that milk fat might be hypercholesterolaemic; however, several studies attribute a protecting potential to milk. It was found that the consumption of dairy products leads to an elevation of HDL cholesterol [29, 30]. Since low serum levels of HDL were also defined as a risk factor for CVD [31], these findings led to the assumption that milk fat can provide health benefits too. Additionally, negative correlations between the intake of dairy products and the LDL/HDL ratio, the body mass index and the waist circumference are reported [32]. Another recent study showed an inverse relationship between the serum cholesterol levels and the intake of SFA with a chain length of 4–15 C-atoms from milk fat [33]. Besides a high concentration of cholesterol, triacylglycerides (TAG) play an important role in the development of CVD. Several studies indicate that milk fat affects the concentration of blood lipids [34–37], while others did not confirm this effect [13, 38].

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The daily intake of fat via dairy products is high in Western diets. Milk fat accounts for about 30% of total fat intake in Germany. In this context, dairy food contributes substantially to the intake of saturated fat (40%) [39]. Hence, it seems reasonable to reduce the LDL-raising potential by modifying the composition of milk fat. There are several recent studies investigating the effect of modified milk fat on human blood lipid profiles. Different methods of replacing the LDL-raising SFA have been proposed, such as modulating the feeding of cows [13] and fractionation technologies [36]. A further approach was the blending of butter with medium-chain triacylglycerol together with safflower oils, resulting in an interesterified mixture of butter [37]. Kraft et al. [40] showed that the proportions of PUFA and total CLA in milk fat are significantly higher in milk from pasture cows in the Alps compared to the milk of indoor cows. The authors attributed this effect to α-linolenic acid-rich mountain pastures. The milk fat investigated in the study of Seidel et al. [3] was modified by feeding cows’ highfat rapeseed cake (16% oil). About 400 g rapeseed oil per cow each day led to a decrease in SFA (C12:0, C14:0 and C16:0) in the milk lipids of about 20% and an increase in UFA (C18:1, C18:2 and C18:3) of about 33%. The above-mentioned study was conducted to specify the effects of modified milk fat compared with conventional milk fat and non-hydrogenated soft margarine on blood lipids in humans. The authors demonstrated that the serum concentrations of HDL cholesterol increase after the consumption of fat-modified milk, leading to a decreased LDL/HDL ratio (Table 14.2). Since a low serum HDL concentration is considered to be an independent risk factor for CVD [41, 42], fat-modified milk products might lower the risk of developing CVD. Also, lipoprotein (a) is suggested to be an independent risk factor for CVD [43–46]. The concentrations of lipoprotein (a) decreased and the concentrations of the TAG showed only a decreasing tendency. Table 14.2 Concentrations of serum total cholesterol (TC), LDL cholesterol (LDL-C), HDL cholesterol (HDL-C) and the LDL/HDL ratio of volunteers after an intervention with modified milk fat (ModFat), regular milk fat (RegFat) and soft margarine (Marg) (modified according to Seidel et al. [3]) Subjects Start RegFat ModFat Marg TC (mmol/l) 5.15 ± 1.08 5.06 ± 1.14 5.02 ± 1.05 5.02 ± 1.07 2.98 ± 0.95a 2.66 ± 1.05b 2.87 ± 0.91a LDL-C (mmol/l) 2.98 ± 0.98a HDL-C (mmol/l) 1.54 ± 0.59a 1.45 ± 0.43a 1.77 ± 0.77b 1.46 ± 0.44a a a b LDL/HDL ratio 2.17 ± 0.95 2.22 ± 0.90 1.79 ± 0.92 2.14 ± 0.91a Values represent mean ± SD. Values in a row not sharing the same superscript letter differ significantly (p < 0.05).

It has been described that a MUFA-rich diet reduces LDL cholesterol levels in comparison with a control diet (more SFA and less MUFA) [47]. Evaluations of several trials indicate that SFA increase serum cholesterol more than PUFA [48] or in contrast to PUFA [10]. The higher content of C18:1n9, C18:2n6 and C18:3n3 in the modified milk fat compared to the regular milk fat might be an explanation for the LDL decrease. High SFA uptake has been linked to increased LDL concentration, diminished LDL receptor activity and impaired clearance of LDL from the blood [49]. Studies in rats indicate that the metabolism of butterfat in chylomicrons is not dependent on its saturation [50, 51]. CLA, naturally occurring in dairy products, have been shown to reduce risk markers of arteriosclerosis [24] and diabetes [25] in animal models and to improve the LDL/HDL ratio in humans [52]. In addition, the latter study reported that different CLA isomers show contrary effects on blood profile. While trans-10,cis-12-CLA increases the ratio of LDL to HDL and of total cholesterol to HDL, cis-9,trans-11-CLA decreases these ratios.

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A lot of epidemiological studies indicate that milk products in general contain cardiovascularprotective components. The CARDIA study observed an inverse relationship (for subjects with a BMI >25 kg/m2 ) between dairy consumption and obesity, dyslipidemia, abnormal glucose homeostasis and hypertension [53]. Wang et al. [1] approved the inverse relationship between the intake of dairy products and hypertension for low-fat products. Studies on the link between dairy consumption and body mass index suggest an inverse relationship [54–56]. However, the data are still conflicting [57]. It is hypothesised that high consumption of dairy foods is a marker of a healthier lifestyle [58]. For diets characterised by a high intake of dairy products, a lower risk of type 2 diabetes is reported [6]. The findings of Krachler et al. [59] indicate an inverse correlation between the development of type 2 diabetes and two milk-derived SFA (C17:0, C15:0), which have been identified as a marker of dairy product consumption [60]. Because recent studies showed that dairy consumption is inversely associated with the risk of several underlying diseases of the metabolic syndrome, health benefits due to nutritional intervention are assumed. Further studies found that the intake of milk may lower the risk of CVD [61] and of acute myocardial infarction [62]. Cohort studies suggest that milk is associated with a small but worthwhile reduction in heart disease and stroke risk [63, 64]. In contrast to these trials, the Seven Countries Study pointed out a significantly positive correlation between the intake of butter and milk with long-term CVD mortality [65]. The authors attributed their findings to the high content of SFA in these foods. Almost 10% of the SFA in milk fat are short-chain fatty acids (SCFA) which are absorbed and metabolised independently from the other lipid classes. Since SCFA have no unfavourable effects on LDL cholesterol levels, they are not linked to an enhanced risk of CVD. Increased dietary calcium and additional milk products are associated with weight loss [66, 67]. In a prospective study, dietary calcium intake, especially from dairy products, was further negatively related to the risk of stroke [68]. As mentioned above, there are several studies [14–16] indicating the hypercholesterolaemic effect of milk products with regard to their high content of SFA, but only regular milk products were tested. Jacques et al. [36], who also tested fat-modified milk (high in MUFA, low in SFA, nearly zero in cholesterol), regular milk fat and non-hydrogenated margarine, reported a significant increase in the LDL/HDL ratio after consumption of the regular milk fat and a nonsignificant increase after the consumption of fat-modified products. Further studies reported a decrease in total cholesterol because of the drop of LDL cholesterol, whereas HDL cholesterol remained unchanged after consumption of fat-modified dairy products [13, 30]. TAG are assumed to be an independent risk factor for CVD [69–71]. Jacques et al. [36] observed decreased levels of TAG after a 4-week intervention with fat-modified milk. Tholstrup et al. [72] found an increase in TAG after consumption of modified butterfat (16% of the SFA was mainly replaced by oleic acid), probably due to the high content of trans fatty acids in this diet.

5 Conclusions In conclusion, fat-modified dairy products seem to provide beneficial effects on human health in comparison to regular milk products. There is evidence that the consumption of fat-modified dairy products lowers the risk factors of the metabolic syndrome. Thus, it is assumed that these products could play a central role in the prevention of CVD.

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5.1 Application For ruminant milk lipids, beneficial as well as unfavourable properties are discussed. However, several studies have clearly remarked that a lot of dairy ingredients provide beneficial effects on human health. A nutritional intervention with fat-modified dairy products for patients high at risk for metabolic disorders or cardiovascular events is recommended.

References 1. Wang L, Manson JE, Buring JE, Lee IM, Sesso HD. Dietary intake of dairy products, calcium, and vitamin D and the risk of hypertension in middle-aged and older women. Hypertension 2008; 51: 1073–1079. 2. Alonso A, Beunza JJ, Delgado-Rodriguez M, Martinez JA, Martinez-Gonzalez MA. Low-fat dairy consumption and reduced risk of hypertension: the Seguimiento Universidad de Navarra (SUN) cohort. Am J Clin Nutr 2005; 82: 972–979. 3. Seidel C, Deufel T, Jahreis G. Effects of fat-modified dairy products on blood lipids in humans in comparison with other fats. Ann Nutr Metab 2005; 49: 42–48. 4. Zemel MB. Role of calcium and dairy products in energy partitioning and weight management. Am J Clin Nutr 2004; 79: 907S–12. 5. Marques-Vidal P, Goncalves A, Dias CM. Milk intake is inversely related to obesity in men and in young women: data from the Portuguese Health Interview Survey 1998–1999. Int J Obes Relat Metab Disord 2005; 30: 88–93. 6. Choi HK, Willett WC, Stampfer MJ, Rimm E, Hu FB. Dairy consumption and risk of type 2 diabetes mellitus in men: A prospective study. Arch Intern Med 2005; 165: 997–1003. 7. Hu G, Qiao Q, Tuomilehto J, Balkau B, Borch-Johnsen K, Pyorala K. Prevalence of the metabolic syndrome and its relation to all-cause and cardiovascular mortality in nondiabetic European men and women. Arch Intern Med 2004; 164: 1066–1076. 8. McNeill AM, Katz R, Girman CJ, Rosamond WD, Wagenknecht LE, Barziley JI, Tracy RP, Savage PJ, Jackson SA. Metabolic syndrome and cardiovascular disease in older people: the cardiovascular health study. J Am Geriatr Soc 2006; 54: 1317–1324. 9. Shah NP. Effects of milk-derived bioactives: an overview. Br J Nutr 2007; 84: 3–10. 10. Hegsted DM, Ausman LM, Johnson JA, Dallal GE. Dietary fat and serum lipids: an evaluation of the experimental data [published erratum appears in Am J Clin Nutr 1993 Aug;58(2):245]. Am J Clin Nutr 1993; 57: 875–883. 11. Temme EH, Mensink RP, Hornstra G. Comparison of the effects of diets enriched in lauric, palmitic, or oleic acids on serum lipids and lipoproteins in healthy women and men. Am J Clin Nutr 1996; 63: 897–903. 12. Hu FB, Stampfer MJ, Manson JE et al. Dietary fat intake and the risk of coronary heart disease in women. N Engl J Med 1997; 337: 1491–1499. 13. Noakes M, Nestel PJ, Clifton PM. Modifying the fatty acid profile of dairy products through feedlot technology lowers plasma cholesterol of humans consuming the products. Am J Clin Nutr 1996; 63: 42–46. 14. Artaud-Wild SM, Connor SL, Sexton G, Connor WE. Differences in coronary mortality can be explained by differences in cholesterol and saturated fat intakes in 40 countries but not in France and Finland. A paradox. Circulation 1993; 88: 2771–2779. 15. Berner LA. Roundtable discussion on milk fat, dairy foods, and coronary heart disease risk. J Nutr 1993; 123: 1173–1184. 16. Kushi LH, Lenart EB, Willett WC. Health implications of Mediterranean diets in light of contemporary knowledge. 1. Plant foods and dairy products. Am J Clin Nutr 1995; 61: 1407S–15. 17. Mata P, Garrido JA, Ordovas JM et al. Effect of dietary monounsaturated fatty acids on plasma lipoproteins and apolipoproteins in women. Am J Clin Nutr 1992; 56: 77–83. 18. Pala V, Krogh V, Muti P, Chajes V, Riboli E, Micheli A, Saadatian M, Sieri S, Berrino F. Erythrocyte membrane fatty acids and subsequent breast cancer: a prospective Italian study. J Natl Cancer Inst 2001; 93: 1088–1095.

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19. Djousse L, Pankow JS, Eckfeldt JH et al. Relation between dietary linolenic acid and coronary artery disease in the National heart, lung, and blood institute family heart study. Am J Clin Nutr 2001; 74: 612–619. 20. Jaudszus A, Krokowski M, Mockel P et al. Cis-9,trans-11-conjugated linoleic acid inhibits allergic sensitization and airway inflammation via a PPAR{gamma}-related mechanism in mice. J Nutr 2008; 138: 1336–1342. 21. O‘Shea M, Bassaganya-Riera J, Mohede ICM. Immunomodulatory properties of conjugated linoleic acid. Am J Clin Nutr 2004; 79: 1199S–206. 22. Ip C, Banni S, Angioni E et al. Conjugated linoleic acid-enriched butter fat alters mammary gland morphogenesis and reduces cancer risk in rats. J Nutr 1999; 129: 2135–2142. 23. Kelley NS, Hubbard NE, Erickson KL. Conjugated linoleic acid isomers and cancer. J Nutr 2007; 137: 2599–2607. 24. Valeille K, Ferezou J, Parquet M et al. The natural concentration of the conjugated linoleic acid, cis-9,trans11, in milk fat has antiatherogenic effects in hyperlipidemic hamsters. J Nutr 2006; 136: 1305–1310. 25. Moloney F, Toomey S, Noone E et al. Antidiabetic effects of cis-9,trans-11-conjugated linoleic acid may be mediated via anti-inflammatory effects in white adipose tissue. Diabetes 2007; 56: 574–582. 26. Kuhnt K, Kraft J, Moeckel P, Jahreis G. Trans-11-18:1 is effectively delta9-desaturated compared with trans12-18: 1 in humans. Br J Nutr 2006; 95: 752–761. 27. Weggemans RM, Rudrum M, Trautwein EA. Intake of ruminant versus industrial trans fatty acids and risk of coronary heart disease—what is the evidence? Eur J Lipid Sci Technol 2004; 106: 390–397. 28. Parodi PW. Milk fat in human nutrition. Aust J Dairy Technol 2004; 59: 3–59. 29. Kiessling G, Schneider J, Jahreis G. Long-term consumption of fermented dairy products over 6 months increases HDL cholesterol. Eur J Clin Nutr 2002; 56: 843–849. 30. Poppitt SD, Keogh GF, Mulvey TB, McArdle BH, MacGibbon AK, Cooper GJ. Lipid-lowering effects of a modified butter-fat: a controlled intervention trial in healthy men. Eur J Clin Nutr 2002; 56: 64–71. 31. Kratz M, Cullen P, Wahrburg U. The impact of dietary mono- and poly-unsaturated fatty acids on risk factors for atherosclerosis in humans. Eur J Lipid Sci Technol 2002; 104: 300–311. 32. Smedman AE, Gustafsson IB, Berglund LG, Vessby BO. Pentadecanoic acid in serum as a marker for intake of milk fat: relations between intake of milk fat and metabolic risk factors. Am J Clin Nutr 1999; 69: 22–29. 33. Samuelson G, Bratteby LE, Mohsen R, Vessby B. Dietary fat intake in healthy adolescents: inverse relationships between the estimated intake of saturated fatty acids and serum cholesterol. Br J Nutr 2001; 85: 333–341. 34. Mekki N, Charbonnier M, Borel P et al. Butter differs from olive oil and sunflower oil in its effects on postprandial lipemia and triacylglycerol-rich lipoproteins after single mixed meals in healthy young men. J Nutr 2002; 132: 3642–3649. 35. Mattes RD. Oral exposure to butter, but not fat replacers elevates postprandial triacylglycerol concentration in humans. J Nutr 2001; 131: 1491–1496. 36. Jacques H, Gascon A, Arul J, Boudreau A, Lavigne C, Bergeron J. Modified milk fat reduces plasma triacylglycerol concentrations in normolipidemic men compared with regular milk fat and nonhydrogenated margarine. Am J Clin Nutr 1999; 70: 983–991. 37. Mascioli EA, McLennan CE, Schaefer EJ et al. Lipidemic effects of an interesterified mixture of butter, medium-chain triacylglycerol and safflower oils. Lipids 1999; 34: 889–894. 38. Judd JT, Baer DJ, Clevidence BA et al. Effects of margarine compared with those of butter on blood lipid profiles related to cardiovascular disease risk factors in normolipemic adults fed controlled diets. Am J Clin Nutr 1998; 68: 768–777. 39. VERA-Schriftenreihe. Lebensmittel- und Nährstoffaufnahme in der Bundesrepublik Deutschland. Vol 12. Niederkleen: Wissenschaftlicher Fachverlag Dr. Fleck, 1994. 40. Kraft J, Collomb M, Mockel P, Sieber R, Jahreis G. Differences in CLA isomer distribution of cow’s milk lipids. Lipids 2003; 38: 657–664. 41. Miller M, Kwiterovich PO Jr. Isolated low HDL cholesterol as an important risk factor for coronary heart disease. Eur Heart J 1990; 11(Suppl H): 9–14. 42. Gotto AM Jr. Low high-density lipoprotein cholesterol as a risk factor in coronary heart disease: a working group report. Circulation 2001; 103: 2213–2218. 43. Danesh J, Collins R, Peto R. Lipoprotein(a) and coronary heart disease. Meta-analysis of prospective studies. Circulation 2000; 102: 1082–1085. 44. Dieplinger H, Kronenberg F. Genetics and metabolism of lipoprotein(a) and clinical implications (Part 2). Wien Klin Wochenschr 1999; 111: 46–55.

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45. Peng DQ, Zhao SP, Wang JL. Lipoprotein (a) and apolipoprotein E epsilon 4 as independent risk factors for ischemic stroke. J Cardiovasc Risk 1999; 6: 1–6. 46. Cantin B, Despres JP, Lamarche B et al. Association of fibrinogen and lipoprotein(a) as a coronary heart disease risk factor in men (The Quebec Cardiovascular Study). Am J Cardiol 2002; 89: 662–666. 47. Williams CM, Francis-Knapper JA, Webb D et al. Cholesterol reduction using manufactured foods high in monounsaturated fatty acids: a randomized crossover study. Br J Nutr 1999; 81: 439–446. 48. Mensink RP, Katan MB. Effect of dietary fatty acids on serum lipids and lipoproteins. A meta-analysis of 27 trials. Arterioscler Thromb 1992; 12: 911–919. 49. Dietschy JM. Dietary fatty acids and the regulation of plasma low density lipoprotein cholesterol concentrations. J Nutr 1998; 128: 444S–8. 50. Phan CT, Mortimer BC, Martins IJ, Redgrave TG. Plasma clearance of chylomicrons from butterfat is not dependent on saturation: studies with butterfat fractions and other fats containing triacylglycerols with low or high melting points. Am J Clin Nutr 1999; 69: 1151–1161. 51. Hodge J, Li D, Redgrave TG, Sinclair AJ. The metabolism of native and randomized butterfat chylomicrons in the rat is similar. Lipids 1999; 34: 579–582. 52. Tricon S, Burdge GC, Kew S et al. Opposing effects of cis-9,trans-11 and trans-10,cis-12 conjugated linoleic acid on blood lipids in healthy humans. Am J Clin Nutr 2004; 80: 614–620. 53. Pereira MA, Jacobs DR Jr., Van Horn L, Slattery ML, Kartashov AI, Ludwig DS. Dairy consumption, obesity, and the insulin resistance syndrome in young adults: the CARDIA study. JAMA 2002; 287: 2081–2089. 54. Mirmiran P, Esmaillzadeh A, Azizi F. Dairy consumption and body mass index: an inverse relationship. Int J Obes Relat Metab Disord 2004; 29: 115–121. 55. Barba G, Troiano E, Russo P, Venezia A, Siani A. Inverse association between body mass and frequency of milk consumption in children. Br J Nutr 2005; 93: 15–19. 56. Marques-Vidal P, Goncalves A, Dias CM. Milk intake is inversely related to obesity in men and in young women: data from the Portuguese health interview survey 1998–1999. Int J Obes Relat Metab Disord 2005; 30: 88–93. 57. Snijder MB, van der Heijden AAWA, van Dam RM et al. Is higher dairy consumption associated with lower body weight and fewer metabolic disturbances? The Hoorn study. Am J Clin Nutr 2007; 85: 989–995. 58. Barba G, Russo P. Dairy foods, dietary calcium and obesity: a short review of the evidence. Nutr Metab Cardiovasc Dis 2006; 16: 445–451. 59. Krachler B, Norberg M, Eriksson JW et al. Fatty acid profile of the erythrocyte membrane preceding development of type 2 diabetes mellitus. Nutr Metab Cardiovasc Dis 2008; 18: 503–510. 60. Wolk A, Furuheim M, Vessby B. Fatty acid composition of adipose tissue and serum lipids are valid biological markers of dairy fat intake in men. J Nutr 2001; 131: 828–833. 61. Ness AR, Smith GD, Hart C. Milk, coronary heart disease and mortality. J Epidemiol Commun Health 2001; 55: 379–382. 62. Warensjo E, Jansson JH, Berglund L et al. Estimated intake of milk fat is negatively associated with cardiovascular risk factors and does not increase the risk of a first acute myocardial infarction. A prospective case–control study. Br J Nutr 2004; 91: 635–642. 63. Elwood PC, Pickering JE, Fehily AM, Hughes J, Ness AR. Milk drinking, ischaemic heart disease and ischaemic stroke I. Evidence from the Caerphilly cohort. Eur J Clin Nutr 2004; 58: 711–717. 64. Elwood PC, Pickering JE, Hughes J, Fehily AM, Ness AR. Milk drinking, ischaemic heart disease and ischaemic stroke II. Evidence from cohort studies. Eur J Clin Nutr 2004; 58: 718–724. 65. Menotti A, Kromhout D, Blackburn H, Fidanza F, Buzina R, Nissinen A. Food intake patterns and 25-year mortality from coronary heart disease: cross-cultural correlations in the seven countries study. The Seven Countries Study Research Group. Eur J Epidemiol 1999; 15: 507–515. 66. Zemel MB, Shi H, Greer B, Dirienzo D, Zemel PC. Regulation of adiposity by dietary calcium. FASEB J 2000; 14: 1132–1138. 67. Carruth BR, Skinner JD. The role of dietary calcium and other nutrients in moderating body fat in preschool children. Int J Obes Relat Metab Disord 2001; 25: 559–566. 68. Iso H, Stampfer MJ, Manson JE et al. Prospective study of calcium, potassium, and magnesium intake and risk of stroke in women. Stroke 1999; 30: 1772–1779. 69. Assmann G, Schulte H. Relation of high-density lipoprotein cholesterol and triglycerides to incidence of atherosclerotic coronary artery disease (the PROCAM experience). Prospective Cardiovascular Munster study. Am J Cardiol 1992; 70: 733–737. 70. Austin MA. Epidemiology of hypertriglyceridemia and cardiovascular disease. Am J Cardiol 1999; 83: 13F–6.

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71. Criqui MH. Triglycerides and cardiovascular disease. A focus on clinical trials. Eur Heart J 1998; 19(Suppl A): A36–A39. 72. Tholstrup T, Marckmann P, Hermansen J, Holmer G, Sandstrom B. Effect of modified dairy fat on fasting and postprandial haemostatic variables in healthy young men. Br J Nutr 1999; 82: 105–113. 73. Hilbig, A., Heuer, T., Krems, C., Straßburg, A., Eisinger-Watzl, M., Heyer, A., Tschida, A., Götz, A., Pfau, C. What does Germany eat?—Evaluation of the Second National Diet Study (NSV II). Ernahrungs-Umschau 2009; 56, 16–23.

Chapter 15

Modified Milk Fat Reduces Plasma Triacylglycerol Concentrations: Health and Disease Effects Hélène Jacques, Nadine Leblanc, and Nathalie Bergeron

Key Points • Milk fat has a unique fatty acid profile and is a very complex mixture of triglycerides and is generally considered a cholesterol-raising ingredient, as it contains a large proportion of saturated fatty acids and moderate amount of cholesterol. • Various techniques are currently under active development to improve the nutritional value of milk fat, and counteract its adverse effect on plasma lipids and atherogenic lipoproteins through modified milk fats. • The effects of reduction of saturated fatty acids and/or cholesterol as well as an elevation of unsaturated fatty acids through various technologies such as the modification of cow feeding, interesterification, and fractionation technologies on various risk factors for cardiovascular diseases are critically reviewed in this chapter. • Modifications of milk fat composition through alteration of cow feeding, incorporation of fish oil into butter blend by enzymatic interesterification, or the application of physical fractionation processes resulting in fat fractions with favorable nutritional properties appear to be among the most promising options. Keywords Modified milk fat · Cow feeding · Interesterification · Fractionation · Plasma lipids and lipoproteins · Cardiovascular diseases

1 Introduction Milk fat represents from 3 to 5% of milk and is composed mainly of triacylglycerols (98%), phospholipids (0.8%), and cholesterol (0.5%) [1]. Milk fatty acids are typically composed of 70% saturated fatty acids, 25% monounsaturated fatty acids, and 5% polyunsaturated fatty acids

H. Jacques () Department of Food Science and Nutrition, Institute of Nutraceuticals and Functional Foods, Laval University, 2425 Agriculture St., Paul-Comtois Building, Quebec, QC, G1V 0A6 Canada e-mail: [email protected] F. De Meester et al. (eds.), Modern Dietary Fat Intakes in Disease Promotion, Nutrition and Health, DOI 10.1007/978-1-60327-571-2_15, © Springer Science+Business Media, LLC 2010

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[2]. The chain length of the fatty acids, their degree of unsaturation, and their position within the triacylglycerol molecules influence the nutritional and physical properties of fatty acids [3]. Myristic (14:0), palmitic (16:0), and stearic (18:0) acids are main saturated fatty acids found in whole milk fat (9–12, 23–32, and 13% of total fat, respectively). The high content of saturated fatty acids in milk fat is a concern because consumption of diets rich in saturated fatty acids has been associated with elevated blood pressure, insulin resistance, increased low-density lipoprotein (LDL) cholesterol [4–8], and postprandial triglycerides [9, 10], all biological markers of cardiovascular risk, whereas unsaturated fatty acids have opposite effects [6, 11]. In addition to saturated fatty acids, dietary cholesterol may also increase the cholesterol-raising effect of saturated fatty acids and raise plasma and LDL-cholesterol concentrations [12–14]. Butter is a water-in-oil emulsion comprised of >80% milk fat and 16% water in the form of tiny droplets. When compared to vegetable oils rich in either saturated fatty acids (coconut) or polyunsaturated fatty acids (safflower), butter increases plasma and LDL cholesterol, as well as plasma apolipoprotein B [15]. Butter has also been shown to induce higher levels of total and LDL cholesterol when compared to margarines with or without trans fatty acids. When comparing the effect of butter, butter–olive oil (50:50) and butter–sunflower oil (50:50), the butter diet produced a small, but significant rise (5%) in total serum cholesterol and LDL cholesterol, relative to the other two diets [16]. This review highlights the major scientific advances in changing dairy fat composition to improve plasma lipid profile. Whether these modified milk fats induce beneficial health effects in humans will also be discussed.

2 Cow Feeding Modification A healthier milk fatty acid composition could be achieved by selecting cows that produce more unsaturated milk fat, or by altering the cow’s diet. Because biohydrogenation occurs in the rumen while the microbial flora hydrolyzes and hydrogenates dietary unsaturated fatty acids, substituting unsaturated fatty acids for saturated fatty acids in dairy foods must be achieved through technology that ensured lipids in bovine feed were protected from hydrogenation in the rumen. Encapsulating coat of casein treated with formaldehyde used to protect unsaturated fatty acids, mainly linoleic and oleic acids, from saturation in the rumen [17], is one process that results in a more unsaturated and less saturated milk fat [18]. Two studies examined the effects of modified milk fats with higher unsaturated milk fatty acids on plasma cholesterol [19, 20]. Nestel et al. [19] studied 33 middle-aged healthy men and women who were eating a low-fat diet supplemented with either regular or fat-modified dairy products with higher amounts of monounsaturated fatty acids and polyunsaturated fatty acids (39 and 10%, respectively) for 3 weeks. The fat-modified dairy products resulted in a 0.28-mmol/L lowering of total cholesterol concentration (p < 0.001). Most of the decrease was in LDL cholesterol (–0.24 mmol/L, p < 0.001), whereas HDL cholesterol and triglycerides remained essentially unchanged [19]. Poppitt et al. [20] showed that the incorporation of a butterfat modified through bovine feeding to replace myristic and palmitic acids predominantly with oleic and linoleic acids resulted in a significant reduction in total (–7.9%) and LDL (–9.5%) cholesterol, without a concomitant decrease in HDL cholesterol in 20 healthy adult males.

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Because of their hard outer coats, oilseeds and their content seem to be protected from rumen biohydrogenation. Hence Tholstrup et al. [21] examined a modified milk fat produced by feeding cows a normal diet supplemented with a concentrate mixture of 50% soybean and 50% crushed double-low rapeseeds. Compared with regular Danish butter, this butter had lower amounts of palmitic acid (21.13 vs. 36.82%) and higher amounts of oleic acid (24.95 vs. 15.33%). The aim was to compare the effects of this modified milk fat with regular Danish milk fat on fasting and postprandial lipids and lipoproteins. Served as a spread and incorporated into breads, rolls, and cakes, this butter was consumed by 18 healthy young men for a 4-week period. This modified butter was also incorporated in a test meal fed on day 21 to assess the postprandial response to this fat. Although Danish milk fat and modified milk fat induced similar effects on total cholesterol, LDL-cholesterol, and apolipoprotein B concentrations, modified milk fat increased plasma fasting triacylglycerol concentrations. The authors suggested that the higher content of trans fatty acids in the modified milk fat used might have counteracted the cholesterol neutral/decreasing effect of oleic acid in this fat, and also contributed to its triacylglycerol-raising effect. The same butter was also tested for its ability to affect various hemostatic variables, such as fasting plasma factor VII coagulant (FVIIc) activity, tissue-type plasminogen activator (t-PA) activity, plasminogen activator inhibitor (PAI-1) antigen, and β-thromboglobulin [22]. Still compared to regular Danish milk fat, the modified milk fat supplemented with rapeseeds showed no benefit on the hemostatic variables measured, leading the authors to conclude that the tested milk fat had the same thrombogenic characteristics as the regular Danish milk fat. More recently, a study conducted by Seidel et al. [23] examined the effect of a modified milk fat obtained when rapeseed cakes were fed to cows, thus increasing unsaturated fatty acids by 33% and decreasing saturated fatty acids by 20% in this milk fat. Compared with regular butter and margarine, this modified milk fat increased lean mass and decreased fat mass. It also decreased LDL cholesterol, a result that was more pronounced in hypercholesterolemic subjects. High-density lipoprotein (HDL) cholesterol was increased, thus leading to a decrease in the LDL/HDL ratio, a well-recognized protective indicator of CVD risk. Several other rumen-protected unsaturated fats could be fed to cows resulting in milk with reduced saturated fatty acids: jet-sploded canola, extruded sunflower, calcium soybean, linseed or canola oil, amide soybean oil, etc. [24]. Further studies are needed to investigate the impact of those fats on plasma lipid and lipoprotein responses and CVD risk.

3 Interesterification Interesterification, performed either chemically or enzymatically, can change the distribution of fatty acids on the glycerol molecule and thereby modify the melting and crystallization characteristics of the original fat [25]. While chemical interesterification results in a random distribution of the fatty acids over all positions in the triglycerides, enzymatic interesterification is more selective and results in better retention of the butter aroma. Christophe et al. were the first researchers to assess whether substituting a chemically interesterified butter for a natural butter would affect plasma lipids and lipoproteins in humans. Human subjects fed 84 g/day of interesterified butter for 20 days had an 11% reduction in mean serum cholesterol compared with those fed natural butter [26] and experienced an earlier peak chylomicronemia in the postprandial state [27], probably due to a faster rate of digestion of this

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modified fat [28]. In contrast to these early studies, replacing natural butter by enzymatically interesterified butter had no beneficial effects on plasma lipids and lipoproteins in man [29]. It could be inferred that this discrepancy in cholesterol response may be due to differences in interesterification procedures used to produce the modified butter fats, although differences in feeding protocols and population groups studied cannot be ruled out. Mutanen et al. studied the postprandial lipoprotein response to high-fat test meals prepared with lipase-catalyzed butter oil in healthy females. They demonstrated that the interesterified butter oil beneficially decreased postprandial triacylglycerol concentrations compared with natural butter and sunflower oil [30]. Another study, conducted in hypercholesterolemic and obese subjects [31], showed that consuming an interesterified mixture of butter, medium-chain triacylglycerols, and safflower oil as compared to natural butter had no appreciable effect on plasma cholesterol concentrations but was associated with a modest rise in plasma triacylglycerols in the fasting state, probably due to the presence of medium-chain triacylglycerols in the fat mixture. Few studies with interesterified butter have been carried out in animals. Pfeuffer et al. tested the effects of a chemically vs. enzymatically interesterified butter. Compared to natural milk fat, enzymatically interesterified milk fat caused a small but significant increase in plasma total and LDL-cholesterol levels (5%) in miniature pigs, whereas the chemically interesterified milk fat significantly reduced LDL cholesterol by 10.8% [32]. In another study assessing the lipid response to butter oil transesterified with rapeseed oil, the authors concluded that this modified fat significantly affects the positional distribution of fatty acids in chylomicron-TG’s, but has no impact on lipid metabolism beyond dietary fat absorption, at least in rats [33]. The above-cited studies report controversial results on the fasting lipid response to interesterified butter and butter oil consumption. However, according to Boudreau and Arul [34], the cost of using milk fat as a brut material coupled to the presence of solvent residues and the loss of flavor of chemically interesterified butter could make it an unappealing commercial product. In light of the beneficial effects of omega-3 fatty acids on plasma triglycerides [35] and cardiovascular death [36], recent research has focused on increasing the content of omega-3 long-chain fatty acids of butter. For this purpose, fish oil was incorporated into butter blends by enzymatic interesterification, and the impact of this interesterified fish oil butter blend was tested in hamsters [37] and in humans [38]. In hamsters, the interesterified fat resulted in higher levels of omega-3 long-chain fatty acids in plasma, erythrocytes, and liver [37]. In humans, the interesterified fish oil butter blend resulted in a significant lower concentration of triacylglycerols in the plasma 2 h after the meal in comparison with the butter blend; there was, however, no significant difference in the IAUC after ingestion of the two different butter products. The authors concluded that fish oil-enriched butter blend could provide a valuable dietary source to increase the intake of n-3 long-chain polyunsaturated fatty acids in the population, leading in turn to a reduction in the postprandial response of plasma triacylglycerols [38].

4 Fractionation Technologies Milk fats are composed of triacylglycerols with various length and molecular weight, degree of unsaturation, and physical properties. At room temperature (20◦ C), milk fat is a mixture of oil, semi-hard, and hard fat. Milk fat also contains a moderate amount of cholesterol. Thus,

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physical modification of milk fat composition through fractionation technology, which could result in fat fractions with favorable food applications and nutritional properties, appears to be a promising option. This technology separates milk fat into liquid and solid fractions, according to their triacylglycerol composition. Different technologies, incorporating solvents, supercritical fluids, short-path distillation, or melt crystallization, can be used to produce a range of fats with different melting properties that can meet a wide range of applications [39].

4.1 Fractionation with Solvents Because fractionation with organic solvents, such as acetone, causes loss of flavor, pigment modification, and solvent residues in the milk fat fractions, it has not been successfully applied in the food industry. However, solvent-based fractionation is commonly used in the laboratory because it is easily accomplished, and the fractions obtained can be easily recrystallized and purified [34]. Using this approach, Lai et al. studied the plasma lipid response to fractionated milk fat in rats comparing intact butterfat, a liquid butterfat fraction enriched in oleic acid and unsaturated triacylglycerols with c40 carbon atoms, a solid butterfat fraction enriched in palmitic and stearic acids, corn oil, and palm oil in rats fed for 20 days. All tested fats were shown to have similar effects on plasma and lipoprotein cholesterol, and on plasma triacylglycerols indicating that fractionation with solvents does not beneficially affect the lipid response in rodents [40].

4.2 Supercritical CO2 Extraction The extraction of cholesterol into the mobile gas phase is determined by the balance of fat interactions: triacylglycerol with CO2 , triacylglycerol and cholesterol, and cholesterol and CO2 . Because there is less competition between triacylglycerols and CO2 for cholesterol at 200 bar pressure and 80◦ C (low gas concentration), triacylglycerols have more affinity for cholesterol. Thus, cholesterol molecules associated with short- and medium-chain triacylglycerols are then eluted into the gas phase together at low gas concentrations. However, the cholesterol molecules associated with long-chain triacylglycerols are not eluted at low gas concentrations, because of their larger size. Cholesterol esters, also because of their large size, would also not be eluted at low gas concentrations [34]. There are many advantages to supercritical CO2 fractionation but financial and energetic cost limits its use.

4.3 Complexation Processes The complexation technique aims to form complexes of cyclodextrins with cholesterol and to subsequently separate these complexes in order to remove cholesterol from animal fat [41]. This can be achieved by mixing an anhydrous milk fat with an aqueous liquid formula and β-cyclodextrin. The aqueous formula consists of a mixture of an alkali metal hydroxide (sodium or potassium), alkaline earth metal such as calcium or magnesium, and a low melting point vegetable oil. Bringing this mixture to an elevated temperature resulted in a soluble fatty acid salt

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and an alkaline metal hydroxide, and simultaneously, the presence of the alkaline earth metal led to the formation of an insoluble fatty acid salt that can be separated from the reaction mixture. Pellizon et al. [42] tested in vivo this cholesterol-reduced modified milk fat by complexation in which 36% saturated fatty acids was replaced by oleic acid. Modified milk fat reduced the LDL/HDL cholesterol ratio in hamsters when compared with regular milk fat. However, this technique is not promising because the pleasant buttery flavor is lost and replaced by off-flavor in the milk fat.

4.4 Short-Path Distillation Short-path distillation is a well-known technique using vacuum to evaporate molecules with low molecular weight, such as cholesterol from milk fat [34]. The cholesterol responses induced by the consumption of modified animal fats (including milk fat and lard) were studied in postmenopausal women [43]. Using short-path distillation, two modified animal fats were produced, one reduced in cholesterol, and the other reduced in cholesterol and then blended with a linoleic acid-rich safflower oil. The fats were incorporated into crackers, cookies, cheese, ice cream, whipped cream, sour cream, shortenings and spreads, and were consumed for 4 weeks. As expected, consuming the cholesterol-reduced animal fats lowered the mean total cholesterol, total/HDL cholesterol ratio, and apolipoprotein B compared with the intact animal fats. Interestingly, the cholesterol-reduced animal fats decreased plasma triacylglycerols when compared not only with the intact animal fats but also with the cholesterolreduced animal fats blended with vegetable oil [43].

4.5 Melt Crystallization Fractionation With melt crystallization fractionation technology, the fat is melted to destroy its crystalline structure and then agitated to cool it down. Filtration or centrifugation is then used to collect the crystals that are produced, but use of this process remains limited due to the presence of impurity in the crystals [39]. A research group from Australia has examined the effects of whole butterfat and fractions from butterfat produced by crystallization at reduced temperature on chylomicron metabolism. They compared the effects of whole butterfat and four fractions of butterfat with high melting points (cocoa butter, palm oil, and palm stearin) and low melting points (safflower oil, olive oil, and palm olein). Cholesterol ester clearance was slower from chylomicrons derived from the solid, high-saturated-butterfat fraction with a high melting point than from chylomicrons derived from whole butterfat, indicating that chylomicron remnant removal was strongly influenced by the type of dietary fat. The authors concluded that acyl arrangements in the lipid class of chylomicrons, and not fat saturation, probably influenced the association with apolipoproteins and receptors, thus in turn affecting remnant removal [44].

4.6 Combining Melt Crystallization with Short-Path Distillation Arul et al. [45] developed a technique that combines short-path distillation and melt crystallization in order to remove first the free cholesterol via the short-path distillation, and then to

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separate by melt crystallization the fats in different fractions according to their melting points. Melt crystallization is based on a slow and gradual cooling process of the fat and on the removal of crystals from the liquid phase by filtration. It is thus possible to produce a range of modified milk fat with various saturated fatty acid contents and various melting points, ranging from a milk fat in a liquid state and rich in triacylglycerols with a low melting profile, to a milk fat in a solid state and rich in triacylglycerols with a higher melting profile. Using this technique, we investigated the effects of a modified milk fat with medium–high melting profile (38◦ C) produced by combined melt crystallization and short-path distillation on plasma total and lipoprotein cholesterol and triacylglycerols in normolipidemic men. The impact of feeding a modified milk fat containing lower amounts of cholesterol (–93%), short-chain fatty acids (–18%), medium-chain fatty acids (–5%), and higher amounts of long-chain unsaturated fatty acids (+5–7%) than regular milk fat was thus investigated in our laboratory. Twenty-one healthy men, aged 22 years on average, with a normal lipid profile, were recruited for this study. Each subject was asked to consume a regular milk fat, a modified milk fat and a mixture of fat similar to the composition of the nonhydrogenated margarine as 16% of total energy intake, incorporated in various preparations, such as cakes and cookies, and used as spreads. Each experimental period lasted 4 weeks and was separated by a 4-week washout period. Compared with regular milk fat, modified milk fat did not change plasma total and LDL cholesterol, nor apolipoprotein B concentrations, but did reduce plasma total (–20%) and VLDL triacylglycerols (–27%) and cholesterol (–39%) as compared to regular milk fat and margarine. HDL2 cholesterol was unchanged following ingestion of the modified milk fat. Taken together these lipid changes following modified milk fat consumption may be viewed as favorable [46]. In the above study, we further tested whether chronic feeding of modified milk fat was associated with a lower fasting and postprandial responses of triacylglycerol-rich lipoproteins (TRL) in a subgroup of 12 normolipidemic men from our cohort. All test meals used for the postprandial study provided 40% of daily energy, with 19% of energy from proteins, 43% from carbohydrate, and 38% from fat. The test meals consisted of boneless, skinless chicken, pasta and sauce, vegetables and banana bread, and differed only with respect to the fat source used to prepare the meal (regular milk fat, modified milk fat, nonhydrogenated margarine). In addition to its impact on fasting lipids, the modified milk fat test meal induced a significantly lower 3 h postprandial increment in TRL-triacylglycerols (Fig. 15.1) and TRL-apolipoprotein B48 (Fig. 15.2) compared to the regular milk fat and nonhydrogenated margarine test meals, suggesting a reduced intestinal

Fig. 15.1 Postprandial changes in plasma triacylglycerols in young men having consumed the regular milk fat (•), the modified milk fat (), and the nonhydrogenated margarine () (p < 0.05). ∗ Significantly different from 0-h value in a given diet group. Values bearing different letters at the same time point are significantly different

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Fig. 15.2 Postprandial changes in plasma TRL-apo B-48 in young men having consumed the regular milk fat (•), the modified milk fat (), and the nonhydrogenated margarine () (p < 0.05). ∗ Significantly different from 0-h value in a given diet group. Values bearing different letters at the same time point are significantly different

absorption of the modified milk fat, presumably due to its greater solid fat content [46]. In addition, and in contrast to the other test fats that were found to induce a prolonged accumulation of TRL-triacylglycerols and apolipoprotein B100 6 h after the meal, men fed the modified milk fat experienced a faster return of these parameters to fasting values, suggesting more efficient removal of liver-derived TRL from the circulation. It has been proposed by Small [47] that fats with high-melting point may be less well digested and absorbed, suggesting that fats in the solid state at body temperature could be less well assimilated than fats in the liquid state. Chylomicrons and VLDL normally compete for hydrolysis by lipoprotein lipase, but because there were presumably less chylomicrons present 3 h postprandially after the modified milk fat diet, lipoprotein lipase activity was probably not rate limiting for hydrolysis of apo B-100 containing VLDL. This could explain the slower rise in apolipoprotein B-100 at 3 h and its faster return to fasting values at 6 h in men fed the modified milk fat test meal (Fig. 15.3).

Fig. 15.3 Postprandial changes in plasma TRL-apo B-100 in young men having consumed the regular milk fat (•), the modified milk fat (), and the nonhydrogenated margarine () (p < 0.05). ∗ Significantly different from 0-h value in a given diet group. Values bearing different letters at the same time point are significantly different

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In a later study in guinea pigs, we then compared the fasting and postprandial lipid responses to various modified milk fat fractions produced by combining melt crystallization with short-path distillation [45], with different melting profiles, with that of whole milk fat and a fat mixture similar in composition to nonhydrogenated margarine [48]. Three modified milk fats with a high (44◦ C), a medium (20◦ C), and a low (13◦ C) melting profile were tested. Guinea pigs were fed diets including 11% of energy in the form of these test fats for 28 days. At the end of this experimental period, the modified milk fat with the highest melting profile showed lower weight gain, lower levels of fasting LDL cholesterol, lower levels of postprandial triacylglycerols and increased excretion of fecal fatty acids, suggesting that this modified milk may cause poor intestinal fat digestion and absorption, and affect food intake, body weight, plasma cholesterol, and early postprandial triacylglycerol response in guinea pigs. In summary, the results from our laboratory in humans and guinea pigs reviewed above [46–48] indicate that the melting profile of modified milk fat can impact plasma fasting and postprandial lipid responses through its influence on fat absorption and/or food intake and body weight.

5 Conclusion The ultimate goal for manipulating milk composition is still directed at using milk to enhance human health. To the extent that clinical diseases such as cardiovascular diseases are linked to milk fat components, modifications of milk fat composition through alteration of cow feeding, incorporation of fish oil into butter blend by enzymatic interesterification, or the application of physical fractionation processes resulting in fat fractions with favorable nutritional properties appear to be among the most promising options.

References 1. Jensen RG. Invited review: the composition of bovine milk lipids: January 1995 to December 2000. J Dairy Sci 2002; 85: 295–350. 2. Grummer RR. Effect of feed on the composition of milk fat. J Dairy Sci 1991; 74: 3244–3257. 3. Hillbrick G, Augustin MA. Milkfat characteristics and functionality: opportunities for improvement. Aust J Dairy Technol 2002; 57: 45–51. 4. Rasmussen BM, Vessby B, Uusitupa M, Berglund L, Pedersen E, Riccardi G, Reveilles AA, Tapsell L, Hermansen K. Effects of dietary saturated, monounsaturated, and n-3 fatty acids on blood pressure in healthy subjects. Am J Clin Nutr 2006; 83: 221–226. 5. Vessby B, Uusitupa M, Hermansen K, Riccardi G, Rivellese AA, Tapsell LC, Nãsé C, Berglund L, Louheranta A, Rasmussen BM, Calvert GD, Maffetone A, Pedersen E, Gustafsson I-B, Storlien LH. Substituting dietary saturated for monounsaturated fat impairs insulin sensitivity in healthy men and women: The KANWU study. Diabetologia 2001; 44: 312–319. 6. Sacks FM, Katan M. Randomized clinical trials on the effects of dietary fat and carbohydrate on plasma lipoproteins and cardiovascular disease. Am J Med 2002; 113: 13S–24S. 7. Mensink RP, Zock PL, Kester ADM, Katan MB. Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials. Am J Clin Nutr 2003; 77: 1146–1155. 8. Nestel P. Effects of dairy fats within different foods on plasma lipids. J Am Coll Nutr 2008; 27: 735S–740S. 9. Kris-Etherton PM, Yu S. Individual fatty acid effects on plasma lipids and lipoproteins: human studies. Am J Clin Nutr 1997; 65: 1628S–1644S.

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10. Thomsen C, Rasmussen O, Lousen T, Holst JJ, Fenselau S, Schresenmeir J, Hermansen K. Differential effects of saturated and monounsaturated fatty acids on postprandial lipemia and incretin responses in healthy subjects. Am J Clin Nutr 1999; 69: 1135–1143. 11. Fernandez ML, West KL. Mechanisms by which dietary fatty acids modulate plasma lipids. J Nutr 2005; 135: 2075–2078. 12. Hopkins PN. Effect of dietary cholesterol on serum cholesterol: a meta-analysis and review. Am J Clin Nutr 1992; 55: 1060–1070. 13. Huff MW. Dietary cholesterol, cholesterol absorption, postprandial lipemia and atherosclerosis. Can J Clin Pharmacol 2003; 10: 26–32. 14. Fielding CJ, Havel RJ, Todd KM, Yeo KE, Schloetter MC, Weinberg V, Frost PH. Effects of dietary cholesterol and fat saturation on plasma lipoproteins in an ethnically diverse population of healthy young men. J Clin Invest 1995; 95: 611–618. 15. Cox C, Sutherland W, Mann J, de Jong S, Chisholm A, Skeaff M. Effects of dietary coconut oil, butter and safflower oil on plasma lipids, lipoproteins and lathosterol levels. Eur J Clin Nutr 1998; 52: 650–654. 16. Wood R, Kubena K, O’Brien B, Tseng S, Martin G. Effect of butter, mono- and polyunsaturated fatty acid-enriched butter, trans fatty acid margarine, and zero trans fatty acid margarine on serum lipids and lipoproteins in healthy men. J Lipid Res 1993; 34: 1–11. 17. Scott TW, Cook LJ, Mills SC. Protection of dietary polyunsaturated fatty acids against microbial hydrogenation in ruminants. J Am Oil Chem 1971; 48: 358–364. 18. Cook LJ, Scott TW, Ferguson KA, McDonald IW. Production of polyunsaturated ruminant body fats. Nature 1970; 228: 178–179. 19. Noakes M, Nestel PJ, Clifton PM. Modifying the fatty acid profile of dairy products through feedlot technology lowers plasma cholesterol of humans consuming the products. Am J Clin Nutr 1996; 63: 42–46. 20. Poppitt SD, Keogh GF, Mulvey TB, McArdle BH, MacGibbon AKH„ Cooper GJS. Lipid-lowering effects of a modified butter-fat: a controlled intervention trial in healthy men. Eur J Clin Nutr 2002; 56: 64–71. 21. Tholstrup T, Sandström B, Hermansen JE, Holmer G. Effect of modified dairy fat on postprandial and fasting plasma lipids and lipoproteins in healthy young men. Lipids 1998; 33: 11–21. 22. Tholstrup T, Marckmann P, Hermansen J, Holmer G,and, Sandström B. Effect of modified dairy fat on fasting and postprandial haemostatic variables in healthy young men. Br J Nutr 1999; 82: 105–113. 23. Seidel C, Deufel T, Jahreis G. Effects of fat-modified dairy products on blood lipids in humans in comparison with other fats. Ann Nutr Meta 2005; 49: 42–48. 24. Jenkins TC, McGuire MA. Major advances in nutrition: impact on milk composition. J Dairy Sci 2006; 89: 1302–1310. 25. Faur L. Transformation des corps gras à des fins alimentaires. Dans. Manuel des corps gras. Chapitre 11. Édition Technique et documentation. Paris, Lavoisier, 1992. 26. Christophe A, Matthys F, Geers R, Verdon G. Nutritional studies with randomized butter. Cholesterolemic effects of butter oil and randomised butter oil in man. Arch Intern Biophys Biochim 1978; 86: 413–415. 27. Christophe A, Verdonk G, Decatelle J, Huyghebaert A. Studies on the chylomicronemic response of loading natural or randomized butter fat. Arch Intern Biophys Biochim 1982; 90: B100–B156. 28. Christophe A, Iliano L, Verdonk G, Lauwers A. Studies on the hydrolysis by pancreatic lipase of native and randomised butter fat. Arch Intern Biophys Biochim 1981; 89: B156. 29. Christophe A, De Greyt W, Delanghe J, Huyghebaert A. Substituting enzymatically interesterified butter for native butter has no effect on lipemia or lipoproteinemia in man. Ann Nutr Metab 2000; 44: 61–67. 30. Mutanen M, Jauhiainen M, Freese R, Valsa LM. Comparison of the effects of interesterified butter oil, natural butter oil, rapeseed oil and sunflower oil on postprandial lipoprotein levels in healthy females. Nutr Metab Cardiovasc Dis 1996; 6: 6–12. 31. Mascioli EA, McLennan CE, Schaefer EJ, Lichtenstein AH, Hoy C-E, Christensen MS, Bistrian BR. Lipidemic effects of an interesterified mixture of butter, medium-chain triacylglycerol and safflower oils. Lipids 1999; 34: 889–894. 32. Pfeuffer M, De Greyt W, Schoppe I, Barth CA, Huyghebaert A. Effect of interesterification of milk fat on plasma lipids of miniature pigs. Int Dairy J 1995; 15: 265–273. 33. Becker C, Lund P, Holmer G. Effect of randomization of mixtures of butter oil and vegetable oil on absorption and lipid metabolism in rats. Eur J Clin Nutr 2001; 40: 1–9. 34. Boudreau A, Arul J. Cholesterol reduction and fat fractionation technologies for milk fat: an overview. J Dairy Sci 1993; 76: 1772–1781. 35. Harris WS. Omega-3 long-chain PUFA and triglyceride lowering: minimum effective intakes. Eur Heart J Suppl 2001; 3: D59–D61.

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36. Harris WS, Kris-Etherton PM, Harris KA. Intakes of long-chain omega-3 fatty acid associated with reduced risk for death from coronary heart disease in healthy adults. Curr Atheroscler Rep 2008; 10: 503–509. 37. Porsgaard T, Overgaard J, Krogh AL, Jensen MB, Guo Z, Mu H. Butter blend containing fish oil improves the level of n-3 fatty acids in biological tissues of hamster. J Agric Food Chem 2007; 55: 7615–7619. 38. Overgaard J, Porsgaard T, Guo Z, Lauritzen L, Mu H. Postprandial lipid responses of butter blend containing fish oil in a single-meal study in humans. Mol Nutr Food Res 2008; 52: 1140–1146. 39. Jiménez-Flores R. Trends in research for alternate uses of milk fat. J Dairy Sci 1997; 80: 2644–2650. 40. Lai HC, Lasekan JB, Monsma CC, Ney DM. Alteration of plasma lipids in the rat by fractionation of modified milk fat (butterfat). J Dairy Sci 1995; 78: 794–803. 41. Awad AC, Gray JJ (2000) Methods to reduce free fatty acids and cholesterol in anhydrous animal fat. US patent no. 6129945. 42. Pellizon M, Ana JS, Buison E, Martin J, Buison A, Jen K-LC. Effect of a modified milk fat and calcium in purified diets on cholesterol metabolism in hamsters. Lipids 2004; 39: 441–448. 43. Labat JB, Martini MC, Carr TP, Elhard BM, Olson A, Bergmann SD, Slavin JL, Hayes KC„ Hassel CA. Cholesterol-lowering effects of modified animal fats in postmenopausal women. J Am Coll Nutr 1997; 16: 570–577. 44. Phan CT, Mortimer B-C, Martins IJ, Redgrave TG. Plasma clearance of chylomicrons from butterfat is not dependent on saturation: studies with butterfat fractions and other fats containing triacylglycerols with low or high melting points. Am J Clin Nutr 1999; 69: 1151–1161. 45. Arul J, Boudreau A, Makhlouf J, Tardif R, Bellavia T. Fractionation of anhydrous milk fat by short-path distillation. J Am Oil Chem Soc 1988; 65: 1642–1646. 46. Jacques H, Gascon A, Arul J, Boudreau A, Lavigne C, Bergeron J. Modified milk fat reduces plasma triacylglycerol concentrations in normolipidemic men compared with regular milk fat and nonhydrogenated margarine. Am J Clin Nutr 1999; 70: 983–991. 47. Small DM. The effects of glyceride structure on absorption and metabolism. Annu Rev Nutr 1991; 11: 413–434. 48. Asselin G, Lavigne C, Bergeron N, Angers P, Belkacemi K, Arul J, Jacques H. Fasting and postprandial lipid response to the consumption of modified milk fats by guinea pigs. Lipids 2004; 39: 985–992.

Chapter 16

Dietary Supplements, Cholesterol and Cardiovascular Disease Hannah R. Vasanthi, Nesrin Kartal-Özer, Angelo Azzi, and Dipak K. Das

Key Points • Cholesterol-lowering nutraceuticals and functional foods play an important role in reducing the risk of coronary heart disease by improving the plasma lipoprotein profile. • Hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol levels, a preponderance of small, dense LDL particles, and an accumulation of cholesterol-rich remnant particles—emerged as the greatest “competitor” of LDL cholesterol among lipid risk factors for cardiovascular disease. • Plant-derived nutraceuticals exhibit varied lipid-lowering effects due to the presence of a number of bioactive compounds which vary with individual nutraceuticals and functional foods. • Future studies could profitably focus on the interaction of the active ingredients with the expression of the genes involved in cholesterol metabolism and the synergistic effects of nutraceuticals on the regulation of blood cholesterol at more than one metabolic site and tested to develop effective cholesterol-lowering functional foods and further translated to the human needs. Keywords Polyphenols · Resveratrol · Tocotrienols · Tocopherols · Nutraceuticals · Atherosclerosis · Cardiovascular diseases · Cholesterol · Reactive oxygen species · Redox signaling

1 Introduction Cardiovascular disease (CVD) remains the principal cause of death in both developed and developing countries accounting for roughly 25% of all deaths worldwide per year. High-fat diet, abnormalities in lipoproteins, diabetes, overweight, sedentary lifestyle, smoking, and genetic factors contribute to the risk of CVD including atherosclerosis and stroke [1]. Lifestyle changes

D.K. Das () Cardiovascular Research Center, University of Connecticut School of Medicine, Farmington, CT, USA e-mail: [email protected] F. De Meester et al. (eds.), Modern Dietary Fat Intakes in Disease Promotion, Nutrition and Health, DOI 10.1007/978-1-60327-571-2_16, © Springer Science+Business Media, LLC 2010

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including diet have been found to reduce the risk for premature CHD by 82% [2], whereas practices related to nutrition alone may reduce the risk by 60% [3]. Recently the American Heart Association Nutrition Committee [4] outlined diet and lifestyle goals for cardiovascular disease risk reduction. Interventions with nutrients include nutritious foods and beverages, functional foods, and dietary supplements. Dietary supplements deliver a concentrated form of a presumed bioactive ingredient (nutraceutical) from a food, in a nonfood matrix (usually in a tablet or capsule form), to enhance health in dosages that exceed those that can be obtained from normal food. The nutraceutical ingredients cover a wide range of chemical entities which include the polyphenols, phytoestrogens, organosulfur compounds, peptides, and vitamins. The bioactive compounds like quercetin, catechin, resveratrol, diosgenin, sulforaphane, lycopene, S-allylcysteine, hydroxytyrosol, and tocotrienol are generally of plant origin and are of interest to combat dyslipidemia and in turn reduce the risk of cardiovascular diseases. This review summarizes the findings of recent studies on the efficacy and mechanism of popular cholesterol-lowering dietary supplements and nutraceuticals.

2 Cholesterol, Cardiovascular Disease, and Its Management Cholesterol has acquired an unsavory reputation for many years due to the strong correlation between the level of blood total cholesterol (TC) and the incidence of coronary heart disease (CHD). Mammals, including humans, require cholesterol for normal metabolism. However, cholesterol is not essentially required in the diet because humans are capable of synthesizing it. CHD induced by atherosclerosis is the main cause of mortality in humans. Elevated levels of plasma TC and LDL-C are the major risk factors for atherosclerosis, whereas a high concentration of plasma HDL-C and a low ratio of TC to HDL-C are protective against CHD [5]. In the United States, 30% of the adult population have levels of blood TC higher than 240 mg/dL, whereas in China 19% of the total population have abnormal blood lipids [6, 7]. Cholesterollowering agents can be classified into six major types: HMG-CoA reductase inhibitors, LDL receptor activators, acyl CoA:cholesterol acyltransferase (ACAT) inhibitors, cholesterol–bile acid absorption inhibitors, CETP inhibitors, and PPAR agonists. HMG-CoA reductase inhibitors. Inhibition of cholesterol synthesis is the most efficient way to reduce serum cholesterol level. Cholesterol synthesis is a multienzyme pathway in which HMG-CoA reductase mediates the rate-limiting step. The discovery of the statin class of drugs (simvastatin and pravastatin) was a significant advance in the treatment of severe hypercholesterolemia. These drugs inhibit HMG-CoA reductase in the liver. However, side effects are associated with the use of these inhibitors, including rashes and gastrointestinal symptoms [8]. LDL receptor activators. Efficient removal of plasma LDL-C is essential for maintaining plasma cholesterol level in a healthy range. Removal of LDL-C from the blood is mediated by receptor-dependent and receptor-independent mechanisms. The former accounts for up to 60–80% of LDL clearance while the latter is responsible for 20–40% cholesterol clearance from the blood. Expression of LDL receptor is a function of cellular free cholesterol. When the cellular cholesterol decreases, the LDL receptor gene is transactivated. In contrast, sufficient cellular free cholesterol downregulates the LDL receptor gene. Theoretically, upregulation of LDL receptor will lead to a lower level of blood cholesterol [9].

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ACAT inhibitors. Two major forms of ACAT, namely ACAT1 and ACAT2, have been identified in mammals. In humans, ACAT2 is important in cholesterol absorption. Reduced absorption of dietary cholesterol can lead to a lower level of blood cholesterol. Intestinal ACAT2 is the primary enzyme responsible for the intracellular esterification of cholesterol. ACAT2 plays an important role in the absorption of cholesterol in the small intestine, before cholesterol is incorporated into CM [10]. In the liver, this enzyme is partially responsible for the assembly of very low-density lipoproteins (VLDL) prior to secretion into the blood [11]. TG-rich VLDL particles derived from the liver are transformed into cholesterol-rich LDL after the removal of their TG by peripheral tissues. Inhibition of ACAT activity, therefore, lowers the plasma cholesterol level by decreasing cholesterol absorption in the intestine and VLDL production in the liver. Bile acid absorption inhibitors. Bile acids are the major metabolites of cholesterol. Bile acid absorption inhibitors are known as bile acid sequestrants. They bind bile acids in the intestine, prevent their reabsorption, and generate an insoluble complex with bile acids that are excreted in the feces. The increased excretion of bile acids leads to an increase in the synthesis of bile acids from cholesterol in the liver. The lowered level of hepatic cholesterol increases the expression of LDL receptors, which remove the cholesterol from the circulation and decrease the LDL level in the blood. Ingestion of bile acid inhibitors is usually associated with upregulation of CYP7A1 encoding cholesterol 7R-hydroxylase in bile acid synthesis. CETP inhibitors. A decreased level of plasma HDL-C and an increased level of plasma LDL-C (e.g., the ratio of LDL-C/HDL-C) have been associated with an increased incidence of heart disease. CETP inhibitors prevent the transfer of cholesteryl ester from HDL to TG-rich lipoproteins in exchange for TG, which has the ability to increase the HDL-C level [12]. PPAR agonists. Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that control the expression of genes involved in carbohydrate and lipid metabolism. Activation of PPARα (e.g., by fibrates) stimulates the uptake and catabolism of fatty acids, promotes lipoprotein lipase-mediated lipolysis, and enhances HDL synthesis, resulting in reductions in plasma TGs and increases in plasma HDL-C [13]. Modulation of PPARγ (e.g., by thiazolidinediones) reduces insulin resistance and enhances peripheral glucose utilization [14]. Hence, current agents that affect nuclear receptors include PPARα and -γ agonists, while in development are newer PPARα, -γ, and -δ agonists, as well as dual PPARα/γ and “pan” PPARα/γ/δ agonists to manage dyslipidemia and associated metabolic events and combat the risk of CHD.

3 Atherosclerosis Atherosclerosis remains the major cause of age-related disease and death in the world. Many epidemiological clinical genetic and animal studies have indicated that it results from interaction between multiple genetic and environmental factorial process in which both elevated plasma cholesterol levels and proliferation of smooth muscle cells play a central role. Monocytes, macrophages, and T cells attracted to the site of injury produce inflammatory cytokines, chemokines, and reactive oxygen species [15–19]. Reactive oxygen species (ROS) are implicated in the pathogenesis of a wide variety of human diseases and atherosclerosis. Oxygen-free radicals and their byproducts that are capable of

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causing oxidative damage, collectively referred to as active or reactive oxygen species, may be cytotoxic when produced in excess. NADPH oxidase is a key enzyme in the generation of ROS that is expressed by many cell types found both in vessel wall and in blood, has been implicated in the pathogenesis of hypercholesterolemia [20–22]. Studies suggest that at moderately high concentrations, certain forms of ROS such as H2 O2 may act as signal transduction messengers [23]. Especially important, although not so extensively studied is the role played by vascular smooth muscle cells (VSMC) in the process of formation of the atherosclerotic plaque. A family of genes, the scavenger receptors (CD 36 is the most important one), recognizes and internalizes modified lipoproteins, making them susceptible to degradation [24]. These cells can accumulate oxidized LDL through their scavenger receptors in an uncontrolled manner leading to formation of the so-called foam cells. There is also an increasing body of evidence showing that VSMC apoptosis is involved in the pathogenesis of atherosclerosis [25]. For example, apoptotic VSMCs are present in human atherosclerotic lesions. Recent investigations have demonstrated that simultaneous treatments with IFN-γ and TNF-α and/or IL-β can trigger apoptosis in cultured human and rat VSMC. Oxidatively modified LDL can induce apoptosis in VSMC. Nevertheless, the mechanisms whereby apoptosis of VSMC is triggered still remain largely unknown. Previous studies have shown that H2 O2 is effective in stimulating the in vitro growth of several cell types. Also human and rat VSMC have been reported to undergo DNA synthesis in response to H2 O2 stimulation. Convicting evidence has been presented to show that intracellular H2 O2 can act as a signaling molecule or as a second messenger involved in many cellular functions such as oxidantinduced stress apoptosis and proliferation [26]. H2 O2 is generated when cells are stimulated with cytokines and growth factors. Intracellularly generated H2 O2 produces its effects through the activation of tyrosine kinase or MAP kinase since catalase or N-acetylcysteine blocks PDGFinduced tyrosine phosphorylation and MAPK activation. It has been also reported that H2 O2 increases CD36 expression [24, 25].

4 Cholesterol-Lowering Nutraceuticals Although several factors play an important role in the metabolism of cholesterol, there is no doubt that plasma TC, LDL-C, and HDL-C levels are influenced profoundly by diets. In general, plasma TC is raised by dietary cholesterol and saturated and trans fatty acids and lowered by monounsaturated and polyunsaturated fatty acids. In recent years, there has been considerable interest in the potential for using natural food components as functional foods to treat hypercholesterolemia, especially for patients whose cholesterol level is marginally high (200–240 mg/dL) and does not warrant the prescription of cholesterol-lowering drugs. Clinical trials of dietary approaches to lowering LDL-cholesterol levels have been reported to be as effective as statin medication. A combination of foods like soy, plant sterols, almonds, and viscous fibers could reduce LDL-cholesterol levels by 20%, and work better together than independently [27]. Enriched margarines were used as the source of the plant sterols; the fiber came from oats, barley, okra, and eggplant; and the soy proteins came from soy milk and tofu. There is now a consensus about recommending the Mediterranean diet pattern for the prevention of coronary heart disease (CHD) since it has a striking effect on survival. Furthermore, the Mediterranean diet appears to be effective at reducing atherosclerosis and the risk of fatal complications (i.e., sudden

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cardiac death and heart failure) of atherosclerosis. Finally, unlike drug therapies, no harmful side effect has been reported following the adoption of this dietary pattern. Many micro- and macronutrients characteristic of the Mediterranean diet interact in a synergistic way to induce states of resistance to chronic diseases [28]. The extra-nutritional constituents known as “bioactive compounds” are naturally occurring in small quantities in plant products and lipid-rich foods [29]. They exhibit a significant role in reducing the risk of CHD by decreasing the total cholesterol, LDL-C, TG, LDL oxidation, cholesterol absorption or by increasing the HDL-C and antioxidant status [30]. The bioactive compounds like quercetin, catechin, resveratrol, diosgenin, sulforaphane, lycopene, S-allylcysteine, hydroxytyrosol, and tocotrienol are of interest to combat dyslipidemia and in turn reduce the risk of cardiovascular diseases, which are discussed in the following sections.

4.1 Polyphenols Phenolic compounds, commonly referred to as polyphenols, are present in all plants and, thus, are in the diet. There are more than 8,000 phenolic structures that have been identified that vary structurally. More than 10 classes of polyphenols have been defined on the basis of chemical structure [31]. The flavonoids are the most common polyphenolic compounds present in plant food. The vast majority of plant phenolics are simple phenols and flavonoids. Although polyphenols are present in virtually all plant foods, their levels vary enormously among diets depending on the type and quantity of plant foods in the diet. For example, some plant foods and beverages that are particularly rich in polyphenols are red wine, apple and orange juices, and legumes. The primary phenols in cereals and legumes are flavonoids, phenolic acids, and tannins. The major polyphenols in wine include phenolic acids, anthocyanins, tannins, and other flavonoids. The most abundant phenolic compound in fruits is flavonol. Nuts are rich in tannins [32]. Olive oil contains both phenolic acids and hydrolyzable tannins. The predominant flavonoid in onions is quercetin glycoside, whereas in tea and apples it is quercetin-3-rutinoside. Several population studies have reported an inverse association between flavonoid intake and risk of coronary disease [32–35]. Much of the epidemiologic evidence suggests that flavonoids have a protective effect against coronary mortality. For those studies that have reported an association, putative mechanisms of action include inhibition of LDL oxidation [36] and inhibition of platelet aggregation and adhesion [37]. The cholesterol-lowering activity of tea catechins has been extensively investigated. Tea, derived from the leaves of Camellia sinensis, is the world’s most popular and widely consumed beverage. Four green tea catechin (GTC) derivatives, namely (–)-epicatechin (EC), (–)-epicatechin gallate (ECG), (–)-epigallocatechin (EGC), and (–)-epigallocatechin gallate (EGCG), have been extensively studied for their wide range of biological and pharmacological properties. GTCs have been shown to lower plasma cholesterol in several animal models and to alter cholesterol metabolism favorably in cell cultures. Although the mechanisms responsible for the cholesterol-lowering activity of GTCs are not yet fully understood, some evidence suggests that they reduce the level probably by the following mechanisms. First, they upregulate the LDL receptor mediated by activation of SREBP-2 [38, 39]. It has been claimed that EGCG was the active ingredient, which was able to increase LDL receptor activity by 3-fold

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and protein by 2.5-fold when it was incubated with HepG2 liver cells [40]. In rats fed a diet containing 2% GTCs, LDL receptor-binding activity and protein were increased by 2.7- and 3.4-fold, respectively [41]. Similarly, LDL receptor activity and protein could be upregulated by 80 and 70%, respectively, in rabbits fed a hypercholesterolemic-GTC diet [42]. Second, GTCs reduce the plasma cholesterol level by increasing fecal bile acid and cholesterol excretion. In hamsters fed a 0.1% cholesterol diet, GTCs not only decreased both plasma TC and TG but also increased excretion of both neutral and acidic sterols [43]. A similar effect was observed in rats fed tea extracts [44]. Third, GTCs have been shown to inhibit cholesterol synthesis in rabbits [42] but not in rats [44]. Data from studies of the cholesterol-lowering effects of GTCs in humans are not consistent. Epidemiological observations indicate that tea consumption is associated with reduced levels of plasma TC and LDL-C in Japanese [45] and Norwegian subjects [46]. One study demonstrated that theaflavin-rich tea extract at a dose of 375 mg a day effectively reduced TC and LDL-C in mild-to-moderate hypercholesterolemia subjects [47]. Another study found that GTCs were able to attenuate the postprandial increase in plasma TG following a fat load [48]. However, some studies did not observe a favorable effect. The results from a cross-sectional study did not demonstrate that drinking green tea was associated with changes in any of the lipid levels [49]. One study found that consumption of 900 mL of green or black tea/day by 45 volunteers for 4 weeks did not affect serum lipid concentration [50]. As the evidence for the cholesterol-lowering activity of tea in humans is mixed, further additional clinical randomized, double-blind crossover studies are needed to clarify the issue. The beneficial effects of polyphenols in red wine are relatively well established. In many countries, a high intake of saturated fats strongly correlates with a high risk of coronary heart disease, but not in France and some regions where wine consumption is high. This paradox has been attributed to the anti-LDL oxidation activity and anti-atherogenic effect of wine polyphenols [51]. The polyphenols present in grape and its seed are mainly hydroxycinnamic acid, resveratrol, flavonols, anthocyanins, catechins, and proanthocyanidins [52]. In addition, favorable modification of lipoproteins by decreasing the LDL-C/HDL-C ratio and LDL-C oxidation has also been claimed to be responsible for the reduced risk of coronary heart disease associated with moderate consumption of red wine [53]. The hypocholesterolemic activity of grape polyphenols has been demonstrated in rats [54] and hamsters [55]. Although they could not lower plasma lipids, grape polyphenols were capable of attenuating atherosclerosis in rabbits [56] and ovariectomized guinea pigs [57]. In postmenopausal women, lyophilized grape powder decreased plasma LDL cholesterol and apolipoproteins B and E [58]. When the diets of both healthy subjects and hemodialysis patients were supplemented with red grape juice, there was a significant decrease in LDL-C and apolipoprotein B-100 concentration and an increase in the concentration of HDL-C and apolipoprotein A-I [59]. In other studies on human subjects, purple grape juice or grape polyphenols did not affect the plasma cholesterol level but were able to reduce the susceptibility of LDL to oxidation and improve the endothelial function [60, 61]. Several mechanisms have been proposed to explain the cholesterol-lowering activity of grape polyphenols. One possibility is that grape polyphenols increase fecal bile acids and reduce cholesterol absorption, as rats given diets containing 2% grape monomer and polymer of anthocyanins had a greater output of fecal acidic and neutral sterols [54]. Indeed, expression of the key enzyme controlling bile acid synthesis, CYP7A1, was upregulated in rats given grape seed polyphenol extract [62]. A second possibility is that the cholesterol-lowering activity of grape polyphenols is mediated by regulating expression of LDL receptor. When HepG2 cells were incubated with dealcoholized wine extract, the mRNA of LDL receptor gene was significantly increased [63]. In HepG2 and HL-60

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cells, red grape juice increased the level of the active form of SREBP, and this was accompanied by greater mRNA expression of LDL receptor [64].

4.2 Phytoestrogens Phytoestrogens are compounds found in plants and have weak estrogenic activity by binding to estrogen receptor and initiating some estrogen-dependent transcription. Phytoestrogens have been claimed to have benefits for heart, bone, breast, and general menopausal health [65]. There is some evidence to suggest that phytoestrogens can reduce blood cholesterol level by inhibiting cholesterol synthesis and increased expression of the LDL receptors [66]. Major classes of phytoestrogens include isoflavones, flavones, flavanones, comestans, lignans, and stilbenes [67]. Resveratrol has been recognized as a phytoestrogen since it possesses structural similarities with estrogenic compounds and may exert some biological activities through estrogen receptors. In some studies, resveratrol has been shown to bind to estrogen receptors as an agonist [68]. Isoflavones have been extensively studied and are mainly found in soybean (genistein, daidzein, glycitein, and their glycosides). Soy isoflavones are the most consumed phytoestrogens in humans. Extensive research has focused on the role of soy phytoestrogens on the plasma cholesterol level in animals [69, 70]. Soy phytoestrogens are hypocholesterolemic in most animal studies. The hypocholesterolemic activity of soy phytoestrogens is mediated by their stimulating effect on LDL receptor like natural estrogen. Dietary isoflavones have been shown to reduce plasma cholesterol and atherosclerosis in C57BL/6 mice but not in LDL receptor-deficient mice [71]. In HepG2 cells, incubation with isoflavonoids, formononetin, biochanin A, and daidzein caused significant elevations in LDL receptor activity [72]. This stimulating effect on LDL receptor is probably mediated by its effect on SREBP-2, which regulates expression of both LDL receptor and HMG-CoA reductase. In phytoestrogen-treated HepG2 cells, a mature form of SREBP-2 was increased, as were LDL receptor and HMG-CoA reductase [73]. The results of randomized clinical trials in humans, however, have been inconsistent. Some clinical trials have shown that soy phytoestrogens reduce plasma TC and LDL-C in hypercholesterolemic subjects [74, 75]. However, it has been demonstrated that soy isoflavones had no dose-dependent effect [76] or had no significant effect on blood cholesterol [77]. In normocholesterolemic subjects, some clinical trials demonstrated that consumption of soy protein with a high isoflavone content significantly decreased plasma LDL-C compared with the same soy intake with a low isoflavone intake [78, 79]. In contrast, other trials found no difference in blood cholesterol between a high-isoflavone and a low-isoflavone diet [80, 81]. To evaluate more precisely the effect of soy isoflavones on plasma TC and LDL-C concentrations, Zhuo et al. [82] performed a meta-analysis of eight clinical trials, concluding that with the same soy protein intake, a highisoflavone diet had greater hypocholesterolemic activity than a low-isoflavone diet and that soy isoflavones had an LDL-C lowering effect independent of soy protein. However, Zhan and Ho [83] performed a meta-analysis of 23 randomized control trials and found that soy protein containing isoflavones significantly reduced plasma TC, LDL-C, and TG and increased HDL-C, whereas tablets containing extracted isoflavones had no effect on these parameters. In this regard, one study found soy protein fortified with isoflavones had greater LDL-C lowering activity than soy protein with isoflavone removed [84]. Further studies are needed to investigate the interaction of soy isoflavones with soy protein or the synergistic action of these two components in their contribution to the hypocholesterolemic activity of soy products.

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4.3 Phytosterols Phytosterols are naturally occurring plant sterols that are present in the nonsaponifiable fraction of plant oils. Structurally, plant sterols are similar to cholesterol except that there are always some substitutions on the sterol side chain at the C24 position. They are not synthesized in humans, are poorly absorbed, and are excreted faster from the liver than cholesterol, which explains their low abundance in human tissues [85]. The primary plant sterols in the diet are sitosterol, stigmasterol, and campesterol. Typical consumption of plant sterols is approximately 200–400 mg/day. The most abundant plant sterol in Western diets is β-sitosterol. Studies with sitosterol or mixtures of plant sterols (approximately 1 g/day) have shown that they reduce serum cholesterol levels in humans by approximately 10% [86]. This discovery has resulted in subsequent research to evaluate the effects of sitosterol derivatives on cholesterol absorption and serum cholesterol levels. Sitostanol (a 5-beta saturated sitosterol) was shown to be more potent in reducing cholesterol absorption and serum cholesterol levels than sitosterol [87]. These findings provided the basis for the current era of research evaluating the effects of sitostanol and sitostanol esters from different plant oil sources. Special margarines are the primary food source of plant sterols/stanols. The plant sterol mixtures are derived from different oil sources, including pine tree wood pulp (tall oil), soybean oil, rice bran oil, and shea nut oil. The stanol/stanol ester margarine studies have fed approximately 2–3 g/day of stanols either as the free or esterified form in full-fat or lower fat margarines or mayonnaise. Typically, there is an approximate 10% reduction in total cholesterol and about a 14% decrease in LDL cholesterol and no change in HDL cholesterol or triglyceride levels [88–93]. With a reduced-fat spread (40% fat) providing 1.1 or 2.2 g/day of plant sterol esters, LDL cholesterol was reduced 7.6 and 8.1% beyond that achieved with a National Cholesterol Education Program Step 1 diet in subjects with mild-to-moderate hypercholesterolemia [94]. Thus, both plant stanol and sterol esters evoke a significant serum cholesterol-lowering response beyond that attained with a cholesterol-lowering diet. The cholesterol-lowering effects of stanol are due to the reduction in total and LDL cholesterol as a result of decrease in cholesterol absorption and an alteration of enzymes involved in cholesterol metabolism and excretion [95]. There is some emerging evidence that the sterols present in the unsaponifiable fraction of rice bran oil, oryzanols (a group of ferulate esters of triterpene alcohols and phytosterols), decrease plasma cholesterol levels [96] and that tocotrienols, another group of phytosterols present in rice bran oil, may have important antioxidant properties [97]. Further work is needed to evaluate the effects of rice bran oil to establish its efficacy as a source of plant sterols that lower CVD risk.

4.4 Organosulfur Compounds Sulfur-containing phytochemicals of two different kinds are present in all Brassica oleracea (Cruciferae) vegetables. These are glucosinolates (GLSs, previously called thioglucosides) and S-methylcysteine sulfoxide (SMCSO). The two types of organosulfur phytochemicals found in all B. oleracea vegetables, GLS and SMCSO, or, more specifically, many of their metabolites show cardioprotective [98] and chemopreventive effect [99]. A recent clinical study with 12 healthy subjects has suggested that consumption of fresh broccoli sprouts (100 g/day) for a week reduced LDL and total cholesterol and increased HDL cholesterol [100]. Another related

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prospective study of 34,492 postmenopausal women in Iowa showed that broccoli was strongly associated with reduced risk of coronary heart disease [101]. The other commonly consumed vegetables in daily diet include the onions and garlic which contain organosulfur compounds such as allicin and S-allylcysteine and are widely regarded as a cholesterol-lowering functional food ingredient, and results from animal trials support this notion [102]. Garlic powder has been shown to suppress serum TC and TG in rats [103], whereas aged garlic extracts decreased TC by 15% and TG by 30% in rats fed a high-cholesterol diet [104]. Interestingly, raw garlic had a pronounced effect in reducing plasma TC and TG levels, whereas boiled garlic had little effect [105]. When garlic powder was added into the diet at 1% level, it not only decreased plasma TC and LDL-C but also increased HDL-C concentration in rabbits [106], thus lowering favorably the LDL-C/HDL-C ratio. Randomized controlled trials in humans have produced conflicting results. Stevinson et al. [107] conducted a meta-analysis of 13 trials and found that garlic was able to reduce blood cholesterol compared with the placebo. Similarly, in an analysis of 10 studies, Alder et al. [108] found that 6 trials demonstrated the cholesterol-lowering activity of garlic. However, some of these randomized controlled trials had methodological shortcomings, including short duration, lack of power analysis, and lack of the control of diet as a confounding variable. The underlying mechanism by which garlic and its active ingredients lower blood cholesterol has been investigated in cell culture and in animals. Principally, garlic inhibits HMGCoA reductase. The water-soluble organosulfur compounds S-allylcysteine, S-ethylcysteine, and S-propylcysteine have been shown to reduce cholesterol synthesis by deactivating HMG-CoA reductase via enhanced phosphorylation, but did not change the levels of mRNA or the amount of the enzyme in cultured rat hepatocytes [109]. To a lesser extent, garlic also inhibits CETP activity and modifies the LDL-C/HDL-C ratio. The effect of garlic supplementation on CETP activity, together with its anti-atherosclerotic effect, has been studied in cholesterol-fed rabbits, and it was found that CETP activity was significantly reduced in the garlic-supplemented group compared to the control group. Thus, garlic not only reduced atherosclerosis lesions but also altered the ratio of LDL-C/HDL-C [106].

4.5 Plant Proteins A major interest for atherosclerosis prevention has been addressed to vegetable proteins, particularly soy proteins whose consumption has been shown to successfully reduce cholesterolemia in experimental animals [110, 111], as well as in humans with cholesterol elevations of genetic or non-genetic origin [112–116]. In addition, prospective observational studies, initially in vegetarians [117], then in Chinese women [118], and more recently in a large population in Japan [119], have shown a reduction of total and LDL cholesterol as well as of ischemic and cerebrovascular events with a daily soy protein intake of more than 6 g compared to less than 0.5 g/day. Beneficial effects of a soy protein-based diet were recently described also in Iranian women with the “metabolic syndrome” [120]. Besides improved lipid metabolism, these women also showed reduced inflammatory markers as well as reduced insulin resistance [121]. The cholesterol-reducing effect of soy proteins, potentially leading to a reduced cardiovascular risk, became the basis for the US Food and Drug Administration (FDA) approval of the health claim for the role of soy protein consumption in coronary disease risk reduction [122]. The numerous ensuing clinical studies were summarized in a meta-analysis [123] of 38 studies up to 1995, in

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both hypercholesterolemic and normolipidemic individuals. This meta-analysis confirmed that serum LDL-C concentrations are modified, dependent on baseline cholesterolemia, from a minimum of −7.7% in subjects with total cholesterol in the normal range (<200 mg/dL) up to −24% in clear-cut hypercholesterolemics. Rodent and in vitro studies have attempted to establish a link between the hypocholesterolemic effects of soy and the activation/depression of liver low-density lipoprotein receptors (LDL-R) [124, 125]. Animals on cholesterol/cholic acid dietary regimens with casein have a dramatic downregulation of liver LDL-R, and this effect is reversed in the presence of soy proteins. Two studies have addressed the potential of soy protein preparations to increase LDL-R expression in human beings. Studies on the mechanism whereby vegetable proteins may reduce cholesterolemia have clearly indicated that the intact soy protein per se is effective for cholesterol reduction, not a mixture of soy amino acids [126]. The identification of soybean components responsible for the hypocholesterolemic effect has received a significant contribution from the early clinical studies where soy protein products contained less than 0.15 mg/g isoflavones [127] versus contents of 2–3 mg/g very frequently encountered in most commercial soybean products. While initially the responsibility of these phytoestrogens in cholesterol reduction was suggested primarily on the base of studies in monkeys [128], a number of more recent reports have definitely concluded that dietary isoflavones make no contribution to the hypocholesterolemic action [129–131], including a clinical study performed on pure genistein [132]. A full understanding of the mechanism of action of soy protein has become vital for the selection of the most appropriate forms of soy for treating hypercholesterolemia. The major storage proteins of soybeans are 7S and 11S globulins: from early studies, the 7S globulin appeared to be primarily responsible for the hypocholesterolemic effects of soy protein preparations, whereas the 11S component appeared essentially inactive [133, 134]. Very recently a hypocholesterolemic protein sub-component has been pinpointed more precisely, i.e., by showing that the isolated 7S globulin subunit given to cholesterol-fed rats leads to a strong upregulation of liver LDL-R activity as well as to dramatic plasma cholesterol/TG reductions [135]. An interesting activity on hypertriglyceridemia and body weight was very recently shown by Kohno et al. [136] confirming prior data by Deibert et al. [137]. The remarkable effectiveness of four candies containing 5 g of 7S globulin, a very simple regimen, thus reinforces the recommendation to increase the intake of soy proteins for cardiovascular protection. Since proteins are hydrolyzed in the gastrointestinal tract, it is quite likely that the hypocholesterolemic soy components are peptides with less than 15 amino acids, considering their potential to be absorbed. Many animal feeding studies as well as in vitro studies have documented the effects of soy peptides on serum lipids and lipid metabolism. Two clinical trials [138, 139] have reported dramatic LDL-lowering effects. In the last few years, other legumes have attracted the attention of research. A very special case is lupin since its seeds contain up to 35–40% protein as soybean, but are completely devoid of isoflavones. Two main species are cultivated: white lupin (Lupinus albus) and narrow-leaf lupin (Lupinus angustifolius). Whole seeds of narrow-leaf lupin showed a remarkable cholesterollowering effect in pigs fed a cholesterol-rich diet, compared with casein [140]. The results of this study are probably due to several bioactive components, such as protein, soluble and insoluble fibers, phytosterols, and possibly others. Other studies were instead focused only on the protein. White lupin protein, evaluated in a rat model of hypercholesterolemia [141], indicated a substantial reduction of cholesterolemia, with moderate changes of TGs and no effect of glucose. The decrease in plasma TG concentrations appears to depend on a downregulation of liver sterol regulatory element-binding protein (SREBP)-1c [142], a transcription factor that regulates the

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expression of lipogenic enzymes. White lupin protein was also evaluated in a rabbit model of focal soft plaque generated in common carotid arteries [143]. In this model, carotid lesions are mostly constituted by extracellular lipids and macrophages, thus reflecting the main feature of the human arterial plaques defined as unstable, frequently associated to acute ischemic events [144]. Dietary treatment with lupin protein significantly reduced atherosclerosis development versus casein. White lupin protein isolate was also shown to significantly lower blood pressure in spontaneous diabetic and hypertensive rats [145], possible consequence of their high content of arginine which may lead to an increased NO production. A preliminary clinical study [146], based on a lupin beverage (daily lupin protein intake = 36 g), confirmed the beneficial activities observed in the animal models. Lupin contains also fiber that added to the diet provides favorable changes in lipid metabolism as shown in a clinical study [147]. Other legumes investigated in the rat model of hypercholesterolemia are pea [148, 149], chickpea [150], and faba bean [151]; all induced a significant decrease of plasma LDL-C. A comparative study of diets containing four different legumes, baked beans, marrowfat peas, lentils, and butter beans [152], showed effectiveness of all, but baked beans and butter beans were the most potent. The hypocholesterolemic activity was confirmed in the pig model of hypercholesterolemia: a study compared bean, pea, lentil, and butter bean [153], while another investigated only pea [154]. Very recently Winham and Hutchins [155] reported that baked bean consumption in moderately hypercholesterolemic adults (mean LDL cholesterol 138 mg/dL) was associated with a reduction of LDL cholesterolemia (5.4%) with no changes in HDL-C levels. In addition, grain legumes are nutritionally important because they are valuable sources of alpha-linolenic acid (ALA) which aids in cardioprotection. Although the clinical data on legumes different from soybean are still very scarce, the general impression is that their consumption may have a very favorable role in the prevention of dislipidemia. Unfortunately data on the other risk factors such as diabetes and hypertension are completely lacking.

4.6 Tocopherols Among the factors which have been found to retard the development of atherosclerosis is the intake with food of a sufficient amount of vitamin E. An inverse association between serum vitamin E and coronary heart disease mortality has been demonstrated in epidemiological studies [156–159]. Some of the effects of α-tocopherol, which is the most active form of vitamin E, can be attributed to special properties of this compound such as the inhibition of smooth muscle cells proliferation, an important event during the progression of atherosclerosis, via inhibition of protein kinase C activity [160–162]. α-Tocopherol at concentrations of 50 μM inhibits rat A7r5 smooth muscle cell proliferation, while β-tocopherol is ineffective. The oxidized product of α-tocopherol, α-tocopherylquinone, is not inhibitory indicating that the effects of α-tocopherol are not related to its antioxidant properties [163]. δ-Tocopherol, α-tocopherol, and γ-tocopherol are within experimental error equally inhibitory [164]. On the other hand, it appears that the inhibition by β-tocopherol is 10-fold less potent relative to the other compounds. Tocotrienols, although possessing a greater antioxidant activity than tocopherols, inhibit cell proliferation to the same extent [164, 165]. Janero et al. [166] have shown in a series of 6-hydroxy-chroman-2-carbonitrile tocopherol derivatives whose antioxidant properties strongly depend on the nature and length of their side chains. These

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compounds were tested in smooth muscle cells (A7r5) and their relative potency in inhibiting cell proliferation was established [164]. Protein kinase C has been originally suggested to be regulated, at a cellular level, by α-tocopherol [164, 167–169]. A number of reports have subsequently confirmed this finding in different cell types, including monocytes, macrophages, neutrophils, fibroblasts, and mesangial cells [170–175]. The inhibitions by α-tocopherol of protein kinase C activity and of proliferation are parallel events in vascular smooth muscle cells. Inhibition is observed to occur at concentrations of α-tocopherol close to those measured in healthy adults [164, 167–169]. While α-tocopherol inhibits protein kinase C activity, β-tocopherol is ineffective. The inhibition by α-tocopherol and the lack of inhibition by β-tocopherol of cell proliferation and protein kinase C activity show that the mechanism involved is not related to the radical scavenging properties of these two molecules, which are essentially equal [169]. Animal works have also confirmed the importance of protein kinase C inhibition by α-tocopherol in vivo showing that vitamin E protects development of atherosclerosis in cholesterol-fed rabbits by inhibiting vascular smooth muscle protein kinase C activity [176–178].

4.7 CD36 and α-Tocopherol CD36 is a multifunctional membrane receptor and a cell adhesion molecule expressed by platelets, monocytes/macrophages and capillary endothelial cells, adipocytes, human cardiac and skeletal muscles, and at very low levels in the liver [179–182]. It has been shown that mice knockouts for the apolipoprotein E exhibited a marked decrease in atherosclerotic lesions if CD36 gene was made inactive [183]. CD36 scavenger receptor has been shown to be expressed in cultured human aortic smooth muscle cells and macrophages; treatment with α-tocopherol (at physiological concentration) downregulates CD36 expression by reducing its promoter activity [187]. A similar phenomenon has been also shown in human monocyte-derived macrophages where α-tocopherol decreases CD36 expression by inhibition of tyrosine kinase [183, 185, 186]. Also in rat liver, it has been shown that vitamin E regulates the scavenger receptor CD36, the coagulation factor IX, the hepatic gamma-glutamylcysteinyl synthetase, and the 5-alpha-steroid reductase type 1 gene at the transcriptional level [186]. Common models of atherosclerosis indicate in the formation of foam cells an early event in the onset of atherosclerosis. Thus, the inhibition of foam cell formation by vitamin E may be important in the prevention of the disease. A central role of CD36 in atherogenesis in a mouse model has been described by Febbraio et al. [188]. This group has shown that targeted disruption of the class B scavenger receptor CD36 protects against atherosclerotic lesion development in mice. In an in vivo model it has been shown that CD36 scavenger receptor is highly expressed in hypercholesterolemic rabbits and that vitamin E downregulates its expression without changing serum cholesterol level significantly. The significance of this finding rests on the fact that vitamin E appears to have a role in the prevention of atherosclerosis. This study also indicates that nongenetic manipulation of the CD36 expression product by vitamin E administration to rabbits on a high-cholesterol diet results in a diminution of CD36 expression and of foam cell formation [189]. Animal model studies cannot be transferred to human situations. However, the following considerations can also be made. As indicated by the propensity to atherosclerosis created in the

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mouse by the knock out of the ApoE gene (and the protection by additional CD36 knockout), also the rabbit may have a genetic background that makes it highly sensitive to the effect of vitamin E on the expression of CD36 and possibly of the SR-A, scavenger receptors [188, 190]. The notion that small intervention studies, conducted with a more homogeneous population, have shown a significant effect of vitamin E suggests that investigations on individuals having a homogeneous genetic background, especially referred to ApoE and other polymorphisms, may lead to a better understanding of the discrepancies among human studies and with the animal ones [191]. The second and more precise paradigm has been that of the identification of some antioxidants provided with different and more specific functions. One of the most important consequences of this concept is that through specific recognition interactions more precise and site-directed events could take place in a cell. This point to the uniqueness of some natural compounds, whose combination of antioxidant and non-antioxidant properties cannot be imitated or substituted for by simple synthetic antioxidants.

4.8 Other Dietary Products Very recently also fish proteins have been considered. Animal studies with fish proteins versus casein have suggested a potential hypocholesterolemic activity [192, 193]. Similar to soy, fish proteins increased liver LDL-R and SREBP-2 mRNA concentrations and significantly reduced cholesterolemia. Different from vegetable proteins, however, an HDL-C reduction was noted, albeit with an increased mRNA expression for apo AI. At present, however, little evidence has come from studies in humans, where at best, fish intake has been linked to a hypotriglyceridemic activity [194].

5 Conclusion Cholesterol-lowering nutraceuticals and functional foods play an important role in reducing the risk of coronary heart disease by improving the plasma lipoprotein profile. More and more attention is now being paid to combined atherogenic dyslipidemia which typically is presented in patients with type-2 diabetes and metabolic syndrome. This mixed dyslipidemia (or “lipid quartet”)—hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol levels, a preponderance of small, dense LDL particles, and an accumulation of cholesterol-rich remnant particles—emerged as the greatest “competitor” of LDL cholesterol among lipid risk factors for cardiovascular disease. Plant-derived nutraceuticals exhibit varied lipid-lowering effects due to the presence of a number of bioactive compounds. However, the action mechanisms for favorable modification of plasma lipids vary with individual nutraceuticals and functional foods. In addition to the nutraceuticals and foods discussed above, almond, fish oil, flaxseed, black rice, licorice, lycopenes, olive, and ginseng oil have also been claimed to possess cholesterol-lowering activity. Future studies could profitably focus on the interaction of the active ingredients with the expression of the genes involved in cholesterol metabolism. The synergistic effects of nutraceuticals on the regulation of blood cholesterol at more than one metabolic site should be tested to develop effective cholesterol-lowering functional foods and translated to the human needs.

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173. Rattan V, Sultana C, Shen YM, Kalra VK. Oxidant stress-induced transendothelial migration of monocytes is linked to phosphorylation of PECAM-1. Am J Physiol Endocrinol Metab 1997; 273: E453. 174. Studer RK, Craven PA, DeRubertis FR. Antioxidant inhibition of protein kinase C-signaled increases in transforming growth factor-beta in mesangial cells. Metabolism 1997; 46: 918. 175. Takehara Y, Kanno T, Yoshioka T, Inoue M, Utsumi K. Oxygen-dependent regulation of mitochondrial energy metabolism by nitric oxide. Arch Biochem Biophys 1995; 323: 27. 176. Özer NK, Sirikci Ö, Taha S, San T, Moser U, Azzi A. Effect of vitamin E and probucol on dietary cholesterol-induced atherosclerosis in rabbits. Free Radic Biol Med 1998; 24: 226–228. 177. Sirikci Ö, Özer NK, Azzi A. Dietary cholesterol-induced changes of protein kinase C and the effect of vitamin E in rabbit aortic smooth muscle cells. Atherosclerosis 1996; 126: 253. 178. Özer NK, Azzi A. Effect of vitamin E on the development of atherosclerosis. Toxicology 2000; 148: 179–185. 179. Aitman TJ. CD36, insulin resistance, and coronary heart disease. Lancet 2001; 357: 651–652. 180. Hirano K, Kuwasako T et al. Pathophysiology of human genetic CD36 deficiency. Trends Cardiovasc Med 2003; 13(4): 136–141. 181. Nicholson AC, Febbraio M et al. CD36 in atherosclerosis. The role of a class B macrophage scavenger receptor. Ann NY Acad Sci 2000; 902: 128–131. 182. Simantov R, Silverstein RL. CD36: a critical anti-angiogenic receptor. Front Biosci suppl 2003; 8: 874–882. 183. Suzuki H, Kurihara Y et al. The multiple roles of macrophage scavenger receptors (MSR) in vivo: resistance to atherosclerosis and susceptibility to infection in MSR knockout mice. J Atheroscler Thromb 1997; 4(1): 1–11. 184. Ricciarelli R, Zingg JM et al. Vitamin E reduces the uptake of oxidized LDL by inhibiting CD36 scavenger receptor expression in cultured aortic smooth muscle cells. Circulation 2000; 102(1): 82–87. 185. Devaraj S, Hugou I et al. Alpha-tocopherol decreases CD36 expression in human monocyte-derived macrophages. J Lipid Res 2001; 42(4): 521–527. 186. Barella L, Muller PY et al. Identification of hepatic molecular mechanisms of action of alpha-tocopherol using global gene expression profile analysis in rats. Biochim Biophys Acta 2004; 1689(1): 66–69. 187. Venugopal SK, Devaraj S et al. RRR-alpha-tocopherol decreases the expression of the major scavenger receptor, CD36, in human macrophages via inhibition of tyrosine kinase (Tyk2. Atherosclerosis 2004; 175(2): 213–220. 188. Febbraio M, Podrez EA et al. Targeted disruption of the class B scavenger receptor CD36 protects against atherosclerotic lesion development in mice. J Clin Invest 2000; 105(8): 1049–1056. 189. Özer NK, Negis Y et al. Vitamin E inhibits CD36 scavenger receptor expression in hypercholesterolemic rabbits. Atherosclerosis 2006; 184(1): 15–16. 190. Trogan E, Feig JE et al. Gene expression changes in foam cells and the role of chemokine receptor CCR7 during atherosclerosis regression in ApoE-deficient mice. Proc Natl Acad Sci USA 2006; 103(10): 3781–3786. 191. Jialal I, Devaraj S. Scientific evidence to support a vitamin E and heart disease health claim: research needs. J Nutr. 2005; 135(2): 348–353. 192. Zhang X, Beynen AC. Influence of dietary fish proteins on plasma and liver cholesterol concentrations in rats. Br J Nutr 1993; 69: 767–777. 193. Shukla A, Bettzieche A, Hirche F et al. Dietary fish protein alters blood lipid concentrations and hepatic genes involved in cholesterol homeostasis in the rat model. Br J Nutr 2006; 96: 674–682. 194. Sirtori CR, Crepaldi G, Manzato E et al. One-year treatment with ethyl esters of n-3 fatty acids in patients with hypertriglyceridemia and glucose intolerance: reduced triglyceridemia, total cholesterol and increased HDL-C without glycemic alterations. Atherosclerosis 1998; 137: 419–427.

Part IV

Contaminants in Fats and Oils: Role in Illness

Chapter 17

Ill Health Effects of Food Lipids: Consequences of Inadequate Food Processing, Storage and Cooking Peter Surai and V.I. Fisinin

Key Points • The effect of nutrition on human health has received tremendous attention and traditional medical teaching that diet and nutrients play only limited roles in human health is being revised. • Toxic products of food oxidation during food processing, storage, and cooking are the major determinants of the detrimental effects of various foods on human health. • Flavor is the trait responsible for consumer preferences for meat and meat products while lipid oxidation during prolonged storage or short-term exposure to high temperatures is often associated with off-flavors. • Lipid oxidation is a major problem in the storage of fatty foods affecting its quality and safety. Changing flavor, color, and texture results in significant generation of cytotoxic and genotoxic compounds and co-oxidizes many vitamins so that improvement of conditions of food processing, storage, and cooking is a frontline of future research. Keywords Lipids · Health · Food · Antioxidants · Cooking

1 Introduction The effect of nutrition on human health has received tremendous attention and traditional medical teaching that diet and nutrients play only limited roles in human health is being revised. In most developed countries nutritional practice has changed the focus from combating nutrient deficiencies to addressing nutrient requirements for maintaining good health throughout life.

P. Surai () Avian Science Research Centre, Scottish Agricultural College, Ayr, UK; Division of Environmental and Evolutionary Biology, University of Glasgow, Glasgow, UK; Szent István University, Gödöll˝o, Hungary; Sumy National Agrarian University, Sumy, Ukraine; Trakia University, Stara Zagora, Bulgaria; Odessa National Academy of Food Technology, Odessa, Ukraine e-mail: psurai@mail ru F. De Meester et al. (eds.), Modern Dietary Fat Intakes in Disease Promotion, Nutrition and Health, DOI 10.1007/978-1-60327-571-2_17, © Springer Science+Business Media, LLC 2010

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Chronic multifactorial diet-related diseases such as coronary heart disease (CHD), stroke, obesity, and diabetes mellitus are the major causes of mortality and morbidity worldwide, in particular in western countries. On average cardiovascular diseases (CVD, which include CHD and stroke) account for 38% of total deaths in the United States. The ratios of cardiovascular to total mortality varies from about 35 to 60% between western and eastern Europe [1]. Collectively, cardiovascular disease (including stroke), cancer, and diabetes account for approximately two-thirds of all deaths in the United States and about $700 billion in direct and indirect economic costs each year [2]. They account for nearly two of every three deaths in the United States—close to 1.5 million people in 2001 [3–5]. There is a range of different diets promoted in various countries by dieticians but, generally speaking, three major principles of healthy nutrition include variety, moderation and physical exercise. They are interlinked and ignorance of any of those causes health – related problems. Unfortunately in a modern society none of those principles are well followed. Considering improvement of the diet it is necessary to make sure that all nutrients in the diet are in optimal amounts and well protected against oxidation. It is believed that the amount and composition of fat in the diet is an important determinant of the pathobiology of many of these conditions. In particular, the relationship between dietary fats and CHD has been extensively studied with evidence emerging from cell culture experiments, animal studies, and observational and intervention studies in humans, indicating that dietary fat concentration and composition are important determinants of disease pathology [1]. However, it seems likely that toxic products of food oxidation during food processing, storage, and cooking are the major determinants of the detrimental effects of various foods on human health. Several types of diseases may be related to the exposure of humans to food-borne breakdown products of heated oils and cooked meat including atherosclerosis, the forerunner to cardiovascular disease; inflammatory joint disease, including rheumatoid arthritis; pathogenic conditions of the digestive tract; mutagenicity and genotoxicity, properties that often signal carcinogenesis; and teratogenicity, the property of chemicals that leads to the development of birth defects [6]. Indeed, the initial step for atherosclerosis development, leading to heart disease and stroke, is thought to be associated with oxidized LDL. Oxidized bases in DNA are potentially mutagenic and so are implicated in the process of carcinogenesis. Diabetes mellitus is also associated with oxidative damage to biomolecules [7]. Recently, the relation between dietary patterns and risk of cardiovascular, cancer, and all-cause mortality among 72,113 women who were free of myocardial infarction, angina, coronary artery surgery, stroke, diabetes mellitus, or cancer and were followed up from 1984 to 2002 has been evaluated [8]. Two major dietary patterns were identified: High prudent pattern scores represented high intakes of vegetables, fruit, legumes, fish, poultry, and whole grains, whereas high western pattern scores reflected high intakes of red meat, processed meat, refined grains, french fries, and sweets/desserts. After multivariable adjustment, the prudent diet was associated with a 28% lower risk of cardiovascular mortality and a 17% lower risk of allcause mortality when the highest quintile was compared with the lowest quintile. In contrast, the western pattern was associated with a higher risk of mortality from cardiovascular disease, cancer, and all causes. Flavor is the trait responsible for consumer preferences for meat and meat products. Watersoluble compounds in the lean portion of muscle impart meat taste while the lipids contribute the meat flavors [9]. Lipid oxidation during prolonged storage or short-term exposure to high temperatures is often associated with “off-flavors,” “warmed over flavor,” “rancid,” and “stale” characteristics in meat which result in product degradation and reduced case-life of an otherwise nutritious protein source. Lipid oxidation has been long recognized as a major problem in the storage of fatty foods affecting its quality and safety. First, it is a process responsible for changes

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in flavor, color, and texture. Second, the oxidation of unsaturated lipids results in significant generation of cytotoxic and genotoxic compounds. Third, the free radicals generated by the process co-oxidize many vitamins, including vitamins A, E, C, and carotenoids and impair the nutritional quality of the foods [10]. It is necessary to take into account that oxidation of fatty acids in animal tissue starts to occur almost instantly after slaughter and various postmortem factors can influence lipid oxidation and decrease the shelf life of meat products due to the initiation of peroxidation. Therefore, improvement of conditions of food processing, storage, and cooking is a frontline of future research.

2 Free Radicals and Reactive Oxygen and Nitrogen Species Free radicals are atoms or molecules containing one or more unpaired electrons. Free radicals are highly unstable and reactive and are capable of damaging biologically relevant molecules such as DNA, proteins, lipids, or carbohydrates. The animal body is under constant attack from free radicals, formed as a natural consequence of the body’s normal metabolic activity and as part of the immune system’s strategy for destroying invading microorganisms. Recently, collective terms such as reactive oxygen species (ROS) and reactive nitrogen species (RNS) have been introduced [11], including not only the oxygen or nitrogen radicals but also some nonradical reactive derivatives of oxygen and nitrogen. Superoxide (O2 ∗– ) is the main free radical produced in biological systems during normal respiration in mitochondria and by autoxidation reactions with half-life at 37◦ C in the range of 1 × 10–6 s. Superoxide can inactivate some enzymes due to formation of unstable complexes with transition metals of enzyme prosthetic groups, followed by oxidative self-destruction of the active site [12]. Depending on condition, superoxide can act as oxidizing or a reducing agent. It is necessary to mention that superoxide, by itself, is not extremely dangerous and does not rapidly cross lipid membrane bilayer [13]. However, superoxide is a precursor of other, more powerful ROS. For example, it reacts with nitric oxide with a formation of peroxynitrite (ONOO– ), a strong oxidant, which leads to the formation of reactive intermediates due to spontaneous decomposition [14, 15]. In fact, ONOO– was shown to damage a wide variety of biomolecules, including proteins (via nitration of tyrosine or tryptophan residues or oxidation of methionine or selenocysteine residues), DNA, and lipids [16]. Superoxide can also participate in the production of more powerful radicals by donating an electron, and thereby reducing Fe3+ and Cu2+ to Fe2+ and Cu+ , as follows: 3+ 2+ O− → Fe2+ /Cu+ +O2 2 +Fe /Cu

Further reactions of Fe2+ and Cu+ with H2 O2 are a source of the hydroxyl radical (∗ OH) in the Fenton reaction: H2 O2 +Fe2+ /Cu+ → ∗ OH + OH− +Fe3+ /Cu2+ The sum of reaction of superoxide radical with transition metals and transition metals with hydrogen peroxide is known as the Haber–Weiss reaction. It is necessary to underline that

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superoxide radical is a “double-edged sword.” It is beneficial when produced by activated polymorphonuclear leukocytes and other phagocytes as an essential component of their bactericidal activities but in excess it may result in tissue damage associated with inflammation. Hydroxyl radical is the most reactive species with an estimated half-life of only about 10–9 s. It can damage any biological molecule it touches; however, its diffusion capability is restricted to only about two molecular diameters before reacting [17]. Therefore, in most cases, damaging effect of hydroxyl radical is restricted to the site of its formation. In general, hydroxyl radical can be generated in human/animal body as a result of radiation exposure from natural sources (radon gas, cosmic radiation) and from man-made sources (electromagnetic radiation and radionuclide contamination). In fact, in many cases hydroxyl radical is a trigger of chain reaction in lipid peroxidation. Therefore, ROS/RNS are constantly produced in vivo in the course of the physiological metabolism in tissues. It is generally accepted that the electron-transport chain in the mitochondria is responsible for a major part of superoxide production in the body [11]. Mitochondrial electron transport system consumes more than 85% of all oxygen used by the cell and, because the efficiency of electron transport is not 100%, about 1–3% of electrons escape from the chain and the univalent reduction of molecular oxygen results in superoxide anion formation [18– 20]. About 1012 O2 molecules processed by each rat cell daily and if the leakage of partially reduced oxygen molecules is about 2%, this will yield about 2 × 1010 molecules of ROS per cell per day [21]. An interesting calculation has been made by Halliwell [18], showing that in the human body about 1.72 kg/year of superoxide radical is produced. In stress condition it would be substantially increased. Clearly, these calculations showed that free radical production in the body is substantial and many thousand biological molecules can be easily damaged if they are not protected. Recently, the role of mitochondria as a permanent source of ROS has been questioned [22]. The most important effect of free radicals on the cellular metabolism is due to their participation in lipid peroxidation reactions. The first step of this process is called the initiation phase, during which carbon-centered free radicals are produced from a precursor molecule, for example, a polyunsaturated fatty acid (PUFA): LH

Initiator −→

L∗

The initiator in this reaction could by the hydroxyl radical, radiation, or some other events or compounds. In presence of oxygen these radicals (L∗ ) react with oxygen-producing peroxyl radicals starting the next stage of lipid peroxidation called the propagation phase: L ∗ + O2 → LOO∗ At this stage, a relatively unreactive carbon-centered radical (L∗ ) is converted to a highly reactive peroxyl radical. A resulted peroxyl radical can attack any available peroxidizable material producing hydroperoxide (LOOH) and new carbon-centered radical (L∗ ): LOO ∗ +LH → LOOH + L∗ Therefore, lipid peroxidation is a chain reaction and potentially large number of cycles of peroxidation could cause substantial damage to cells. In membranes, the peroxidizable material is

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represented by PUFAs. It is generally accepted that PUFA susceptibility to peroxidation is proportional to the amount of double bonds in the molecules. In fact, docosahexaenoic acid (DHA, 22:6n–3) and arachidonic acid (AA, 20:4n–6) are among major substrates of the peroxidation in the membrane. It is necessary to underline that the same PUFAs are responsible for maintenance of physiologically important membrane properties including fluidity and permeability. Therefore, as a result of lipid peroxidation within the biological membranes their structure and functions are compromised. Proteins and DNA are also important targets for ROS. The complex structure of proteins and a variety of oxidizable functional groups of the amino acids make them susceptible to oxidative damage. In fact, the accumulation of oxidized proteins has been implicated in the aging process and in other age-related pathologies. A range of oxidized proteins and amino acids has been characterized in biological systems [23, 24]. In general the accumulation of oxidized proteins depends on the balance between antioxidants, prooxidants, and removal/repair mechanisms. Oxidation of proteins leads to the formation of reversible disulfide bridges. More severe protein oxidation causes a formation of chemically modified derivatives, e.g., Schiff’s base [25]. Nitric oxide, hydroxyl radical, alkoxyl, and peroxyl radicals as well as carbon-centered radicals, hydrogen peroxide, aldehydes or other products of lipid peroxidation can attack protein molecules. Usually, oxidative modification of proteins occurs by two different mechanisms: a site-specific formation of ROS via redox-active transition metals and nonmetal-dependent ROS-induced oxidation of amino acids [25]. The modification of a protein occurs by either a direct oxidation of a specific amino acid in the protein molecule or cleavage of the protein backbone. In both cases, biological activity of the modified proteins would be compromised. The degree of protein damage depends on many different factors [26]: • • • •

the nature and relative location of the oxidant or free radical source; nature and structure of protein; the proximity of ROS to protein target; the nature and concentrations of available antioxidants.

Normally, there is a delicate balance between the amount of free radicals generated in the body and the antioxidants to protect against them. For the majority of organisms on Earth, life without oxygen is impossible, animals, plants, and many micro-organisms rely on oxygen for the efficient production of energy. However, they pay a high price for pleasure of living in an oxygenated atmosphere since high oxygen concentration in the atmosphere is potentially toxic for living organisms. Formation of ROS in foods during storage, processing, and cooking is closely interrelated among ROS. The most important ROS are hydroxy radical and singlet oxygen. Hydrogen peroxide and superoxide anion are important precursors for hydroxyl radical and singlet oxygen formation. It is extremely important to control the formation of ROS in foods to improve the food quality [27].

3 Three Levels of Antioxidant Defense During evolution, living organisms have developed specific antioxidant protective mechanisms to deal with ROS and RNS [11]. Therefore, it is only the presence of natural antioxidants in living

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organisms, which enable them to survive in an oxygen-rich environment [18]. These mechanisms are described by the general term “antioxidant system.” It is diverse and responsible for the protection of cells from the actions of free radicals. This system includes • Natural fat-soluble antioxidants (vitamins A, E, carotenoids, ubiquinones, etc.); • Water-soluble antioxidants (ascorbic acid, uric acid, taurine, etc.); • Antioxidant enzymes: glutathione peroxidase (GSH-Px), catalase (CAT), and superoxide dismutase (SOD); • Thiol redox system consisting of the glutathione system (glutathione/glutathione reductase/glutaredoxin/glutathione peroxidase) and a thioredoxin system (thioredoxin/thioredoxin peroxidase/thioredoxin reductase). The protective antioxidant compounds are located in organelles, subcellular compartments, or the extracellular space enabling maximum cellular protection to occur. Thus, antioxidant system of the living cell includes three major levels of defense [28–31]: The first level of defense is responsible for prevention of free radical formation by removing precursors of free radicals or by inactivating catalysts and consists of three antioxidant enzymes namely SOD, GSH-Px, and CAT plus metal-binding proteins. Since the superoxide radical is the main free radical produced in physiological conditions in the cell [18] superoxide dismutase (EC 1.15.1.1) is considered to be the main element of the first level of antioxidant defense in the cell [29]. This enzyme dismutates the superoxide radical in the following reaction: 2O∗2 + 2H+ → H2 O2 + O2 The hydrogen peroxide formed by SOD action can be detoxified by GSH-Px or CAT which reduce it to water as follows: H2 O2 + 2GSH → GSSG + 2H2 O 2H2 O2 → 2H2 O + O2 Transition metal ions also accelerate the decomposition of lipid hydroperoxides into cytotoxic products such as aldehydes, alkoxyl radicals, and peroxyl radicals: LOOH + Fe2+ → LO∗ +Fe3+ +OH− LOOH + Fe3+ → LOO∗ +Fe2+ +H+ Therefore, metal-binding proteins (transferrin, lactoferrin, haptoglobin, hemopexin, metallothionein, ceruloplasmin, ferritin, albumin, myoglobin, etc.) also belong to the first level of defense. It is necessary to take into account that iron and copper are powerful promoters of free radical reactions and therefore their availability in “catalytic” forms is carefully regulated in vivo [32]. Therefore, organisms have evolved to keep transition metal ions safely sequestered in storage or transport proteins. In this way, the metal-binding proteins prevent formation of hydroxyl

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radical by preventing them from participation in radical reactions. For example, transferrin binds the iron (about 0.1% of the total-body reserves), transports it in the plasma pool, and attaches it to the transferrin receptor. The important point is that iron associated with transferrin will not catalyze free radical reaction. Ferritin is considered to be involved in iron storage (about 30% of the total-body reserves) within the cytosol in various tissues including liver and spleen. Major part of iron in the body (55–60%) is associated with hemoglobin within red cells and about 10% with myoglobin in muscles [33]. A range of other iron-containing proteins (mainly enzymes) can be found in the body, including NADH dehydrogenase, cytochrome P450, ribonucleotide reductase, proline hydroxylase, tyrosine hydroxylase, peroxidases, catalase, cyclooxygenase, aconitase, succinate dehydrogenase, etc. [33]. Despite an importance of iron in various biochemical reactions, iron can be extremely dangerous when not carefully handled by proteins. In fact, in many stress conditions a release of free iron from its normal sites and its participation in Fenton chemistry mediate damages to cells. For example, superoxide radical can release iron from ferritin and H2 O2 degrades the heme of hemoglobin to liberate iron ions [34]. Unfortunately, this first level of antioxidant defense in the cell is not sufficient to completely prevent free radical formation and some radicals do escape through the preventive first level of antioxidant safety screen initiating lipid peroxidation and causing damage to DNA and proteins. Therefore, the second level of defense consists of chain-breaking antioxidants—vitamin E, ubiquinol, carotenoids, vitamin A, ascorbic acid, uric acid, and some other antioxidants. Glutathione and thioredoxin systems also have a substantial role in the second level of antioxidant defense. Chain-breaking antioxidants inhibit peroxidation by keeping the chain length of the propagation reaction as small as possible. Therefore, they prevent the propagation step of lipid peroxidation by scavenging peroxyl radical intermediates in the chain reaction: LOO∗ +Toc → Toc∗ +LOOH (LOO∗ is lipid peroxyl radical; Toc – tocopherol, Toc∗ – tocopheroxyl radical, LOOH – lipid hydroperoxide) Vitamin E, the most effective natural free radical scavenger identified to date, is the main chain-breaking antioxidant in the cell. However, hydroperoxides, produced in the reaction of vitamin E with the peroxyl radical, are toxic and if not removed impair membrane structure and functions. In fact, lipid hydroperoxides are not stable and in the presence of transition metal ions can decompose producing new free radicals and cytotoxic aldehydes [35]. Therefore, hydroperoxides have to be removed from the cell in the same way as H2 O2 , but catalase is not able to detoxify these compounds and only Se-dependent GSH-Px can deal with them converting hydroperoxides into nonreactive products [36] as follows: ROOH + 2GSH → ROH(nontoxic) + H2 O + GSSG Thus, vitamin E performs only half the job in preventing lipid peroxidation by scavenging free radicals and forming hydroperoxides. The second part of this important process of antioxidant defense is due to Se-GSH-Px. It is necessary to underline that vitamin E and selenium work in a tandem; and even very high doses of dietary vitamin E cannot replace Se which is needed (in the form of GSH-Px and thioredoxin reductase) to complete the second part of antioxidant defense as mentioned above. Thus, Se as an integral part of the GSH-Px and thioredoxin reductase belongs to the first and second levels of antioxidant defense.

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Coenzyme Q is considered to be an important antioxidant, which is synthesized in vivo (see Chapter 28), and is an important integral part of the antioxidant defense system in the cell. Carotenoids recently were included into the family of natural antioxidants. They exhibit their maximum antioxidant activity at low oxygen pressures, which prevail in healthy tissues. It has been recently hypothesized that carotenoids are not the major antioxidant players themselves but rather are an important part of the antioxidant system [30]. Therefore, antioxidant interactions including their recycling provide an effective and reliable system of defense from free radicals and toxic products of their metabolism. Vitamin C is a hydrophilic antioxidant functioning in an aqueous environment and possessing high free radical-scavenging activity [17]. It directly reacts with O2 – and OH∗ and various lipid hydroperoxides and is taking part in the vitamin E recycling [17, 37]. Ascorbic acid is protective against a number of ROS [37–39]. Glutathione (GSH) is the most abundant nonprotein thiol in avian and mammalian cells and considered to be an active antioxidant in biological systems providing cells with their reducing milieu [40]. Cellular GSH plays a key role in many biological processes [41, 42]. Therefore, a crucial role for GSH is as a free radical scavenger, particularly effective against the hydroxyl radical [43], since there are no enzymatic defenses against this species of radical. Usually, decreased GSH concentration in tissues is associated with increased lipid peroxidation [44]. Furthermore in stress conditions, GSH prevents the loss of protein thiols and vitamin E [45] and plays an important role as a key modulator of cell signaling [46]. Animals and humans are able to synthesize glutathione. Uric acid is traditionally considered to be a metabolically inert end product of purine metabolism in man, without any physiological value. However, this ubiquitous compound has proven to be a selective antioxidant [47, 48]. However, even the second level of antioxidant defense in the cell is not able to prevent damaging effects of ROS and RNS on lipids, proteins, and DNA. In this case, the third level of defense is based on systems that eliminate damaged molecules or repair them. This level of antioxidant defense includes lipolytic (lipases), proteolytic (peptidases or proteases), and other enzymes (DNA repair enzymes, ligases, nucleases, polymerases, proteinases, phospholipases, and various transferases). In spite of important roles of protein oxidation in pathogenesis of the development of various diseases, mechanisms for the control of protein oxidation and their repair have not been well studied and this has been a topic of great interest for the last few years. The oxidative damage to proteins is associated with alteration of transport proteins and ion dis-balance, disruption to the receptors and impair signal transduction, enzyme inactivation, etc. It is believed that conversion of –SH groups into disulfides and other oxidized species (e.g., oxyradicals) is one of the earliest events during the radical-mediated oxidation of proteins. Therefore, thioredoxin plus thioredoxin reductase deal with these changes by reducing protein disulfides to thiols and regulating redox-sensitive transcription factors [24]. The role of protein oxidation in food quality deterioration is still the subject of active discussion. For example, rainbow trout fillets were stored for 13 months at –20, –30, or –80◦ C, and samples were analyzed at regular intervals for lipid and protein oxidation markers. Detection of protein oxidation using immunoblotting revealed that high molecular weight proteins were oxidized already at t = 0 and that no new protein oxidized during storage, irrespective of the storage time and temperature [49].

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It is interesting that reversible oxidation of cysteine could be an important cellular redox sensor in some proteins [50]. Methionine residues in proteins are also very susceptible to oxidation with methionine sulfoxide formation, which was detected in native proteins [51]. This could affect activity of various proteins. In fact, almost all forms of ROS oxidize methionine residues of proteins to a mixture of the R- and S-isomers of methionine sulfoxide [52]. Methionine sulfoxide reductase (Msr) can reduce either the free or the protein-bound methionine sulfoxide back to methionine. Therefore, Msr is considered a repair mechanism for dealing with the product of reaction of oxidants with methionine residues [53]. The authors hypothesized that methionine residues function as a “last chance” antioxidant defense system for proteins. It was shown that in bacterial glutamine synthetase surface-exposed methionine residues surrounding the entrance to the active site are preferentially oxidized and other residues (e.g., cystein) within the critical regions of the protein are protected without loss of catalytic activity of the protein [53]. Indeed, due to Msr activity the methionine–methionine sulfoxide pair can function catalytically. MsrA is present in most living organisms and is encoded by a single gene and the mammalian enzyme has been detected in all tissues studied. In particular it is found in the cytosol and mitochondria of rat liver cells [54]. Msr is considered to have at least three important functions in cellular metabolism including antioxidant defense, repair enzyme, and a regulator of certain enzyme function and possibly participation in signal transduction [52, 55]. MsrA has been known for a long time, and its repairing function is well characterized; however, recently, a new methionine sulfoxide reductase was characterized [56]. It was referred to as MsrB and it was shown that the gene of MsrB is present in genomes of eubacteria, archaebacteria, and eukaryotes. Therefore, in mammals two methionine sulfoxide reductases, MsrA and MsrB, are expressed with different substrate specificity [56]. They catalyze the thioredoxin-dependent reduction of the S-isomer and R-isomer of methionine sulfoxide to methionine. Recently, the major mammalian MsrB has been identified as a selenoprotein [57, 58]. In fact it has been found that selenoprotein R is a zinc-containing stereo-specific Msr [58]. Moreover, Se deficiency in a mouse was associated with a substantial decrease in the levels of MsrB-catalytic activity, MsrB protein, and MsrB mRNA in liver and kidney tissues [59]. It has been reported that human and mouse genomes possess three MsrB genes responsible for synthesis of the following protein products: MsrB1, MsrB2, and MsrB3 [60]. In particular, MsrB1 (Selenoprotein R) was present in the cytosol and nucleus and exhibited the highest methionine-R-sulfoxide reductase activity due to the presence of selenocysteine (Sec) in its active site. Other mammalian MsrBs are not selenoproteins and contain cysteine in place of Sec and were less catalytically efficient [60, 61]. All these antioxidants are operating in the body in association with each other forming an integrated antioxidant system. The cooperative interactions between antioxidants in the cell are vital for maximum protection from the deleterious effects of free radicals and toxic products of their metabolism. For example, it is well established that vitamin E is the major antioxidant in biological membranes, a “head quarter” of antioxidant network. However, it is usually present there in low molar ratios (one molecule per 2000–3000 phospholipids) but vitamin E deficiency is difficult to induce in adult animals. It is probably due to the fact that oxidized vitamin E can be converted back into the active reduced form by reacting with other antioxidants: ascorbic acid, glutathione, ubiquinols, or carotenoids. A connection of antioxidant defense to the general body metabolism (the pentose phosphate cycle is the major producer of reducing equivalents in the form of NADPH) was demonstrated and involvement of other nutrients in this process was shown this process. For example, dietary protein is a source of essential amino acids for glutathione

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synthesis, riboflavin is an essential part of glutathione reductase, niacin is a part of NADPH, and Se is an integral part of thioredoxin reductase. At the same time, thiamine is required for transketolase in the pentose phosphate pathway. It is proven that the antioxidant protection in the cell not only depends on vitamin E concentration and location but also relies on the effective recycling. Indeed, if the recycling is effective then even low vitamin E concentrations are able to maintain high antioxidant protection in physiological conditions. For example, this could be demonstrated using chicken brain as a model system. Indeed, our data [30] indicate that the brain is characterized by extremely high concentrations of long-chain polyunsaturated fatty acids predisposing this tissue to lipid peroxidation. Furthermore, brain contains much lower levels of vitamin E than other body tissues. However, in fresh chicken brain, levels of products of lipid peroxidation are very low, which could be a reflection of an effective vitamin E recycling by ascorbic acid which is present in this tissue in comparatively high concentrations. Antioxidant recycling is the most important element in understanding mechanisms involved in antioxidant protection against oxidative stress. The rate of regeneration, or recycling, of the vitamin E radicals may affect both its antioxidant efficiency and its lifetime in biological systems. As can be seen from data presented above the antioxidant defense includes several options [30, 31]: • Decrease localized oxygen concentration; • Prevention of first-chain initiation by scavenging initial radicals (SOD, GSH-Px, and catalase); • Binding metal ions (metal-binding proteins); • Decomposition of peroxides by converting them to nonradical, nontoxic products (SeGSH-Px); • Chain breaking by scavenging intermediate radicals such as peroxyl and alkoxyl radicals (vitamins E, C, glutathione, uric acid, ubiquinol, bilirubin, etc.); • Repair and removal of damaged molecules.

4 Meat Consumption and Cancer Most of the published literature on meat in relation to cancer development has focused on colorectal cancer (CRC). There have been some studies investigating possible associations between meat and other types of cancer, including gastric, breast, prostate, and kidney cancers and cancer of the pancreas; however, the evidence in relation to these other types of cancer has been found to be weak or inconsistent [62]. It is important to mention that CRC is the third most common cancer in the world. In the United States, the estimated new cancer cases for colon and rectum cancer in 2008 were approximately 108.1 and 40.7 thousands, respectively, and estimated death for CRC was about 50,000 people [63]. It is believed that 80% of cases of CRC are sporadic (i.e., arise spontaneously) and appear to be influenced by environmental and lifestyle factors, such as diet and physical activity level. High meat intake has been associated with an increased risk of colon cancer in several studies. In particular, consumption of red meat related directly to the incidence of CRC [64]. However, the question whether red meat itself or oxidative products produced as a result of meat cooking

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influences risk of CRC remains to be resolved. The relation between dietary factors and the risk of colorectal cancer was investigated in a case–control study conducted in Pordenone province, northeastern Italy, on 123 cases of colon cancer, 125 of rectal cancer, and 699 controls admitted to hospital for acute, non-neoplastic or digestive disorders [65]. Consistent positive associations CRC were observed with more frequent consumption of bread, pasta, polenta, cheese, eggs, and red meat. Risk of colon or rectal cancer was about twice as great among those who consumed these foods more frequently. Using data from a case–control study conducted between 1985 and 1992 in northern Italy on 828 cases of colon cancer, 498 cases of rectal cancer, and 2,024 controls in hospital were investigated [66]. In particular, it was shown that 17% of CRC cases were attributable to consumption of red meat. Recently, a case–control study was conducted to evaluate the interaction between red meat consumption and colorectal cancer incidence in Ontario, Canada [67]. Colorectal cancer cases diagnosed during 1997–2000 in people of 20–74 years of age, were identified. Controls were sex-matched and age group-matched random samples of the Ontario population. Epidemiologic and food questionnaires were completed by 1,095 cases and 1,890 controls; blood was provided by 842 and 1,251, respectively. Multivariate logistic regression was used to obtain adjusted odds ratio (OR) estimates. When comparison was made between people consuming >5 red meat servings per week and those consuming ≤2 servings/week, a 1.7-fold increased colorectal cancer risk was observed. Colorectal cancer risk also increased significantly with well-done meat intake. A case–control study of 146 cases of colorectal adenoma and 228 polyp-free controls was conducted [68]. It was shown that there was a twofold increased risk of CRC in the highest, compared with the lowest, quartile of processed meat intake. Two meta-analyses on relationship between meat consumption and CRC incidence have been published. Thirteen studies were included in the first meta-analysis [69]. Pooled results indicated that a daily increase of 100 g of all meat or red meat was associated with a significant 12–17% increased risk of colorectal cancer. A significant 49% increased risk was found for a daily increase of 25 g of processed meat. Some studies have implicated red meat (including high-temperature cooked meats), whereas others have implicated processed meats. However, the second meta-analysis conducted by Norat et al. [70] found that total meat consumption was not significantly associated with risk of CRC, but that consumption of red meat and processed meat was associated with about a 33% greater risk of CRC. Therefore, it seems likely that meat cooking is responsible for formation of by-products, which are involved in cancer promotion. It has been suggested that cancer results from the accumulation of multiple mutations in key growth regulatory genes [71]. These genetic changes are a consequence of the inherent chemical instability of DNA under physiological conditions, errors made by the DNA replication and maintenance machinery, and replication of DNA bases that are chemically modified as a result of exposure to exogenous or endogenous genotoxins [72]. The loss of genomic stability and resulting gene alterations are key molecular pathogenic steps that occur early in tumorigenesis; they permit the acquisition of a sufficient number of alterations in tumor suppressor genes and oncogenes that transform cells and promote tumor progression [73].

5 Lipid Peroxidation in Food and Its Consequences The food, as a whole, is a particularly complex chemical matrix and lipid peroxidation is a leading cause of its quality deterioration. While in the raw foods the enzymatic oxidation plays a most significant role, in the processed foods, the chemical initiation (presence of free iron or

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copper) is probably the main determinant of the process [74]. It is generally accepted that in modern food technology low-level oxidation of lipids in meat, poultry, and milk during storage and processing is practically unavoidable [75]. In fact, lipid stability in meat and meat products depends on many factors. They include • • • • • •

species, muscle type, the amount and type of fat in the diet, the nutritional status of the animal at slaughter, the presence or absence of disease or infection, and the type of processing to which the meat is subjected [76].

It is generally accepted that most fried meat products contain lipid peroxides in various concentrations and if cooked meat is stored, the level of peroxidized PUFAs increases dramatically. For example, in heated turkey red muscle (a fast food) the level of lipid peroxides was found to be about 100-fold higher than in fresh turkey red meat [77] and this comprised only part of total lipid peroxides consumed every day. Fish and fish oil are especially susceptible to peroxidation due to presence of highly unsaturated docosahexaenoic (DHA, 22:6n–3), docosapentaenoic (DPA, 22:5n–3), and eicosapentaenoic (EPA, 20:5n–3) fatty acids. Once a free radical is generated, the chain reaction of oxidation is initiated, new free radicals, carbon and oxygen centered, are formed and the process is easily propagated. The net chemical result of lipid oxidation is very complex. Lipid hydroperoxides (LOOH) derived from unsaturated fatty acids are important intermediates of peroxidative reactions induced by ROS. Lipid hydroperoxides are not stable and in the presence of transition metal ions can decompose producing new free radicals and cytotoxic aldehydes [35]. This decomposition proceeds by hemolytic cleavage of a peroxy bond to form alkoxy radicals and they undergo carbon–carbon cleavage to form breakdown products including aldehydes, ketones, alcohols, hydrocarbons, esters, furans, and lactones. Indeed, lipid oxidation yields a very complex group of by-products that contribute to the flavor deterioration of foods and implicated in biological oxidation and can cause oxidative stress [78]. It is interesting to mention that the oxidation products of fatty acids, the hydroperoxides usually are tasteless and are not responsible for the off-flavors. It is their shorter chain derivatives, i.e., the hydrocarbons, alcohols, ketones, and aldehydes which are responsible for the rancidity [27]. Oxidized lipids are partly absorbed in the digestive tract [79] and incorporated into membrane phospholipids altering their structure and properties [80]. For example, chylomicrons isolated from subjects consuming oxidized fat are more susceptible to lipid peroxidation ex vivo, suggesting that at least some oxidized fatty acids are absorbed [81]. In animal models it has been shown that oxidized lipids in the diet can suppress growth [82, 83], reduce vitamin E level in tissues increasing their susceptibility to lipid peroxidation [84], increase tissue protein oxidation [85], and increase the number of aberrant crypts in the intestine [85, 86]. In particular, in rats consuming thermally oxidized corn oil, increased concentrations of lipid peroxides were observed in the liver and kidney, in association with a decreased growth rate, food, and protein efficiency ratio [87, 88]. The gastrointestinal epithelium of swine and chickens responded to oxidant stress imposed by oxidized fat by increased enterocyte turnover and the gut associated immune system was compromised [89]. The consumption of oxidized fats is associated with

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diarrhea, liver enlargement, growth depression, and histological changes in tissues of experimental animals [90–93]. Heated oils also showed potent teratogenic actions in experimental animals [94]. The genotoxicity of heated cooking oil vapors has been demonstrated [95]. In mice, the tumor-initiating activity of oil used repeatedly to fry fish has also been reported [96]. The presence of 4-oxo-2-hexenal (4-OHE) may partly explain these genotoxicity results. Indeed, 4-OHE was detected in the human diet and in cooking vapor [97]. It may be involved in cancer induction in the digestive tract, such as stomach, esophagus, and colon, because the 4-OHE-DNA adduct was detected in mouse digestive tract organs after oral administration. Malondialdehyde (MDA) is an endogenous genotoxic product of enzymatic and oxygen radical-induced lipid peroxidation whose adducts are known to exist in DNA isolated from healthy human beings. MDA is mutagenic in bacterial and mammalian cell assays, and it is carcinogenic in rats [98]. Recently, the biological consequences of the replication of MDAmodified double-stranded DNA in human cells have been studied [72]. The study revealed that MDA-induced DNA damage is mutagenic; it also provided evidence for the occurrence of a previously undetected lesion that may be highly mutagenic. This lesion may contribute significantly to the genotoxicity associated with lipid peroxidation and oxidative stress. MDA is one of the most abundant lipid peroxidation cytotoxins formed in foods, especially in meat, or endogenously in vivo [10]. After ingestion of peroxidized foods, animals and humans have been shown to excrete an increased amount of MDA in the urine and recent results revealed a relatively rapid accumulation of MDA in plasma, with a maximum level achieved 3 h after the meal [99]. During the storage or cooking of foods, lipid peroxidation proceeds and is accelerated by heat, light, and transition metals. As secondary products, various electrophilic compounds, such as malondialdehyde and α,β-unsaturated aldehydes including acrolein, crotonaldehyde, and 4-hydroxynonenal (4-HNE), are formed [100]. They readily react with DNA and have mutagenic and genotoxic potential [101, 102]. In particular, 4-HNE is a product of omega-6 fat peroxidation and forms a cyclic 1,N2 -propano-deoxyguanosine adduct upon reaction with DNA [103]. 4-HNE is a strong alkylating agent reacting rapidly with proteins, an interaction resulting in the inhibition of DNA, RNA, and protein synthesis. Possibly connected with this effect is the observation that HNE inhibits cell proliferation and at concentrations >10 μM induces irreversible cellular damage. Besides, HNE was shown to induce significant amounts of DNA fragmentation, significant levels of sister chromatid exchanges, and a dose-dependent increase in the number of mutations to 6-thioguanine resistance [104]. Indeed, 4-HNE shows mutagenicity in V79 Chinese hamster lung cells [105] and in human cells [106]. A related compound, 4-oxo-2-nonenal (4-ONE), is also produced via 4-hydroperoxy-2-nonenal as a product of lipid peroxidation [107], and it forms adducts with deoxynucleosides and DNA [108]. The cyclic 1,N [2]-propanodeoxyguanosine adducts, derived from α,β-unsaturated aldehydes, including acrolein (Acr), crotonaldehyde (Cro), and trans-4-hydroxy-2-nonenal (HNE), have been detected as endogenous DNA lesions in rodent and human tissues. Collective evidence has indicated that the oxidative metabolism of PUFAs is an important pathway for endogenous formation of these adducts [109]. One of the biggest contributors to the consumption of lipid peroxides are fast foods, since the typical American consumes approximately three hamburgers and four servings of fries per week [110]. They could provide a significant amount of potentially hazardous peroxides as well as trans-fatty acids. The percentage of fat from fast foods and ethnic foods increased from 1% in 1965 to 11% in 1996 [111]. In particular oils, which are used for deep-fat frying (e.g., chips and

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French fries preparation), are heated to very high temperature and decomposition products are formed [112]. In fact, most of the oxidized lipids in foods come from fats and oils heated at high temperature in particular from frying fats [111]. During frying, the oil undergoes three deleterious reactions: hydrolysis caused by water, oxidation, and thermal alteration caused by oxygen and heat [110]. These reactions cause the formation of polymerization products, of which over 400 have been identified [113]. Furthermore, decomposition products, which are formed as a result of reactions between food ingredients and oil, comprise another large group of potentially toxic compounds [114]. It is generally accepted that oxygen plays a major role in the deterioration of the oil during frying and selective absorption may occur, enriching the food product with breakdown oil compounds [110]. Products of lipid oxidation formed in the food depend on the temperature. For example, at low or moderate temperature hydroperoxides are the major products formed while in high-temperature-treated products secondary oxidized triacylglycerol monomers and polymers are more common compounds [111]. Therefore, food frying in fastfood restaurants may be problematic due to lengthy oil exposure to extreme conditions and the lack of adequate oil replenishment and discarding. In particular, a significant number of oils and fats from fast-food outlets contain more than 25% newly formed compounds [111]. Lipid peroxidation is associated with the formation of a wide range of secondary aldehyde products such as n-alkanals, trans-2-alkenals, 4-hydroxy-trans-2-alkenals, and MDA [115]. While linoleic, gamma-linolenic and arachidonic acids found in different foods were precursors of hexanal, propanal was the dominant aldehyde formed from the breakdown of alpha-linolenic, eicosapentaenoic, and docosahexaenoic acids [116]. For example, propional, pentenal, hexanal, and 4-hydroxynonenal were the primary aldehydes formed during lipid oxidation in beef [115]. Those products are shown to be comparatively stable and can readily diffuse into cells causing toxicological effects [117]. Therefore, prolonged frying caused a substantial rise in MDA concentration [110] which is shown to be toxic and mutagenic. Furthermore, MDA can damage proteins and phospholipids by covalent bonding and cross-linking [118]. Rats fed a diet containing MDA suffered from retarded growth, irregular intestinal activities, enlarged liver and kidneys, anemia, and low serum and liver vitamin E [119]. Similarly, the results of Raza et al. [120] showed that 4-hydroxynonenal (HNE), a reactive by-product of lipid peroxidation, caused mitochondrial oxidative stress leading to a decrease in the GSH pool and increased membrane lipid peroxidation. It is necessary to underline that heat treatment of the food can also cause heterocyclic amine formation. For example, approximately 20 heterocyclic amines of high mutagenesis were isolated and identified from protein-rich foods [110]. Furthermore, mutagenic activity was found in beef cooked in regular domestic conditions [121]. It has been shown that heterocyclic amines can cause oxidative stress leading to DNA adduct formation and oxidative DNA damage [122]. Therefore, heterocyclic amines formed during the cooking of meat and fish and possessing mutagenic, genotoxic, and carcinogenic properties can be detected in burgers, steaks, pork ribs [123, 124]. Acrylamide in food products chiefly in commercially available potato chips, potato fries, cereals, and bread was determined by liquid chromatography-tandem mass spectrometry in 30 food samples [125]. Concentrations of acrylamide varied from 14 ng/g (bread) to 3700 ng/g (potato chips) and the WHO estimates the average consumer ingests about 0.8 μg/kg body weight daily [126]. It is necessary to take into account that acrylamide caused an increase in lipid peroxidation and decrease in glutathione contents and activity of glutathione-S-transferase in the rat liver in a dose-dependent manner [127].

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The biggest killers of the modern society, cardiovascular diseases including atherosclerosis, may result at least partly from processes that occur after ingestion of high-fat foods that contain lipid oxidation end products, some of which are cytotoxic and genotoxic compounds such as oxycholesterol, 4-hydroxy-nonenal, and MDA [10, 99]. Evidence for a putative role of some of these compounds in accelerating events in the atherogenic process—the initiation of endothelial injury, the accumulation of plaque, and the termination phase of thrombosis—comes from both animal and human studies [128]. Therefore, products of oxidation of food could contribute to CVD and cancer development in various countries worldwide and prevention of food oxidation is an important task for food industry. However, in a recent UK study consumption of red or processed meat assessed separately was not related to the major risk factors for CHD [129]. Similarly, partial replacement of dietary carbohydrate with protein from lean red meat does not elevate oxidative stress or inflammation [130].

6 Antioxidants and Food Quality For the last few years consumer demands regarding aspects of meat quality have substantially increased. Therefore, a challenge to the meat industry is to enhance the image of meat purchased at the supermarket [131]. There are many meat quality characteristics that attract consumer attention. They include appearance, texture, and flavor [132] as well as tenderness, juiciness, aroma [131], and other subjective characteristics. Among these, appearance has a major impact on the initial decision of the customer to purchase or reject the product [133]. Consumers prefer fresh meat with a minimum loss of water during handling and cooking. Therefore, water-holding capacity of the meat [134] as well as color [135] and absence off-flavors [133] are considered among most important meat quality characteristics. It has been shown that sensory quality of meat is affected by muscle biochemistry and modern processing technologies [136]. For example, grinding increases oxygen incorporation into muscle and cooking releases protein-bound iron into the intracellular pool [137]. As shown above, in this process free radical production and lipid peroxidation cause membrane structure disruption, which leads ultimately to significant losses in food quality, including off-flavor, off-colors, poor texture, etc. [138]. One approach to enhancing oxidative stability of meat is to add antioxidants either into the animal diet or directly during processing [139]. For example, an increasing body of evidence indicates that increased vitamin E supplementation is an effective means of meat quality improvement in chickens, turkeys, cattle, pigs, and lambs [132, 133, 140, 141]. However, when a nutritional strategy for improving meat quality is developing it is necessary to take into account antioxidant interactions in the diet and in the cell. For example, synergism between Se and vitamin E could be used for further improvement of meat antioxidant status and decreasing lipid peroxidation during meat processing, storage, and cooking. In fact, it has been shown that GSHPx activity in muscles did not change significantly over 8-day storage of beef [142]. This means that once GSH-Px activity is elevated it is maintained postmortem. Therefore, one might expect a stabilizing effect of dietary Se supplementation during meat storage. Indeed, supplementing broiler diets with 0.25 ppm Se substantially increased GSH-Px activity in breast (2.1-fold) and leg (4.1-fold) muscle, and as a result decreased lipid peroxidation was detected (2.5-fold in breast muscle and 3.3-fold in leg muscles) after 4 days storage at 4◦ C compared to the control group

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[143]. These data clearly indicate that GSH-Px significantly contributes to the overall antioxidant defense of muscle, decreasing tissue susceptibility to lipid peroxidation and that increasing oxidative stability of skeletal muscle can be accomplished by organic Se supplementation of the diet. Protective effects of Se may be not direct, but are mediated via improvement of other chains of antioxidant defense. For example, Se in combination with vitamin E increased activity of SOD in chicken serum [144]. A stabilizing effect of Se in combination with other antioxidants on meat quality would be a great advantage in producing the so-called “designer” meat. For example, meat enriched with n–3 PUFAs was shown to have increased TBA values during storage; and the same meat from antioxidant-supplemented (Se + vitamins E and C) chickens showed lower TBA values and greater color stability during storage [145–147] inclusion of organic selenium in the chicken diet increased Se-GSH-Px activity in muscles more than twofold. A combination of organic selenium and vitamin E supplementation was associated with the highest Se-GSHPx activity in muscles. The highest level of the final product of lipid peroxidation in muscle after 2-year storage at –20◦ C was found in muscles from chickens fed on a semi-synthetic diet and characterized by the lowest vitamin E and Se-GSH-Px activity. The lowest initial level of MDA was found in muscles from birds fed diets supplemented with either 200 ppm vitamin E or 100 ppm vitamin E in combination with 0.4 ppm organic selenium. There is a great body of information indicating on one hand that adding other antioxidants into the animal diet is not as effective as vitamin E or Se and on the other hand, adding various plant extracts directly to the meat could be an effective approach to decrease lipid peroxidation and maintain meat quality. For example, supplementation of pig diets with green tea catechins is not associated with improved antioxidant status and meat quality under practice-oriented conditions [148]. Natural tocopherols (TC), rosemary (RO), green tea (GT), grape seed, and tomato extracts were supplemented in single and in combinations at total concentrations of 100 and 200 mg/kg of feed in a 4% linseed oil-containing diet to investigate the oxidative stability of broiler breast muscle [149]. The muscle alpha-tocopherol content linearly responded to the feed alpha-tocopherol content and thus there were no indications for a sparing effect on alpha-tocopherol from other antioxidant treatments. In summary, dietary natural antioxidant extracts were less effective than the treatment with synthetic antioxidants combined with alpha-tocopheryl acetate for protecting against oxidation. Thirty-six 12-week-old turkeys were distributed into six groups and were raised for 4 weeks on rations containing 0, 0.5, or 1.0% dehydrated rosemary leaves as antioxidants in the presence of alpha-tocopheryl acetate from 10 to 300 mg/kg [150]. No significant (p >0.05) changes could be observed in the alpha-tocopherol content of breast and thigh of turkeys consuming rations containing up to 1% dehydrated rosemary leaves. The refrigeration of the meats led to spontaneous increase in the MDA content of the breast and thigh meat samples. Samples from turkeys fed rations containing 300 mg/kg alpha-tocopheryl acetate showed the lowest mean levels of MDA after the 9-day refrigerated period. The incorporation of rosemary in the rations led to a modest decrease in the formation of MDA in the meats compared with the respective mean control values. The combination of alpha-tocopheryl acetate and rosemary was not associated with an additional decrease in MDA formation. There were quite a few products tested as additives to processed meat. For example, inclusion of 3% dried plum puree was effective as a natural antioxidant for suppressing lipid oxidation in precooked pork sausage patties [151]. Similarly, grape seed extract was shown to be an effective antioxidant in ground chicken thigh meat that does not affect moisture content or pH during storage, inhibits TBARS formation, helps to mitigate the prooxidative effects of NaCl, and may alter the effect of NaCl on protein solubility in salted chicken patties [152]. Indeed, grape seed

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extract at 0.02% has the potential to reduce oxidative rancidity and improve shelf life of refrigerated cooked beef and pork patties [153]. The antioxidant and antimicrobial effects of equivalent concentrations of fresh garlic (FG), garlic powder (GP), and garlic oil (GO) were investigated against lipid oxidation and microbial growth in raw chicken sausage during storage at 3◦ C [154]. Addition of either garlic or BHA (0.1 g/kg) significantly delayed lipid oxidation when compared with control. The results suggest that fresh garlic and garlic powder, through their combined antioxidant and antimicrobial effects, are potentially useful in preserving meat products.

7 Conclusions: Future Trends in Food Industry From information presented above it is clear that in most cases producers and consumers themselves are responsible for increased levels of prooxidants in the diet and ultimately in the GIT. Therefore, there is a need for changes in ways our food is produced, prepared, stored, and eaten (Table 17.1). It is possible to improve the situation both at the producer and at the consumer levels. Table 17. 1 Healthy meals via antioxidant enrichment and decreased lipid peroxidation (Adapted from Surai [31])

Meat

Egg

Fish

Technological improvement at the producer level Vitamin E enrichment Selenium enrichment Carotenoid enrichment

+++ +++ +

+++ +++ +++

+++ + +++

Food preparation Cooking oil Boiling vs frying Spices and herbs

Olive + +++

Olive +++ +++

Olive + +++

Food serving With vegetables

+++

+++

+++

Meal composition Fruit Fruit juice Red wine Tea

+++ +++ +++ +++

+++ +++ + +++

+++ +++ + +++

7.1 At the Producer Level • To enrich meats and meat-related food with vitamin E. Indeed, there is a great body of information accumulated indicating that chicken [155], turkey [156, 157], pork [141], beef [132], lamb [158], as well as meat from other species [159] can be enriched with vitamin E and this technological solution can substantially decrease lipid peroxidation in meat during processing, storage, and cooking. • To enrich meat with organic selenium. This could be beneficial in terms of preventing lipid peroxidation in meat [146, 147, 160] but more importantly, selenium is absolutely essential

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for expression of GI-GSH-Px, the main defense against lipid peroxide absorption in GIT [36]. Selenium is also important for expression of other selenoproteins (e.g., thioredoxin reductase etc.), which play an important role in antioxidant defense in the intestine and in other tissues. In fact, Se-enriched eggs, meat, and milk are already on the market in various countries in the world [30, 31]. • To improve product storage by decreasing oxygen availability and lipid peroxidation. To minimize storage of cooked products, which are especially susceptible to peroxidation • In the fast-food restaurants, to change frying oils more often and use olive oil which is less sensitive to peroxidation [161] and to enrich frying oils with natural antioxidants (e.g., tocopherol mixture). It would be an advantage to serve fast food with bigger portions of salads and use more sauces providing additional antioxidants. Some other oils (e.g., rapeseed oil) enriched with tocopherols can also be considered to be useful. • To produce antioxidant-enriched sources, especially for fast-food restaurants. Therefore, it is possible to provide consumers with a range of animal-derived products with nutritionally modified composition in such a way that they can deliver substantial amount of health-promoting nutrients to improve the general diet and help to maintain good health, in fact, in the United Kingdom in main supermarkets there are such products (Tesco, Morrisons, etc.). Therefore, without changing habits and traditions of various populations it is possible to solve problems related to deficiency of various nutrients, in particular selenium. The consumer will go to the same supermarket to buy the same animal-derived products (egg, milk, and meat), cook and consume them as usual. The only difference will be in the amount of specific nutrients delivered with such products.

7.2 At the Consumer Level • To choose olive oil for frying food. This will decrease accumulation of oxidation products [161] and will be beneficial in terms of decreasing omega-6 PUFA consumption and increasing MUFA consumption in accordance with recent health-related findings [162]. Rapeseed oil enriched with tocopherols is also an important choice. • To use more spices and herbs during cooking. This will decrease oxidation and prevent accumulation of the lipid peroxides. • To decrease usage of cooked meals after storage. • To decrease consumption of fast food, prepared by current technology of deep-frying. Use more sauces, which can provide additional antioxidants. • To make sure that meat meals are served with plenty of vegetables, providing necessary antioxidants. • To increase vegetable and fruit consumption on everyday basis. Therefore, since we cannot avoid prooxidants in our food we need to make sure that they are compensated by consumption of increased levels of natural antioxidants. For this reason, it would be advantage if our meat and fish meals are served with plenty of vegetables. Various sauces (e.g., tomato sauce) could provide additional antioxidants. Red wine could also add additional flavonoids as a source of antioxidants. Various juices are also good sources of natural antioxidants

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as well as fruits. If a meal is finished with tea, this will also add to antioxidant potential of the digesta. All these suggestions are in the line of traditional meals served in various countries of the world. Antioxidants compensate prooxidants and a positive balance in the digestive tract is the first step to healthy life. All the future exists in the past.

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Chapter 18

Mycotoxins in Human Diet: A Hidden Danger Peter Surai, Miklos Mezes, T.I. Fotina, and S.D. Denev

Key Points • Fungal metabolites called mycotoxins are considered to be unavoidable contaminants in foods and feeds and are a major problem all over the world with 25% of world’s crop production contaminated with mycotoxins. • While biological effects of mycotoxins, organ toxicity, mutagenicity, carcinogenicity, teratogenicity, and modulation of the immune system, are well documented, the relevance of mycotoxins in human medicine remains largely underestimated. • Mycotoxins may affect the reproductive system and the immune system, exhibit hormonal activity, affect specific target organs and may be neurotoxin. Development of effective technologies to prevent food contamination with mycotoxins awaits a solution. Keywords Mycotoxins · Human health · Gene expression · Oxidative stress

1 Introduction Mycotoxin contamination of the feed and food is a global problem. The major mycotoxinproducing fungal genera are Aspergillus, Fusarium, and Penicillium. The primary classes of mycotoxins are aflatoxins, zearalenones, trichothecenes, fumonisins, ochratoxins, and ergot alkaloids. However, one of the most common grain-contaminating genus of fungi, Fusarium spp., is also capable of producing other toxic secondary metabolites—the so-called emerging mycotoxins such as fusaproliferin, beauvericin, enniatins, and moniliformin. There are several unresolved questions in this regard. First, more than 25% of world’s grain production is contaminated by mycotoxins. In particular, Fusarium mycotoxins (so-called field mycotoxins) contaminate up to

P. Surai () Scottish Agricultural College, Edinburgh, Scotland, UK; Univesity of Glasgow, Glasgow, Scotland, UK; Szent István University, Gödöll˝o, Hungary; Sumy National Agrarian University, Sumy, Ukraine; Trakia University, Stara Zagora, Bulgaria e-mail: psurai@mail ru F. De Meester et al. (eds.), Modern Dietary Fat Intakes in Disease Promotion, Nutrition and Health, DOI 10.1007/978-1-60327-571-2_18, © Springer Science+Business Media, LLC 2010

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100% of the grain. Since these mycotoxins are coming from the field it is difficult to deal with them, and various technological approaches including plant selection for mycotoxin resistance did not produce any significant results. Second, in nature there are more than 300 mycotoxins, but analytical techniques for routine mycotoxins analysis are developed only for about 30 major mycotoxins. Therefore, if there is a conclusion from the analytical lab that “the mycotoxins are not found,” this means that 10–30 mycotoxins analyzed were not found. As for others, there is no answer. Third, sampling for mycotoxins analysis is extremely difficult and is an important source of errors. Fourth, there are no safe levels of mycotoxins, because of synergistic interactions of many mycotoxins: several mycotoxins in low concentrations could cause more problems than a single mycotoxin at higher dose. The various biological effects of mycotoxins such as organ toxicity, mutagenicity, carcinogenicity, teratogenicity, and modulation of the immune system are well documented by in vitro and animal experiments. Furthermore, cases of intoxication by mycotoxins are well known in veterinary medicine. However, the relevance of mycotoxins in human medicine remains largely underestimated, because material from patients with characteristic symptoms is rarely tested for mycotoxins [1]. Recent results show that in many cases membrane-active properties of various mycotoxins determine their toxicity. Indeed, incorporation of mycotoxins into membrane structures causes various detrimental changes. These changes are associated with alteration of fatty acid composition of the membrane structures and with peroxidation of long-chain PUFAs inside membranes. This ultimately damages membrane receptors, causing alterations in second messenger systems, inactivation of a range of membrane-binding enzymes responsible for regulation of important pathways. Finally, this causes alterations in membrane permeability, flexibility, and other important characteristics determining membrane function. Detrimental effects of mycotoxins on DNA, RNA, and protein synthesis together with pro-apoptotic action further compromise important metabolic pathways. There are also changes at the gene level, and mycotoxicogenomics is an emerging area of research. Consequently, changes in physiological functions including growth, development, and reproduction occur.

2 Mycotoxins of Concern Three major economically important genera of mycotoxin-producing fungi are Aspergillus, Penicillium, and Fusarium. Mould growth and mycotoxin production are related to the following: • • • • •

the presence of fungal inoculum on susceptible crops; plant stress caused by extreme weather; faulty water and fertilization balance; insect damage; and inadequate storage conditions.

In general, biotic and abiotic stresses (heat, water, and insect damage) cause plant stress and predispose plants in the field to mycotoxin contamination [2]. It is necessary to take into account that there are many different species of each of the mentioned genera. For example, Aspergillus species comprise a group of more than 150 members. About 45 of them, 75 Penicillium species

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and 25 Fusarium species are known to produce mycotoxins. Furthermore, mycotoxins can be toxic at very low concentrations. They appear at different stages of grain production. For example, Fusarium species are known to invade grains during the growth of the plant and they produce so-called field mycotoxins. On the other hand, Aspergillus and Penicillium species generally develop during grain storage and so may be called “storage mycotoxins.” This simple classification tends to oversimplify the situation. However, two facts are clear: mycotoxin contamination depends on moisture content of grain which should be less than 15% and drought stress can also increase fungal contamination of grain. In practice, a range of mycotoxins can be found in contaminated feeds, the type and level depending on climatic and storage conditions. Temperate climates with high moisture conditions, e.g., Canada, USA, and Europe, encourage the growth of Fusarium and Penicillium species and DON, zearalenone, ochratoxin A, and T-2 toxin that are of concern for animal and human health. On the other hand, warm and humid climatic conditions, e.g., Latin America, Asian countries, and some parts of Australia, are ideal for the growth of Aspergillus and the production of Aflatoxin, considered to be a carcinogen. The winter season in these countries favors the development of zearalenone, DON, T-2 toxin, ochratoxin A, etc. Worldwide trade in feed ingredients leads to a wide distribution of the mycotoxins. The most significant mycotoxins in feeds and foods are [3–5] the following: • Aflatoxin (AF) • They are unavoidable natural contaminants produced by Aspergillus flavus and Aspergillus parasiticus. • They are common fungal contaminants of nuts but are also found growing on a variety of feedstuff, including maize, wheat, rice, and cottonseed. • Although 20 AFs have been identified, only four of them, that is, the AFs B1 , B2 , G1 , and G2 (AFB1 , AFB2 , AFG1 , and AFG2 ) occur naturally and are significant contaminants of a wide variety of foods and feeds. • AFs may be converted to more reactive, electrophilic epoxides by phase I metabolism occurring primarily in the liver [6]. • This group of mycotoxins also possesses high teratogenic, mutagenic, and immunosuppressive activities. • The liver is the main target organ for AF toxicity and carcinogenicity. Aflatoxicosis can progress to potentially lethal acute hepatitis with vomiting, abdominal pain, hepatitis, and eventually death. • AFs can cross placental barrier, and thus can adversely affect fetal systems, to increase stillbirths and neonatal mortality. • The aflatoxins are known causes of acute aflatoxicosis in humans. But chronic forms of aflatoxicosis, especially carcinomas, are more problematic because epidemiological evidence is not as clearly defined due to other factors such as hepatitis B that may be interactive in the disease process. AFB1 is considered to be the most toxic and carcinogenic compound of this group of mycotoxins. It is classified by the International Agency of Research on Cancer as Group 1 human carcinogen. • Kwashiorkor, a severe malnutrition disease of children in Northern Africa and elsewhere in undernourished populations, which is usually attributed to nutritional deficiencies, may also be related to AF intake based on observational studies [5]. It has been hypothesized that kwashiorkor may be a form of pediatric aflatoxicosis. Further early speculations that

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AF might be involved in Reye’s syndrome, encephalopathy, and fatty degeneration of the viscera in children and adolescents have not been substantiated [7]. Exposure to AF in the diet is considered an important risk factor for the development of primary hepatocellular carcinoma, particularly in individuals already exposed to hepatitis B. AFs outbreak affecting a large geographical area and causing over 123 deaths were reported in Kenya in 2004 and 2005 [8]. • Ochratoxin A • A secondary fungal metabolite is produced by Penicillium and Aspergillus species of fungi during the storage of cereals, cereal products, and other plant-derived products, and as a result it is found in various compounded feeds. • There are four ochratoxin homologues: A, B, C, and D. Ochratoxin A is the most prevalent, whereas ochratoxins A and C are the most toxic [6]. • OTA can enter the human food chain by almost the totality of foods, i.e., cereals, wine, coffee, spices, beer, cocoa, dried fruits, and pork meats. • The main source of dietary OTA intake in Europe is cereals and their derived products, which account for around half of intake, with wine and coffee taking second and third places, contributing about 10 and 9%, respectively. • Although mechanism of action of OA remains unclear, it has been suggested that ochratoxins act by disrupting phenylalanine metabolism, interfering with signal transduction pathways in cells, and imposing oxidative stress and apoptosis. • It is immunosuppressive, genotoxic, teratogenic, and carcinogenic to monogastric animals and human. The most prominent effect of OA being nephrotoxicity. • OA can alter both barrier and absorption function of the intestinal epithelium causing intestinal injuries, including inflammation and diarrhoea [9]. • OA in combination with AF showed a synergistic toxicity [10]. • For OA the elimination half-life in human was calculated to be 840 h [11]. • The consumption of small amounts of fungal toxins may result, earlier than organ toxicity, in impaired immunity, and decreased resistance to infections at doses which do not cause nephrotoxicity or clastogenic effects [12]. • OTA has been classified as a possible human carcinogen (group 2B) by the International Agency for Research on Cancer. • Nephrotoxic effects of OTA have been linked to the Balkan endemic nephropathy characterized by tubule interstitial nephritis and associated with high incidence of kidney, pelvis, ureter, and urinary bladder tumors in some Eastern European countries. In fact, in 1956, the first clinical description of a human kidney disease known as Balkan endemic nephropathy was published. With the recognition that mycotoxins can cause nephropathies and the epidemiological evidence of ochratoxin A in food of patients in the Balkan countries, ochratoxin A became a prime suspect in the causation of this disease [4]. Moreover, tumors of the upper urinary tract have been associated with exposure to OA. • According to the intracellular concentration and cell-specific susceptibility, three scenarios relevant for OTA carcinogenicity may take place [13] • Toxicity and cell death. OTA toxicity may induce cell regeneration and proliferation, which may then lead to cell transformation and tumor development.

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• Apoptosis. It is advocated that OTA-mediated apoptosis could lead to the selection of apoptosis-resistant cells, which may be characterized by a higher probability of transformation into tumor cells. In addition, as for necrosis, apoptosis can stimulate a compensatory cell loss response resulting in cell proliferation and cancer development. • Transformation/proliferation. Low but sustained level of chronic oxidative stress can result in cell proliferation. This ultimately may convert DNA damage into mutations, leading to carcinogenesis. • T-2 toxin • The trichothecene group of mycotoxins accounts for over 100 fungal metabolites, of which T-2 toxin, produced by the Fusarium fungus (Fusarium graminearum, F. sporotrichioides, and Stachybotrys chartarum) was the first to be studied. • It contaminates mainly corn, wheat, barley, and oat. • The adverse effects of T-2 toxin on health are expressed in a diverse range of symptoms including skin lesions, immunosuppression, hepatotoxicity, nephrotoxicity, neurotoxicity, genotoxicity, and even death. • The damage caused by T-2 toxin results primarily from the toxin’s interruption of cell division in bone marrow, immunocompetent organs, and intestinal mucosa, resulting in a serious immunosuppressive effect. • T-2 toxin also has a strong inhibitory effect on protein synthesis, which in turn results in the inhibition of DNA and RNA synthesis. • It affects the actively dividing cells such as those lining the gastrointestinal tract, skin, lymphoid, and erythroid cells. • It can decrease antibody levels, immunoglobulins, and certain other humoral factors such as cytokines. • After ingestion of T-2 toxin into the organism, it is processed and eliminated. Some metabolites of this trichothecene are equally toxic or slightly more toxic than T-2 itself, and therefore, the metabolic fate of T-2 toxin has been of great concern. • It has been postulated that T-2 toxin is associated with a human disease called alimentary toxic aleukia (ATA) that affected a large population in the Orenburg district of the former USSR during the Second World War. The symptoms of the disease include inflammation of the skin, vomiting, and damage to hematopoietic tissues. The acute phase is accompanied by necrosis in the oral cavity; bleeding from the nose, mouth, and vagina; and central nervous system disorders [8]. Akakabi-byo (red mold disease) in Japan and swine feed refusal in the central United States are also related to trichothecene mycotoxins [14]. • Vomitoxin (deoxynivalenol, DON) • DON is produced worldwide by the Fusarium genus (F. graminearum and Fusarium culmorum). • It contaminates different cereal crops (wheat, maize, and barley) used for food and feed production, and it is one of the least acutely toxic trichothecenes. • The main toxic effect is associated with inhibition of protein synthesis via binding to the ribosome. Induction of apoptosis is also considered to play an important role in DON toxicity in intestinal cells [9].

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• DON in moderate to low doses can cause a number of detrimental effects including immunosuppression and it alters brain neurochemicals. • In children, ingestion of heavily DON-contaminated food results in vomiting within hours. • Many outbreaks of acute human disease involving gastrointestinal upset and diarrhoea have been registered in Asia due to consumption of Fusarium-contaminated grains [11]. • DON is of public health concern because of its often unavoidable capacity to contaminate agricultural commodities, recalcitrance to degradation during milling or processing, and potential to cause human and animal toxicity [15]. • Fumonisin B1 • The fumonisins are the most recently discovered family of aminopolycarboxylic acids. They were discovered in 1988 following an outbreak of equine leukoencephalomalacia in South Africa in 1970. • Fumonisins are mycotoxins produced by at least 11 species of the fungus Fusarium, including Fusarium moniliforme as well as the maize pathogens Fusarium verticillioides and Fusarium proliferatum. • Fumonisins are detected mainly in maize and maize-based products. • Several different derivatives of this mycotoxin have been described of which fumonisin B1 (FB1) is recognized as the most toxic and has been shown to be responsible for some major toxicological effects in animals. • Toxic effects of FB1 are associated with the fact that it resembles the structure of cellular sphingolipids and therefore impairs ceramide synthesis by inhibiting ceramide synthetase. • Epidemiologic studies suggest a link between exposure to fumonisin B1 (FB1 ) and esophageal cancer. • Consumption of moldy sorghum or maize containing high levels of fumonisin B1 caused an outbreak a human disease in India involving gastrointestinal symptoms [11]. • Zearalenone (ZEA) • Zearalenones are non-steroidal estrogenic mycotoxins and have been associated with estrogenic syndromes in swine and experimental animals. • ZEA is produced primarily by F. graminearum, Fusarium avenaceum, and Fusarium nivale which occurs naturally in high-moisture corn and has been found in moldy hay and pelleted feeds. Fungi-producing ZEA contaminates corn and also colonize, to a lesser extent, barley, oats, wheat, sorghum, millet, and rice. • ZEA production is favored by high humidity and low temperatures, conditions that often occur in the Midwest during autumn harvest. • It is a stable compound, both during storage/milling and the processing/cooking of food. • It is fairly rapidly absorbed following oral administration. • It competitively binds to estrogen receptors in a number of in vitro systems and in the uterus, mammary gland, liver, and hypothalamus of different species. • ZEA causes a variety of toxic effects in both experimental animals and livestock, and possibly, in humans. It has estrogenic and anabolic activity and has been shown to be immunotoxic and genotoxic, and to induce DNA-adduct formation in vitro cultures of bovine lymphocytes. ZEA alters various immunological parameters.

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• It causes alterations in the reproductive tract of laboratory and domestic animals causing decreased fertility; increased embryolethal resorptions; reduced litter size; changed weight of adrenal, thyroid, and pituitary glands; and change in serum levels of progesterone and estradiol. Teratogenic effects of ZEA were found in pigs and sheep. • ZEA may be associated with precocious puberty and possibly cervical cancer. • Patulin • Patulin is a mycotoxin produced by several Pencillium and Aspergillus, Byssochlamys species, but Pencillium expansum is the most commonly encountered species. • It is a common contaminant of ripe apples used for the production of apple juice concentrates and it has been shown to be mutagenic, carcinogenic, and teratogenic. • Patulin also has an immunosuppressive effect and inhibits DNA synthesis. • The Joint Food and Agriculture Organization-World Health Organization Expert Committee on Food Additives has established a provisional maximum tolerable daily intake for patulin of 0.4 mg/kg of body weight/day. • The cellular mechanism of patulin toxicity is attributed to binding to sulfhydryl groups in proteins and amino acids in the plasma membrane, which is supported by a reduction in glutathione levels and subsequent oxidative damage leading to mitochondrial disfunction in addition to its direct effects on the plasma membrane. • Patulin is shown to affect the barrier function of the intestinal epithelium by inducing epithelial cell degeneration, inflammation, ulceration, and hemorrhages [16]. • Ergot • Ergot alkaloids are mycotoxins produced by Claviceps purpurea and are known to be a problem on cereal grains. • There are three main actions of ergot alkaloids: peripheral, neurohormonal, and adrenergic blockage. • The ergot alkaloids are indole compounds that are biosynthetically derived from L -tryptophan and represent the largest group of nitrogenous fungal metabolites found in nature. Over 80 different ergot alkaloids have been isolated, mainly from various Claviceps species (over 70 alkaloids), but also from other fungi and from higher plants [17]. • Ergot alkaloids are mycotoxins that affect the nervous and reproductive systems of exposed individuals through interactions with monoamine receptors. • The most important peripheral effect is smooth muscle contraction typified by vasoconstriction and uterotonic effects. Ergot neurohormonal effects are observed in serotonin and adrenaline antagonism. • Ergotism is one of the oldest mycotoxicoses with ancient records of its occurrence. In these cases, signs of gangrene, central nervous system, and gastrointestinal effects were observed. The first documented epidemic of ergotism likely occurred in 944–945 AD, when some 20,000 people of the Aquitaine region of France (about half of the population) died of the effects of ergot poisoning. Some 50 years later, about 40,000 people reportedly died because of the “holy fire.” [17].

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3 Synergistic Interactions Among Mycotoxins Mold species coexist and most of them can produce more than one mycotoxin. There are synergistic interactions between mycotoxins meaning that combinations of mycotoxins have bigger effect than singly mycotoxins. As a result, low levels of individual mycotoxins (sometimes lower than legal limits for each of them) in combination can cause substantial health-related problems. Fusarium mycotoxin natural co-occurrence is an increasing concern due to the hazards of exposures of humans to mixtures of mycotoxins, which could be expected to exert greater toxicity and carcinogenicity than exposure to the single mycotoxins. For example, in a recent survey 30 samples of rice (n = 10), maize (n = 10), and peanuts (n = 10) from Côte d’Ivoire were analyzed for aflatoxin B1, fumonisin B1, and zearalenone and ochratoxin A [18]. Some samples contained four mycotoxins (86%). In general, concentrations of ochratoxin A, zearalenone, and fumonisin B1 were low and may not cause problems per se; however, fears remain that the tolerable daily intake may be exceeded due to eating habits and synergistic effects could be important with the combination of several mycotoxins. It is proven in experiments with some domestic species [19]. For example, a toxicological synergism between deoxynivalenol and fusaric acid has been demonstrated piglets, where deoxynivalenol toxicity was augmented when fusaric acid was added in the diet [20]. A synergistic interaction between DON and T-2 toxin was shown in an experiment with chickens [21]. Aflatoxins, ochratoxins, and other mycotoxins have also been demonstrated to interact synergistically. For example, a combination of AFB1 and OA was more toxic for chickens than single mycotoxins [22]. Citrinin (CTN) and penicillic acid were also found to potentiate the nephrotoxic and carcinogenic effects of ochratoxin A [23, 24]. Synergistic effects of fumonisin B1 and ochratoxin A are also shown in in vitro cytotoxicity study [25]. Mixtures of ZEA or FB1 and DON display synergistic effects in lipid peroxidation [26]. Futhermore, ZEA, DON, and FB1 induce DNA fragmentation individually. However, mixtures of these mycotoxins always damage DNA to a greater extent. Recent results of Bouslimi et al. [27] showed that cultured renal cells respond to OTA and CTN exposure by a moderate and weak inhibition of cell proliferation, respectively. However, when combined, they exert a significant increase in inhibition of cell viability. Similar results were found for the investigated genotoxicity end points (DNA fragmentation and chromosome aberrations). Altogether, this study showed that OTA and CTN combination effects are clearly synergistic. A combination of FB1 + α-zearalenol produces a synergistic inhibition of porcine cell proliferation [28]. Porcine kidney epithelial PK15 cells were treated with FB1, beauvericin (BEA) and OA singly, or with the combinations of two or all three mycotoxins for 24 and 48 h [29]. Combined treatment with FB1, BEA, and OTA resulted mostly in additive effects on LDH activity and additive and synergistic effects on caspase-3 activity and apoptotic index. The effect of AFB and FB on the morphology, the capacity of cellular proliferation, cytotoxicity, and interleukin-8 (IL-8) synthesis in a porcine intestinal epithelial cell line (IPEC-1), was evaluated [30]. The results indicate that the combination of AFB/FB in low concentrations showed a synergy effect, altering the cellular morphophysiology, which can imply in vivo the entrance of other toxins or biological agents for alteration of the intestinal barrier impacting negatively in the human or animal health. In a study conducted by McKean et al. [31] the acute and combinative toxicity of AFB1 and T-2 were tested in F-344 rats, mosquito fish (Gambusia affinis), immortalized human hepatoma cells (HepG2), and human bronchial epithelial cells (BEAS-2B). The results of this study demonstrated that these two toxins interacted to

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produce alterations in the toxic responses generally classifiable as additive; however, a synergistic interaction was noted in the case of BEAS-2B. From the above-presented data it is clear that mycotoxin interactions and their possible synergistic effect deserve more attention and research in this important field just started.

4 Food Contamination with Mycotoxins At least 25% of world’s grain production is contaminated with mycotoxins, which are a worldwide problem [32]. For example, AFs are considered to be unavoidable contaminants of food, since they cannot be prevented or eliminated by current agricultural practice [33]. The intake of AFM1 from milk was calculated to vary from 0.1 ng/person/day in Africa up to 12 ng/person/day in Far East countries [11]. Milk and dairy products purchased at Egyptian markets and breast milk from lactating mothers were analyzed. Three of 15 cow’s milk samples were found positive for AFM1 with mean value 6.3 mg/kg. Twenty percent of hard cheese samples contained detectable levels of AFM1 and one sample from ten contained AFB1 and AFG1. For breast milk, two of ten samples were positive for AFM1 with mean value 2.75 μg/kg, while three of ten samples were positive for OA [34]. In Turkey, the incidence of AFM1 in cheese was 89.5% with the highest concentration to be 810 ng/kg [35]. From 54 samples of fresh full cream and skimmed milk, powdered milk, yoghurt, and infant formula collected in Kuwait, 28% were contaminated with AFM1 with 6% being above the maximum permissible limit of 0.2 μg/L [36]. Recently, it has been reported that breast milk samples obtained from 388 Egyptian women had detectable AFM1 levels (13.5 pg/mL) in nearly 37% of samples [37]. During 2006, 82 samples of human mature milk were collected at Italian hospitals and checked for AFM1 and OA by immunoaffinity column extraction and HPLC [38]. AFM1 was detected in 5% of milk samples (55.4 ng/L) while OA was detected in 74% of milk samples (30.4 ng/L). International comparisons of AFM1 levels in urine are shown in Table 18.1. The chance of getting traces of mycotoxins in our diet is very high. For example, the results of survey of 313 UK retail foods and 153 UK cereal samples showed that OA was detected in 25% samples with 27 samples containing OA at concentrations above 4 ng/g [39]. Incidence

Table 18.1 International comparisons of AFM1 levels in urine (Adapted from Polychronaki et al. [111]) Samples Mean AFM1 levels Country studied Positive (%) (pg/mL) (range) Year Egypt Guinea Egypt

Sierra Leone China China China China China

Children Children Children Kwashiorkor Marasmus Children Adults Adults Adults Adults Adults

50 50

8 64

5.5 (5.0–6.2) 97.0 (8.0–801)

30 30 234 300 27 145 317 252

13 7 44 44 89 54 21 12

22 (10–30) 55 (40–70) NS 8 (60–120) 120 (0.6–800) 9.6 (3.6–246) NS (0.17–5.2) 600 (30–3,200)

2008 2008 2005

2001 2005 2001 1999 1994 1987

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Table 18.2 Incidence and mean values of OTA content of wheat bread from different countries (Adapted from Bento et al. [112])

Country

Samples

Incidence (%)

Mean (ng/g)

Spain Holland The United States Switzerland Brazil France Italy Germany Ireland Austria Tunisia Belgium Morocco Germany

93 29 24 20 15 14 12 11 9 9 9 7 100 986

100 100 100 100 100 100 100 100 100 100 100 100 48 91

0.45 0.39 0.41 0.07 0.09 0.25 0.34 0.35 0.36 0.08 0.30 0.23 13.00 0.17

of OA contamination of the bread in various countries was also quite high (Table 18.2). In the United Kingdom composite duplicate diet samples from 50 individuals and corresponding plasma and urine samples were obtained over 30 days. Average intake of OA varied in a range of 0.24–3.54 ng/kg body weight/day, and OA was detected in all plasma samples and in 92% of urine samples [40]. In Germany the absolute OA intake was approximately 28.7–290.8 ng/day in 1996–1999 and the calculated total daily intake of OA varied between 0.9 ng/kg body weight in Germany and 4.6 ng/kg body weight in Italy [41]. OA was found in a number of samples of feed and food from various countries with its detection in human blood [33]. In fact, OA can be detected at levels greater than 0.1 ppb in more than 90% of human and swine blood samples in central European countries [41]. Indeed, OA has been found in human blood samples in number of countries in cool temperate areas of the Northern Hemisphere [11]. When blood analyses were performed in Scandinavian blood donors, the mean plasma levels of OA was 0.18 μg/L in Oslo and 0.21 μg/L in Visby [42]. In particular in Croatia, OA consumption was estimated to be 0.4 ng/kg body weight [33]. About 60% of the Moroccan human plasma sampled was positive for OTA (61.5% in the male and 56% in the female population), and an average concentration of 0.29 ng/mL (0.31 ng/mL in males, 0.26 ng/mL in females; [8]). OA concentrations found in tissue and fluids of humans from various countries are shown in Table 18.3. Table 18.3 Ochratoxin in tissue and fluids of humans from various countries (Adapted from Task Force Report [4]). Tissue or fluid Country No. of samples Positive (%) Range or mean (ng/mL) Serum Serum Serum Plasma Plasma Serum Milk Milk Blood Serum

Yugoslavia Poland Germany Denmark Bulgaria Bulgaria Germany Italy Canada France

639 1,065 306 96 312 576 36 50 159 –

6.6 7.2 56.5 47.9 14.4 19.1 11.1 18.0 39.6 22.0

1–57 x = 0.27 0.1–14.4 0.1–9.2 x = 14 x = 18 0.017–0.3 1.7–6.6 0.27–35.33 0.1–6

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Table 18.4 Natural distribution of Fusarium sp. mycotoxins in France in 1996 and 1997 (Adapted from Yiannikouris and Jouany [113]) Amount of toxin in positive samples Cereal No. of samples Mycotoxins Positive (%) (μg/kg) Wheat 1996

46

Wheat 1997

69

Maize 1996

17

Maize 1997

24

DON NIV ZEN DON NIV ZEN DON NIV ZEN FB1 DON NIV ZEN FB1

40 28 12 90 92 12 84 78 95 72 76 47 90 66

39 24 9 87 32 7 400 276 335 370 100 69 15 320

DON was detected in various food products (bread, breakfast cereals, beer, baby, and infant foods) in Europe and Northern America [11]. When 88 commercially available samples of wheatbased breakfast cereals were randomly collected from different supermarkets in Lisbon, 72.8% samples contained levels of DON between 103 and 6,040 μg/kg with mean level of 754 μg/kg [43]. When 363 cereal-based infant foods in the Canadian retail market were analyzed for mycotoxins, DON was detected in 63% of the samples [44]. A European survey of foods from 12 countries found that of a total of 11,022 samples analyzed for DON, 57% were positive for this trichothecene [45]. The rate of Fusarium contamination of wheat and maize in France in 1996–1997 was comparatively high (Table 18.4). One hundred and fifty-six samples of breakfast cereals were collected from the Canadian retail marketplace over a 3-year period and analyzed for various mycotoxins. Overall, DON was the most frequently detected mycotoxin; it was detected in over 40% of all samples analyzed [46]. Fumonisins and ochratoxin A were each detected in over 30% of all samples. Zearalenone was detected in over 20% of all samples. Nivalenol and HT-2 toxin were each detected in only one sample. The survey clearly demonstrated regular occurrence of low levels of multiple mycotoxins in breakfast cereals on the Canadian market. Zearalenone was also detected in blood samples of children with precocious puberty in Puerto Rico and of those with premature telarche in the southeast part of Hungary [5]. Some national estimates of intake of fumonisin B1 in Europe and in the world are shown in Table 18.5. Estimated intake of fumonisin in Europe, Far East, Latin America, Middle East, and Africa comprises (μg/kg body weight) 0.2, 0.7, 1.0, 1.1, and 2.4, respectively [11]. Maximum limits for mycotoxins in foods in various European countries and USA are presented in Table 18.6.

5 Mycotoxins and Human Health Mycotoxins have been associated with a number of human diseases, some acute and others chronic (Table 18.7). From the one hand, detrimental effect of mycotoxins on animal health and

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Table 18.5 Some national estimates of intake of fumonisin B1 in Europe and in the world (Adapted from Creppy [11])

Country

Intake (μg/kg of body weight/day

Argentina Canada The Netherlands Switzerland The United Kingdom The United States Africa Middle East Latin America Far East Europe

0.2 0.02 0.06 0.03 0.03 0.08 2.4 1.1 1.0 0.7 0.2

Table 18.6 Maximum limits for mycotoxins in foods in various European countries and the United States (Adapted from Creppy [11]) Maximum limit μg/kg or Mycotoxin Country μg/L Foods Aflatoxin B1

Finland Germany The Netherlands Belgium Portugal

Spain Luxemburg Ireland Denmark Greece Sweden

2 2 5 5 25 5 20 1 2 1 2 5 5 5 5 5 5

All All All All Peanuts Children’s food Others All Cereals, nuts All Maize, cereals All All All All All All

Norway

5

Finland Germany

5 4 0.05

The United Kingdom France Italy Austria

4 10 50 5 (B2+G1+G2) 0.02 (M1+B1+B2+G1+G2) 5 (B2+G1+G2)

Peanuts, Brazil nuts, buckwheat All All Enzymes and enzyme formulations Nuts and dried figs All Peanuts All Children’s food All

Austria Switzerland

Aflatoxin B1, B2, G1, G2

Switzerland

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Table 18.6 (continued) Mycotoxin

Country USA Belgium Bosnia

Aflatoxin M1

Sweden Austria Germany The Netherlands

Russia Switzerland

Belgium USA Czech Republic France

DON

Ochratoxin A

Bulgaria USA Russia Austria Romania Czech Republic Denmark

Fumonisin B1+B2 Zearalenone

T-2 toxin

Austria Switzerland Greece France The Netherlands Switzerland Romania Austria France Russia Russia

Maximum limit μg/kg or μg/L 0.01 20 5 1 (B1+G1) 5 0.05 0.05 0.05 0.05 0.02 0.2 0.5 0.02 0.05 0.25 0.05 0.5 0.1 0.5 0.03 0.05 0.5 1,000 1,000 750 5 1 20 5 25 5 2 20 5 0 1,000 30 60 200 1,000 100

Foods Baby food All Peanuts Cereals Beans Liquid milk products Milk Milk Milk Butter Cheese Baby food Milk and milk products Cheese Milk Milk Children’s milk Adult’s milk Children’s milk Adult’s milk Wheat Cereals Wheat All Children’s food Cereals Pigs Cereals cereals All All Cereals Maize Cereals, vegetable oils Cereals Cereals, vegetable oils Cereals, vegetable oils All

clinical changes associated with mycotoxicoses are well described. On the other hand, only rarely has a direct connection been established between mycotoxin exposure and human illnesses and much remains to be done to establish the etiology of many suspect human mycotoxicoses [47]. Selected mycotoxin-producing fungi related to children’s health are shown in Table 18.8.

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Table 18.7 Some human diseases in which analytic and/or epidemiologic data suggest or implicate mycotoxin involvement (Adapted from Task Force Report [4]) Disease Species Substrate Etiologic agent Akakabio-byo Alimentary toxic aleukia (ATA or septic angina) Balkan nephropathy Cardiac beriberi

Human Human

Wheat, barley, oats, rice Cereal grains (toxic bread)

Fusarium spp. Fusarium spp.

Human Human

Cereal grains Rice

Celery harvester’s disease Dendrodochiotoxicosis

Human

Celery (Pink rot)

Penicillium Aspergillus spp., Penicillium spp. Sclerotinia

Horse, human

Ergotism Esophageal tumors Hepatocarcinoma (acute aflatoxicosis) Kashin Beck disease, “Urov disease” Kwashiorkor

Human Human Human

Fodder (skin contact, inhaled fodder particles) Rye, cereal grains Corn Cereal grains, peanuts

Human

Cereal grains

Human

Cereal grains

Onyalai Reye’s syndrome Stachybotryotoxicosis

Human Human Human, horse other livestock

Millet Cereal grains Hay, cereal grains, fodder (skin contact, inhaled hay dust)

Dendrodochium toxicum

Claviceps purpurea Fusarium moniliforme Aspergillus flavus, A. parasiticus Fusarium Aspergillus flavus, A. parasiticus Phoma sorghina Aspergillus Stachybotrys atra

Table 18.8 Selected mycotoxin-producing fungi of relevance to children’s health (Adapted from Sherif et al. [5]) Fungus Mycotoxins Associated health effects Aspergillus flavus, A. parasiticus Fusarium verticillioides

Aflatoxins Fumonisins

Fusarium culmorum Fusarium sporotrichiodes

Deoxynivalenol T-2 toxin

Aspergillus ochraceus, A. niger Penicillium expansum Fusarium graminearum

Ochratoxins Patulin Zearalenone

Claviceps purpurea

Ergot alkaloids

Vomiting, hepatitis, liver cancer Vomiting, neural tube defects, esophageal cancer Vomiting Alimentary toxic aleukia, vomiting, hemorrhage Balkan nephropathy, renal cancer Vomiting, cancer (suspect) Estrogenic effects, cervical cancer (suspect) Ergotism

Adverse human health effects from the consumption of mycotoxins have occurred for many centuries. At the mycotoxin contamination levels generally found in food products traded in these market economies, adverse human health effects have largely been overcome. Although mycotoxin contamination of agricultural products still occurs in the developed world, the application

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of modern agricultural practices and the presence of a legislatively regulated food processing and marketing system have greatly reduced mycotoxin exposure in these populations. However, in the developing world, where climatic and crop storage conditions are frequently conducive to fungal growth and mycotoxin production, much of the population relies on subsistence farming or on unregulated local markets. Therefore, mycotoxin exposure is more likely to occur in parts of the world where poor methods of food handling and storage are common, where malnutrition is a problem, and where few regulations exist to protect exposed populations [4]. Even in developed countries, specific subgroups may be vulnerable to mycotoxin exposure. In the USA, for example, Hispanic populations consume more corn products than the rest of the population, and inner city populations are more likely to live in buildings that harbor high levels of molds [7]. Humans likely are exposed to mycotoxins through several routes such as ingestion (the most prominent means of exposure), contact, and inhalation. Mycotoxins may affect the reproductive system and the immune system, exhibit hormonal activity, affect specific target organs, and may be neurotoxin. Developmental defects including birth defects are another possible adverse effect following exposure to mycotoxins. In addition to these diverse organ or site-specific actions, mycotoxins may affect the gastrointestinal system, cause skin irradiation, have hematological effects, and reduce growth. The various biological effects of mycotoxins such as organ toxicity, mutagenicity, carcinogenicity, teratogenicity, and modulation of the immune system are well documented by in vitro and animal experiments.

6 Molecular Mechanisms of Mycotoxin Action Include Four Major Points 6.1 Oxidative Stress as a Consequence of Mycotoxicoses A delicate balance between antioxidants and pro-oxidants in the body in general and specifically in the cell is responsible for regulation of various metabolic pathways leading to maintenance of immunocompetence, growth, and development and protection against stress conditions associated with commercial animal/poultry production. This balance can be regulated by dietary antioxidants, including vitamin E, carotenoids, and selenium. On the other hand, nutritional stress factors have a negative impact on this antioxidant/pro-oxidant balance. In this respect mycotoxins are considered to be among the most important feed-born stress factors. It is not clear at present if mycotoxins stimulate lipid peroxidation directly by enhancing free radical production or the increased tissue susceptibility to lipid peroxidation is a result of compromised antioxidant system. It seems likely that both processes are involved in this stimulation. In most cases lipid peroxidation in tissues caused by mycotoxins was associated with decreased concentrations of natural antioxidants [3]. It has been shown that OTA, T-2 toxin, DON, aflatoxins, fumonisins, and zearalenon impose an oxidative stress and have a stimulating effect on lipid peroxidation. In most of cases, thiobarbituric acid reactive substances (TBARS) accumulation was used as a measurement of lipid peroxidation. Furthermore, ethane exhalation, EPR registered free radicals, hydroxyl radical formation, single-strand cleavage DNA, DNA adduct formation as well as LDH release were also used to confirm pro-oxidant properties of mycotoxins. Various in vitro and in vivo systems were also used including liver microsomes, phospholipid vesicles, primary cell cultures, whole organs,

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and whole body. TBARS accumulation was substantially increased and at the same time vitamin E and GSH concentrations and activities of antioxidant enzymes significantly declined as a result of mycotoxicosis.

6.2 Mycotoxins and Apoptosis The maintenance of tissue homeostasis involves the removal of superfluous and damaged cells. This process is often referred to as “programmed cell death” or “apoptosis” since it is thought that cells activate an intrinsic death program contributing to their own demise. Several processes, such as initiation of death signals at the plasma membrane, expression of pro-apoptotic oncoproteins, activation of death proteases, end nucleases, ultimately coalesce to a common irreversible execution phase leading to cell demise. A balance between cell death and cell survival factors plays a major role in the decision-making process as to whether a cell should die or must live (for review see Surai [3]. Apoptosis is distinguishable from necrosis. When cell death is induced by osmotic, physical, or chemical damage, early disruption of external and internal membranes takes place with subsequent liberation of denatured proteins into the cellular space and induction of an inflammatory response in the vicinity of the dying cell. In contrast, apoptosis is characterized by cell shrinkage, nuclear pyknosis, chromatin condensation, DNA cleavage into fragments of regular sizes, and activation of the cysteine proteases called caspases. Reactive oxygen species are thought to play a major role in apoptosis, being involved in the initiation as well as execution of apoptosis. GSH depletion increases the percentage of apoptotic cells in a given population; and increased GSH concentration is shown to decrease the percentage of apoptosis in fibroblasts [48]. In fact, GSH depletion sensitizes cells for intracellular induction of apoptosis. In general, apoptosis is considered as a common mechanism of toxicity of various mycotoxins. Since antioxidant–prooxidant balance in the cell (redox status) is responsible for a regulation of apoptosis, it seems likely that natural antioxidants and selenoproteins such as GSH-Px, thioredoxin reductase, and methionine sulfoxide reductase B could be potentially involved in prevention of mycotoxin-related apoptosis. Therefore, antioxidant status of the animals and human could be an important factor in their resistance to mycotoxicoses.

6.3 Mycotoxins and Gene Expression Recently it has been suggested that toxic effects of various mycotoxins are mediated via changes in gene expression and it seems likely that it is a characteristic of major mycotoxins.

7 T-2 Toxin To examine morphological and gene expression changes induced by T-2 toxin in the fetal brain in detail, pregnant rats on day 13 of gestation were treated orally with a single dose of T-2 toxin (2 μg/kg) and sacrificed at 1, 3, 6, 9, 12, and 24 h after treatment (HAT). Microarray analysis

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showed that the expression of oxidative stress-related genes (heat shock protein 70 and heme oxygenase) was strongly induced by T-2 toxin at 12 HAT, the peak time point of apoptosis induction [49]. The expression of mitogen-activated protein kinase (MAPK)-related genes (MEKK1 and c-jun) and other apoptosis-related genes (caspase-2 and insulin-like growth factor-binding protein-3 (IGF-BP3) was also induced by the T-2 toxin treatment. From the results of microarray analysis and histopathological examination, T-2 toxin seems to induce oxidative stress in these tissues, following the changes in metabolism-related genes expression. These changes may alter the intracellular environments resulting in the induction of apoptosis [50]. Furthermore, Sehata et al. [51] suggested that the mechanism of T-2 toxin-induced toxicity in rats is due to oxidative stress followed by the activation of the MAPK pathway, finally inducing apoptosis. They showed increased expression of oxidative stress- and apoptosis-related genes in the liver of dams, placenta, and fetal liver of pregnant rats treated with T-2 toxin at the peak time point of apoptosis. Decreased expression of lipid metabolism- and drug-metabolizing enzyme-related genes was also detected in these tissues. In addition, increased expression of the c-jun gene was consistently observed in these tissues and it could well be that the c-jun gene may play an important role in T-2 toxin-induced apoptosis. In an experiment conducted in the Institute of Endemic Disease in China, it was shown that T-2 toxin induced a time-dependent and dose-dependent inhibition of cellular proliferation in human chondrocytes. Evidence of various steps of apoptotic cell death and shrinkage of chondrocytes, as well as margination and condensation of nuclear chromatin, was found based on electron microscopic observations [52]. It was shown that the apoptosis induced by T-2 toxin involved an increased Bax/Bcl-2 ratio. In fact, Bcl-2 mRNA expression remained unchanged in chondrocyte apoptosis induced by T-2 toxin treatment, while Bax mRNA expression increased following treatment with T-2 toxin. Indeed, Bcl-2 is a member of a family of genes that regulates apoptosis. The family includes members responsible for death suppression by production of anti-apoptotic proteins (Bcl-2 and Bcl-xl) and death promotion by producing pro-apoptotic proteins (Bax, Bak, Bik, and Bcl-Xs). It is believed that the ratio of Bax to Bcl-2 protein can determine whether cells will die via apoptosis or be protected from it. In particular, Bcl-2 homodimers can prevent apoptosis by prevention of activation of the caspase cascade, blocking the loss of mitochondrial membrane potential, inhibiting release of cytochrome c from mitochondria. High levels of Bax relative to Bcl-2 after a death signal may increase the cell’s susceptibility to apoptosis [52]. Recently, human chondrocytes have been treated with T-2 toxin (1-20 ng/mL) for 5 days. Fas, p53, and other apoptosis-related proteins such as Bax, Bcl-2, Bcl-xL, caspase-3 were determined by Western blot analysis and their mRNA expressions were determined by reverse transcriptasepolymerase chain reaction [53]. Increases in Fas, p53, and the pro-apoptotic factor Bax protein and mRNA expressions and a decrease of the anti-apoptotic factor Bcl-xL were observed in a dose-dependent manner after exposures to 1–20 ng/mL T-2 toxins, while the expression of the anti-apoptotic factor Bcl-2 was unchanged. These data suggest a possible underlying molecular mechanism for T-2 toxin to induce the apoptosis signaling pathway in human chondrocytes by regulation of apoptosis-related proteins. The expression of apoptosis-related genes (c-fos and c-jun) mRNAs markedly increased before the development of apoptosis in the T-2 toxin-treated keratinocytes primary cultures [54]. It is necessary to underline that it is believed that c-fos belongs to immediate-early response genes, and its activation with other factors such as c-jun is considered to be an early response to cell injury, resulting in an increased sensitivity of keratinocytes to apoptosis. In the same

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study it was also shown that the expression of pro-inflammatory cytokines TNF-α mRNA and IL-1β mRNA increased in the T-2 toxin-treated keratinocytes cultures throughout the experimental period. Similar increases in the expression of TNF-α and IL-1β mRNA were also observed after T-2 toxin application in earlier in vivo experiments [55]. Pigs were offered over a 28-day period either a control diet or diets contaminated with 540, 1,324, or 2,102 μg pure T-2 toxin/kg feed. The livers of pigs exposed to T-2 toxin presented normal cytochrome P450 content, UGT 1A and P450 2B, 2C, or 3A protein expression, and glutathione- and UDP glucuronosyltransferase activities [56]. However, P450 1A-related activities (ethoxyresorufin O-deethylation and benzo-(a)-pyrene hydroxylation) were reduced for all pigs given T-2 toxin, with P450 1A protein expression decreased in pigs fed the highest dose. In addition T-2 toxin exposure reduced certain N-demethylase activities. The results of this study confirm the immunotoxic properties of T-2 toxin, in particular toward the humoral immune response. The reduction of monooxygenase activities, even though the liver presented no tissue lesion or lipid peroxidation, suggests possible deleterious interactions of T-2 toxin with these enzymes.

8 DON The effects of the ribotoxic trichothecene deoxynivalenol (DON) on mitogen-activated protein kinase (MAPK)-mediated IL-8 expression were investigated in cloned human monocytes and peripheral blood mononuclear cells (PBMC; [57]). It was shown that DON (250–1,000 ng/mL) induced both IL-8 mRNA and IL-8 heteronuclear RNA (hnRNA), an indicator of IL-8 transcription, in the human U937 monocytic cell line in a concentration-dependent manner. Expression of IL-8 hnRNA, mRNA, and protein correlated with p38 phosphorylation and was completely abrogated by the p38 MAPK inhibitor SB203580. Zhou et al. [58] reported that DON can induce phospho-p53 and p21 protein expression at 30 min after 250 ng/mL in macrophage cells, but the epithelium did not respond to DON by inducing p53 and p21 protein in that early time point. Furthermore, DON was proven to arrest G2 /M phase in the human intestinal epithelial cells via elevated p21 gene expression [59]. Signaling pathways associated with DON-induced p21 gene expression included PI3 kinase and ERK1/2 MAP kinase cascade. It should be noted that upregulation of p21 gene expression is generally associated with G1 phase arrest by DNA damage or cellular senescence, which is under the transcriptional control of p53 protein. DON-induced chemokine interleukin (IL)-8 expressions are likely to be mediated at the transcriptional level by NF-κB, specifically p65, but does not appear to involve mRNA stabilization [60]. Indeed, when NF-κB subunit binding to a specific IL-8 promoter probe was evaluated by enzyme-linked immunosorbent assay DON was observed to increase p65 binding by 21-fold. Similarly DON induced pro-inflammatory IL-1β, IL-6, and TNF-α gene expression [61]. It is well accepted that TNF-α and IL-6 mediate injurious inflammatory processes and IL-1 is associated with leukocyte apoptosis [62]. Treatment with DON elevated IL-8 production in the human epithelial intestine 407 cells. Particularly, ribotoxin DON markedly elevated the phosphorylated extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), mitogen-activated protein kinase (MAPK) which mediated DON-induced IL-8 production [63]. DON-activated ERK1/2 also mediated the production of early growth response gene 1 (EGR-1) in the epithelial cell line and EGR-1 had the positive regulatory effect on the IL-8 production in the human epithelial cells. Indeed, DONactivated MAPK sentinel signals of the epithelial cells which promoted IL-8 production and

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its positive modulator EGR-1. These findings will provide insight into the possible mechanism associated with the early epithelial inflammation by ribotoxic insults. Mice were treated orally with 25 mg/kg body weight DON, and 2 h later spleens were collected for macroarray analysis. Expression of 116 out of 1,176 genes was significantly altered compared to average expression levels in all treatment groups. When genes were arranged into an ontology tree to facilitate comparison of expression profiles between treatment groups, DON was found primarily to modulate genes associated with immunity, inflammation, and chemotaxis [64]. Therefore, trichothecenes can up-regulate or down-regulate expression of immune- and inflammation-associated genes. Stimulation of mononuclear phagocytes by low doses or concentrations of trichothecenes elicit expression of inflammation-related genes in vivo and in vitro including cyclooxygenase-2 (COX-2), proflammatory cytokines, and numerous chemokines [65]. It seems likely that the ribosome plays a central role as a scaffold in the ribotoxic stress response to DON. Indeed, in mononuclear phagocytes, DON induced p38 mobilization to the ribosome and its subsequent phosphorylation [66]. Oral exposure to DON induced robust proinflammatory cytokine gene expression after 60 and 120 min [67]. In contrast, inductions of IL-1β, IL-6, and TNF-α mRNAs in nasally exposed mice were 2–10, 2–5, and 2–4 times greater, respectively, than those in the tissues of orally exposed mice.

9 OA It was shown that OTA also can affect gene expression. Human renal cells were exposed to 50 μM OA during 6 and 24 h, and gene expression profiles were analyzed [68]. In the experiment, few gene expression changes were identified at 6 h (179 genes), but many genes were differentially expressed at 24 h (2,083 genes). Down-regulation was the predominant effect, with 90 and 67% of genes down-regulated at 6 and 24 h, respectively. After 6 h, with slight cytotoxicity (83% survival), genes involved in mitochondrial electron transport chain were up-regulated; and after 24 h, with a more pronounced cytotoxicity (51% survival), genes implicated in oxidative stress response were also up-regulated. Increase in intracellular ROS level and oxidative DNA damage was evident at both exposure times being more pronounced with high cytotoxicity [68]. Exposure to OA also significantly unregulated GSH-Px1 and GSH-Px3 as well as extracellular SOD, probably reflecting adaptive changes to stress. Rats were gavaged daily with OA (500 μg/kg bw) and gene expression profiles in target and non-target organs were analyzed after 7 and 21 days administration. The number of differentially expressed genes in kidney was much higher than in liver (541 vs. 11 at both time points). Great differences were found with previous in vitro gene expression data, with the exception of DNA damage response which was not observed at mRNA level in any of our study conditions [69]. Down-regulation was the predominant effect. Oxidative stress response pathway and genes involved in metabolism and transport were inhibited at both time points. RGN (regucalcin)—a gene implicated in calcium homeostasis—was strongly inhibited at both time points and genes implicated in cell survival and proliferation were up-regulated at day 21. Moreover, translation factors and annexin genes were up-regulated at both time points. Apart from oxidative stress, alterations of the calcium homeostasis and cytoskeleton structure may be present at the first events of OTA toxicity.

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OA modulation of lipopolysaccharide (LPS) induced inflammatory process in the macrophagic cell line, J774A was described [70]. OA (30–100 μM) induces a timeand concentration-dependent cytotoxic effect, increased when cells were co-stimulated with LPS (100 ng/mL), a concentration that alone did not modify the cellular viability. Moreover, OA (3 μM) alone induces a significant increase in cyclooxygenase-2 (COX2) and inducible nitric oxide synthase (iNOS) expression, while at the highest concentration (10 μM) a reduced expression of both enzymes was shown, consistently with the mycotoxin-cytotoxic profile. These results confirm the pro-inflammatory role of OA by itself and demonstrate the impaired capability of OA-treated macrophages to respond properly to noxious stimuli, such as LPS, mimicking the environmental co-exposure to both compounds. In cultured kidney tubulus cells OA down-regulated GST mRNA and activity levels [71]. Lower GST levels were accompanied by a decreased transactivation of activator protein-1 (AP-1) and NF-E2-related factor-2 (Nrf2), which mediate GST gene transcription. Present data indicate that enhanced ROS production and an impairment of GST activity, possibly due to an AP-1 and Nrf2 dependent signal transduction pathway, may be centrally involved in OA induced nephrotoxicity. In cultured porcine kidney tubulus cells (LLC-PK1) OA significantly decreased γ-glutamylcysteinyl synthetase and glutathione-S-transferase mRNA levels in LLCPK1 cells [72]. Decreased mRNA levels of γ-glutamylcysteinyl synthetase and glutathioneS-transferase were accompanied by a lowered nuclear translocation and transactivation of Nrf2. Furthermore, OA also lowered Nrf2 mRNA levels. Current data indicate that OA nephrotoxicity may be, at least partly, mediated by an Nrf2-dependent signal transduction pathway. In another study using cDNA microarray technology, Luhe et al. [73] showed that OA-induced changes on genes related to DNA damage response, apoptosis, inflammation, and oxidative stress in rat kidney in vivo and in primary cultures of renal proximal tubular cells, in vitro. There is some evidence to suggest that oxidative stress in response to OA may result from downregulation of genes involved in antioxidant defense [74, 75]. Indeed, many affected genes are involved in chemical detoxication and antioxidant defense. The depletion of these genes is likely to impair the defense potential of the cells, resulting in chronic elevation of oxidative stress in the kidney [75]. OA was also found to strongly increase in glial cells the expression of genes related to brain inflammatory response, such as iNOS and peroxisome proliferator activating receptor-γ [76]. Repeated administration of OA to male F344/N rats for 14, 28, or 90 days resulted in a doseand time-dependent increase in the expression of novel biomarkers of nephrotoxicity including kidney injury molecule-1, tissue inhibitor of metalloproteinases-1, lipocalin-2, osteopontin, clusterin, and vimentin [77]. Changes in gene expression were found to correlate with the progressive histopathological alterations and preceded effects on traditional clinical parameters indicative of impaired kidney function. It is important to mention that OA exposure not only changed antioxidant defenses but also affected the ability of cells to properly respond to stress. For example, Human Hep G2 hepatocytes and monkey kidney Vero cells were exposed to OA, ranging from non-cytotoxic to sub-lethal [78]. The results clearly showed that OA inhibits cell proliferation, strongly reduces protein synthesis and induces the decrease of GSH in concentration-dependent manner in both Hep G2 and Vero cells. However, although cytotoxicity and oxidative damage (main inducers of Hsp expression) occur, no change was observed in Hsp 70 level under the multiple tested conditions.

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10 AFB1 It seems likely that AFB1 is also involved in gene regulation changes. The gene expression pattern of diploid yeast cells exposed to AFB1 using high-density oligonucleotide arrays comprising specific probes for all 6,218 open reading frames were analyzed [79]. Among 183 responsive genes, 46 are involved in either DNA repair or in control of cell growth and division. Eleven of the 15 inducible DNA repair genes, including RAD51, participate in recombination. For 28 days, pigs were fed a control diet or a diet contaminated with 385, 867, or 1,807 μg pure AFB1/kg feed and the expression level of pro-inflammatory (TNF-α, IL-1β, IL-6, IFN-γ) and regulatory (IL-10) cytokines was assessed by real-time PCR in spleen [80]. A significant upregulation of all five cytokines was observed in spleen from pigs exposed to the highest dose of AFB1. The effects of AFB1 on polymorphonuclear leukocyte (PMN) chemotaxis and chemiluminescence (CL) were studied [81]. In reverse transcriptase (RT)-PCR analysis, gene expression levels of CXC chemokine receptor (CXCR)1/2, whose ligands are IL-8, granulocyte chemotactic protein (GCP)-2, neutrophil attractant-activation protein (NAP)-2, and epithelial neutrophilactivating protein (ENA)-78, which regulate PMN chemotaxis, were also down-regulated in a dose-dependent manner by 50 ng/mL AFB1. mRNA expression levels of CXCR1/2 were downregulated to approximately 85% of that in the controls when PMNs were treated with 100 ng/mL AFB1. These results suggest that a high concentration of AFB1 reduces the chemotactic ability of PMNs via the CXCR1/2 cascade indirectly.

11 FB1 There is also evidence that FB1 is also able to change gene expression. For example, in porcine renal epithelial cells (LLC-PK1) FB1 (1 μmol/L for 5 min) transiently activated PKCα and increased nuclear translocation of NF-κB, followed by their down-regulation at later time points [82]. TNFα mRNA expression was increased after 15 min exposure to FB1. In addition, an increase in caspase-3 activity was observed after addition of FB1 for 1 h. In murine microglial BV-2 cells and primary astrocytes, the expression of TNFα and IL-1β analyzed by real-time polymerase chain reaction was down-regulated at 6 or 24 h FB1 treatment [83]. In all cell types tested, the FB1 treatment caused accumulation of free sphinganine and decrease in free sphingosine levels at selected time points. The toxic effects on the neuronal tissue may therefore be secondary to modulation of astrocyte or glial cell function. Mice were fed control diets or diets containing 300 ppm FB1 or F. verticillioides culture material (CM) providing 300 ppm FB1. Hepatotoxicity found in FB1- and CM-fed mice characterized by apoptosis and cell proliferation. Transcript profiling using oligonucleotide arrays showed that CM and FB1 elicited similar expression patterns of genes involved in cell proliferation, signal transduction, and glutathione metabolism [84]. Ninety-six birds were allotted to four treatments fed with diets containing 0 (control), 5, 10, or 15 mg/kg of FB1 for 3 weeks. A FB1 challenge for 3 weeks increased cytokine mRNA abundance in broilers. The results also showed that 15 mg FB1/kg feed significantly inhibited the expression of IL-1β, IL-2, IFN-α, IFN-γ, but had no effect on iNOS [85]. The macrophage functional profile was significantly changed under an exposure of 15 mg FB1/kg for 3 weeks. It is interesting to note that deletion of iNOS gene did

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not prevent FB1-dependent induction of inflammatory cytokines, namely tumor necrosis factor alpha, interferon gamma, and interleukin-12 [86].

12 Zearalenone Zearalenone is also involved in gene expression regulation [87] showing pro-proliferative activity. Recent results of microarrays analysis have shown that Zen induced an up-regulation of ATM and p53 genes family [88]. ATM pathway responds primarily to DNA double-strand breaks and has been involved in the activation and stabilization of p53. The activation of p53 was accompanied by an up-regulation of GADD45 to arrest the cell cycle and to allow the repair mechanisms to take place. In addition, results of genes profiling as well as western-blotting analysis showed that Zen increased the ratio of pro-apoptotic factors/anti-apoptotic factors which led to the loss of mitochondrial potential, Bax translocation, and cytochrome c release.

13 Protection Against Mycotoxins The range of mycotoxins that can contaminate feed and food and their different chemical structure make protection against mycotoxin-related toxicity a difficult task. There are various approaches to control or combat mycotoxin problems. The simplest strategy is based on the prevention of the formation of mycotoxins in feeds by special management programs including storage at low moisture levels and prevention of grain damage during processing [89]. However, modern agronomic technology is not able to eliminate pre-harvest infection of susceptible crops by fungi [90]. Therefore this strategy can only partially be effective; and in countries with warm and humid conditions, this strategy could be quite costly. Other strategies based on use microbial or thermal inactivation of toxins, physical separation of contaminated feedstuffs, irradiation, ammoniation, and ozone degradation have not been developed to the industrial level because they are either time-consuming or comparatively expensive [89]. In recent years, nutritional manipulation has been actively used to improve animal self-defense against mycotoxins or to decrease detrimental consequences of mycotoxin consumption. Since lipid peroxidation plays an important role in mycotoxin toxicity, a protective effect of antioxidants is expected [91, 92]. Indeed, as can be seen from review by Surai [3], protective effects against lipid peroxidation caused by mycotoxins was attributed to various antioxidant compounds including vitamins A and E, ascorbic acid, CoQ10 , selenium, antioxidant enzymes as well as various plant extracts. In spite of positive effects of natural antioxidants on animals fed mycotoxin-contaminated diets, the most promising and practical approach has been the addition of adsorbents to contaminated feed [93]. Mycotoxins can be bound to the adsorbent and pass harmlessly through the digestive tract. Many compounds have been tested for adsorbent effects, however, comparatively few have proven successful and still fewer (mainly bentonites, zeolites, alumosilicates, and glucan fraction of the yeast) are used commercially [3]. The extent to which various compounds

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bind specific toxins varies considerably. Many products only bind aflatoxin, leaving such mycotoxins as T-2 and DON in the intestinal tract without alteration. In addition to the various clays and zeolites, a yeast cell wall-derived glucomannan (Mycosorb) has been shown to be effective against a wide range of mycotoxins [94]. Protected effects of esterified glucomannans (E-GM, Mycosorb) have been shown in poultry, pigs, dairy, and horses. In particular, in broilers the naturally contaminated diet with mycotoxins significantly decreased body weight and feed consumption and resulted in poor feed efficiency. E-GM effectively alleviated the growth depression caused by the naturally contaminated diet [95]. Similarly supplementation of E-GM counteracted most of the blood parameter alterations caused by the Fusarium mycotoxin-contaminated grains and reduced breast muscle redness [96], as well as preventing mycotoxin-induced decreases in B-cell counts [97]. In addition, E-GM added to the aflatoxin-containing diet at 0.5 and 1 g/kg diminished the severity of pathological changes in broilers [98]. The mycotoxin feeding of contaminated grains to broiler breeders decreased antibody titers against infectious bronchitis virus at the end of week 12, and this was prevented by dietary supplementation with E-GM [99]. Layer performance and metabolism were adversely affected by chronic feeding of a combination of Fusarium mycotoxins, and that E-GM prevented many of these effects [100]. In turkeys, performance and some blood and immunological parameters were adversely affected by feedborne Fusarium mycotoxins, and E-GM prevented many of these effects [101]. In particular there were adverse effects of mycotoxins on intestinal morphology during early growth phases of turkeys, and E-GM was effective in their prevention [102]. Furthermore, mycotoxins adversely altered the pons serotonergic system of turkeys. Supplementation with E-GM partially inhibited these effects [103]. Supplementation of feed with E-GM was also effective in reduction of aflatoxin B [1]-induced hepatic injury in ducklings [104]. The feeding of grains naturally contaminated with Fusarium mycotoxins reduced growth, altered brain neurochemistry, increased serum Ig concentrations, and decreased organ weights in starter pigs. Some of the Fusarium mycotoxin-induced changes in neurochemistry and serum Ig concentrations were prevented by the feeding of E-GM [97]. Similarly, feeding gilt diets that are naturally contaminated with Fusarium mycotoxins increased the incidence of stillborn piglets and this effect was reduced by dietary supplementation with E-GM [105]. Furthermore, the feeding of diets naturally contaminated with Fusarium mycotoxins to lactating sows reduced feed intake and increases BW losses. Supplementing contaminated feed with E-GM could counteract the reduction in serum protein and serum urea observed in sows fed contaminated feed [106]. Recent data showed that E-GM can reduce AFM1 in milk of cows fed AFB1-contaminated feed [107]. Feed naturally contaminated with Fusarium mycotoxins can also affect the metabolic parameters and immunity of dairy cows and E-GM can prevent some of these effects [108]. Protective effects of E-GM were also evident in horses consuming grains naturally contaminated with Fusarium mycotoxins [109]. In various in vitro systems E-GM was able to bind up to 70% zearalenone [110]. Therefore, if proper mycotoxin binders are used, it is possible to substantially decrease mycotoxin contamination of animal-derived products including eggs, meat, and milk. It seems likely that a combination of mycotoxin binders with natural antioxidants, in particular with organic Se and vitamin E, could be the next step in preventing damaging effects of mycotoxins on animals and decreasing animal-derived food contamination. However, a problem of mycotoxin contamination of other foods, including bread, awaits an effective solution.

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14 Conclusions The wide range of mycotoxins that can contaminate animal/poultry feed and their different chemical compositions make protection against mycotoxin-related toxicity a difficult task. There are several problems that complicate mycotoxin prevention issues: • In many cases, the low levels of mycotoxins remain undetected in feed ingredients and their effects may also go unseen. For example, detrimental effects on the immune system would be even more difficult to assess. • Very often, a combination of various mycotoxins is present in the feed because the various fungal species can produce several toxins. A combination of several mycotoxins in low doses can have a bigger detrimental effect than a single mycotoxin at a higher dose. • Mycotoxins can contaminate practically all feed ingredients and foods. For example, Fusarium species have been found in wheat, maize, barley, oats, and rye. On the other hand, aflatoxins can also contaminate oilseeds and other feed ingredients. • International trade of feed ingredients, e.g., maize and soybeans, especially long shipments from Latin America to European and Asian countries, is another important risk factor. • Most of mycotoxins are stable compounds that do not degrade during storage, milling, or high-temperature feed manufacturing processes. • There are no safe doses of mycotoxins. A dose that does not affect animal or human at short exposure could be toxic at longer consumption. • It is proven that most mycotoxins impose an oxidative stress, promote free radical formation, suppress antioxidant defense mechanisms, associated with apoptosis, and changes in gene expression. • Usage of proper mycotoxin binders in the diet of farm animals could decrease detrimental effects of mycotoxins on animal health and decrease animal-derived food contamination. • The development of effective technologies to prevent plant-derived food contamination with mycotoxins awaits a solution.

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Chapter 19

Nutrition–Toxicological Dilemma on Fish Consumption Isabelle Sioen, Stefaan De Henauw, and Johan Van Camp

Key Points • Fish is important in a healthy and balanced omnivorous human diet due to high-quality amino acids, long-chain ω-3 fatty acids, vitamin D, iodine, and other trace elements. • The favourable health perception of seafood is troubled by less favorable information regarding the potential adverse health impact that contaminants in seafood may have on the general population and particularly on pregnant women and the unborn child they are bearing. • The overall picture with health benefits and risks of fish is a potential basis for an important public health conflict between dietary recommendations on the one hand and toxicological safety assurances on the other hand. Keywords Risk–benefit · Fish consumption · ω-3 fatty acids · Methyl mercury · Dioxins · Seafood

1 Introduction Today it is generally accepted that fish is important in a healthy and balanced omnivorous human diet [1]. Fish is an important dietary source of proteins (consisting of high-quality amino acids), long-chain omega-3 fatty acids, vitamin D, iodine, and other trace elements. Moreover, fish is low in saturated fat [2]. In the scientific world, there is no doubt that fish is the most rich natural source of long-chain (LC) omega-3 polyunsaturated fatty acids (PUFAs), in particular eicosapentaenoic acid (EPA, C20:5n-3) and docosahexaenoic acid (C22:6n-3). Together with the fact that, in developed countries, there is an imbalance between the current intake of LC n-3 PUFA and the recommendations and that an increase in the n-6/n3 PUFA ratio in most Western countries is seen, a further stimulation in fish consumption should be an evident solution.

I. Sioen () Department of Public Health, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium e-mail: [email protected] F. De Meester et al. (eds.), Modern Dietary Fat Intakes in Disease Promotion, Nutrition and Health, DOI 10.1007/978-1-60327-571-2_19, © Springer Science+Business Media, LLC 2010

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However, the favourable health perception of seafood is troubled by less favourable information regarding the potential adverse health impact that contaminants in seafood may have on the general population and particularly on pregnant women and the unborn child they are bearing (Smith et al. 2005). During the last decades an increasing number of data on high levels of contaminants in seafood are published in scientific literature as well as in public media [3–11]. These contaminants can be naturally present in the environment or can be the result of man-made processes. After all, as a result of the industrial revolution, oceans, seas, lakes, and rivers are contaminated with many persistent, chemical contaminants. Due to biomagnification and bioaccumulation, these contaminants are concentrated in the aquatic food chain to the concentrations that could form a health risk for consumers [12]. Well-known examples of persistent compounds accumulating in the aquatic environment are polychlorinated biphenyls (PCBs), dioxin-like substances [dioxin-like PCBs (dl PCBs), polychlorinated dibenzop-dioxins (PCDDs), and polychlorinated dibenzofurans (PCDFs)], polybrominated diphenyl ethers (PBDEs), and organochlorine pesticides, as well as heavy metals like cadmium, lead, mercury, and arsenic. As a result, increasing seafood consumption to achieve adequate nutrient intake will increase the contaminant intake at the same time, possibly to levels of toxicological concern [13, 14]. This overall picture with health benefits and risks is a potential basis for an important public health conflict between dietary recommendations on the one hand and toxicological safety assurances on the other hand. In contrast, consumers decreasing their seafood intake in order to avoid contaminant exposure may be incurring an inadequate intake of LC n-3 PUFAs [15]. This nutritional–toxicological conflict is summarised in the scheme below (Fig. 19.1).

LC n-3 PUFAs

Positive to human health

Nutritional-toxicological

Seafood consumption

conflict Contaminants (dioxins, mercury, …)

Negative to human health

Fig. 19.1 Nutritional–toxicological conflict related to increased seafood consumption

Recently, the debate on health benefits versus risks of fish consumption has reached a great scientific and social interest [15–23]. The nutritional–toxicological conflict related to seafood consumption is already discussed at the Commission of the Codex on Contaminants in Food (Commission of the Codex Alimentarius) and an FAO/WHO expert consultation on the risks and benefits of seafood consumption is actually scheduled in January 2010, showing the pertinence of this subject [24].

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2 The Beneficial Aspects of Fish Consumption Several nutritional benefits are related to fish and other seafood. Fish contains very high-quality proteins, being second only to egg protein in digestibility and supporting growth, and very high in omega-3 fatty acids. With respect to vitamin content, seafood is an excellent source of the B vitamins niacin and B12 and is in general a better source of vitamin D and A compared to other protein sources as beef, pork, or chicken. Seafood can also contribute appreciable amounts of heme iron and zinc, nutrients that tend to be low in people’s diets and it is among the best sources of dietary selenium. However, in this chapter three nutritional compounds will be described in detail: 1. the sum of EPA and DHA, the LC n-3 PUFAs most abundantly present in fish; 2. the fat-soluble vitamin D; 3. the trace element iodine. The reason to focus on these three is that they are present in a relatively high concentration in fish when compared to other food items.

2.1 EPA and DHA The group of PUFAs is divided into two groups: n-3 and n-6 PUFAs, differing in the position where the first C double bond is located. Two PUFAs are called “essential fatty acids” since they cannot be synthesised in the human body and are vital for physiological integrity. Therefore, they must be obtained from the diet. One is linoleic acid (LA, C18:2n-6) and belongs to the n-6 family. The other one is α-linolenic acid (LNA, C18:3n-3) belonging to the n-3 family. These essential parent compounds can be converted to LC fatty acids in the human body, but humans cannot interconvert n-3 and n-6 fatty acids [25]. LA can be converted to arachidonic acid (AA, C20:4n6) and further on to longer chain derivates, and LNA to eicosapentaenoic acid (EPA, C20:5n-3) in the first step and docosahexaenoic acid (C22:6n-3) in the next step. Different enzymatic steps are needed to fulfil these conversions which include desaturation and elongation. A crucial point is that the first enzymatic step in the desaturation of both LA and LNA involves the enzyme 6 desaturase. This results in a competition of both substrates for 6 desaturase. High intakes of LA have been suggested to decrease the desaturation of LNA to EPA and DHA and favour higher levels of AA.

2.1.1 The Presence of EPA and DHA in the Human Diet In developed countries dietary intakes of LA have increased over the last century from ∼3 to 5–7% of total energy intake due largely to an increased consumption of LA-rich vegetable oils [25–27]. As a result, the conversion of LNA to LC n-3 PUFAs in the human body is even more limited. In adult men conversion to EPA is limited to approximately 8% and conversion to DHA is extremely low (<0.1%). In women conversion to DHA appears to be greater and affected by

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the physiological state (e.g. higher conversion during pregnancy to meet the provision of foetal DHA) [28, 29]. It is questioned whether all human requirements for LC n-3 PUFAs can be met from the endogenous supply [25, 27, 29, 30]. Therefore, most nutritional guidelines now include recommendations for increased intakes of these fatty acids. As already stated, over the past decades, the balance of fatty acids in the diet has shifted away from n-3 PUFAs to n-6 PUFAs. Explanations for this shift include changing farming practices resulting in meat being less rich in n-3 PUFAs, low consumption of seafood, and developments in food technology leading to increased supply and high consumption of n-6-rich food products (e.g. margarines) [31, 32]. As a result, the ratio of n-6 to n-3 PUFAs increased in developed countries. Simopoulos [32, 33] indicates that human beings evolved on a diet with a ratio of n-6 to n-3 fatty acids of around 1–4 whereas in Western diets the ratio is now 15/1–16.7/1. Considering the dietary sources of n-3 PUFAs, LNA can be found in plant sources, including green leafy vegetables, some seed oils (linseed oil, rapeseed oil, flaxseed oil, and soybean oil), and nuts (e.g. walnuts). Synthesis of EPA and DHA occurs in phytoplankton and animals, but not in plants. It is by planktivorous fishes that LC n-3 PUFAs enter in the marine food chain and accumulate in seafood (mainly in oily fish) [27, 34]. Therefore, seafood is the food group with the highest natural LC n-3 PUFA concentration, followed by poultry and eggs since poultry also synthesise a considerable amount of LC n-3 PUFAs. Moreover, the fatty acids content of their feed will influence their LC n-3 PUFA content.

2.1.2 The Role of Omega-3 Fatty Acids in the Human Body Scientific evidence exists that LC n-3 PUFAs play an essential role in human health during all stages of life [2, 10, 25, 31, 35–38]. During the development of an unborn child, DHA plays an essential role in the brain and eye function [31]. Therefore, the maintenance of an adequate level of DHA in both the brain and the retina is important for proper nervous system and visual functions [39–41]. A supply of n-3 PUFAs from seafood and other food items may have led to large brain expansion during the long evolution of hominids to Homo sapiens. Studies suggest that it is unlikely that the foetus can make sufficient DHA to support brain development. Given that maternal DHA stores compensate for the limited ability of the foetus to synthesise DHA, it is likely that an adequate intake of LC n-3 PUFA could impact foetal development [25, 28]. Next, several prospective epidemiological studies have investigated the relationship between intake of n-3 PUFA and fatal coronary heart disease (CHD). Nowadays a large body of evidence exists to suggest beneficial effects of fish, oily fish, and LC n-3 PUFAs on the molecular, cellular, and whole-body pathogenic processes of atherosclerosis and thrombosis [2, 29, 35, 36]. Largescale epidemiologic studies suggest that people at risk for CHD benefit from consuming n-3 PUFAs from plant and marine sources [2]. However, evidence from trials with n-3 PUFAs is less clear. Moreover, a recent meta-analysis has revealed a lack of consistency between the different trials studying the influence of n-3 PUFAs on the risk of CHD [42]. The antiarrhythmic effect of fish oil remains unproven although the idea is still viable and is being actively tested in further trials [43]. As a consequence, there is a need for further large-scale, well-executed, randomised controlled trials to reach a consensus with regard to the role of these fatty acids in prevention of CHD and CVD in general [44].

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Benefits from EPA and DHA are also related to a number of other diseases. Lands [41] stated that man must better balance n-3 and n-6 fatty acid intake to temper an overactive eicosanoid system that leads to development of chronic inflammatory diseases. Eicosanoids are produced from LC PUFAs and are biologically active substances, which act locally to influence a wide range of functions in cells and tissues, including inflammation. Moreover, LC n-3 PUFAs give rise to a family of antiinflammatory mediators. Modulation of LC PUFA intake, mostly by increasing the relative proportion of n-3 versus n-6 PUFAs, may as such play a role in the prevention of diseases as asthma, rheumatoid arthritis, and bowel disease [45, 46]. Moreover, increasing evidence from animal and in vitro studies indicates that n-3 PUFAs present in fatty fish and fish oil inhibit carcinogenesis [47, 48]. Ecologic studies have shown that high per capita fish consumption is correlated with a lower incidence of cancer in the populations [49–52]. Several mechanisms whereby n-3 PUFAs may modify the carcinogenic process have been proposed. These include suppression of AA-derived eicosanoid biosynthesis, influences on transcription pathways, alteration of oestrogen metabolism, increased or decreased production of free radicals and reactive oxygen species, and mechanisms involving insulin sensitivity and membrane fluidity. On the basis of these multiple mechanisms, n-3 PUFAs may have an important influence on carcinogenesis. Finally, research-related lower intakes of LC n-3 PUFAs with mental illness. Epidemiological studies have found that countries with high seafood consumption tend to have a low prevalence of major depression [53]. However, Appleton et al. [54] reported in a recent review that trial evidence that examines the effects of n-3 PUFAs on depressed mood is limited and is difficult to evaluate because of considerable heterogeneity. The evidence available provides little support for the use of n-3 PUFAs to improve depressed mood. Furthermore, indications exist that imbalances in PUFA status could be linked to behavioural and learning disorders such as attention-deficit hyperactivity disorder, dyslexia, dyspraxia, and autism [55–57].

2.2 Vitamin D Seafood—especially oily fish—is frequently regarded as the most important food source of the fat-soluble vitamin D. The letter D origins from the German word “Dörschleberöl”, which means cod liver oil, hereby showing the historical link between vitamin D and seafood. Vitamin D is not an essential vitamin sensu stricto, since ultraviolet (UV)-induced skin production constitutes the main contributor to vitamin D in humans who are sufficiently exposed to sunlight [58]. Apart from this endogenous synthesis, food also provides vitamin D. Nevertheless, next to oily fish only a relatively small number of food items such as eggs, liver, and butter contain nutritionally significant quantities of vitamin D [59–61]. The principal physiologic function of vitamin D is to maintain calcium homeostasis. Vitamin D functions as a hormone, synthesised far from the sites of biological action and reaching these distant sites through the blood stream. Vitamin D acts by binding to vitamin D receptors principally located in the nuclei of target cells. Due to that binding, the receptor will act as a transcription factor that modulates the gene expression of transport proteins, e.g. calbindin [62]. Severe deficiency of vitamin D leads to rickets in children and osteomalacia in adults [60]. Yet, an adequate dietary intake of vitamin D is of great importance for young children, pregnant

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women, and elderly people. Vitamin D is one of the target nutrients when considering the role of nutrition in the prevention of osteoporose. Besides its role in the calcium homeostasis, more extensive roles for vitamin D were suggested by the discovery of the vitamin D receptor in tissues that are not involved in the calcium metabolism. As such, the role of vitamin D in regulation of the immune system and its possible role in the prevention and treatment of cancer and immune-mediated diseases was discovered [63].

2.3 Iodine Oceans are considered as a huge natural reservoir of iodine. Iodine is distributed from the ocean in the atmosphere by evaporation and by rain it returns to earth. The biological function of iodine in the human body relates to its incorporation in the thyroid hormones [64]. The iodine content in most foods is low and can be affected by the content of the soil, irrigation, and fertilizers. Foods of marine origin have higher concentrations of iodine because marine species concentrate iodine from the seawater [65, 66]. Another important dietary source is dairy food, due to the secretion of iodine in cow’s milk. Lack of sufficient iodine results in inadequate thyroid production leading to the so-called iodine-deficiency disorders, including mental retardation, hypothyroidism, goitre, cretinism, and varying degrees of other growth and developmental abnormalities [64].

3 The Toxicological Aspects of Fish Consumption As mentioned in the introduction, the aquatic environment is contaminated partially due to manmade processes. Although a very wide range of contaminants is accumulated in the marine food chain, it was decided to limit this description to the most important ones based on an advice of the European Food Safety Authority (EFSA). The EFSA panel identified methylmercury (MeHg), a non-carcinogenic contaminant, and dioxin-like compounds, having carcinogenic charachteristics, as the most critical contaminants in seafood.

3.1 Mercury Seafood is the most important source of mercury (Hg) in the human food chain. Moreover, in the marine environment, inorganic Hg is to high extent transformed to methyl mercury (MeHg), which further accumulates in the marine food chain [67]. This organic MeHg is very toxic for humans [68, 69]. The primary target of MeHg is the central nervous system and the developing brain is thought to be the most sensitive target organ for MeHg toxicity [68]. In addition, there are indications that Hg can inhibit the preventive role of LC n-3 PUFAs on cardiovascular diseases [70, 71].

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For MeHg, a tolerable weekly intake (TWI) of 1.6 μg/kg bw/week is proposed by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) taking into account the latest epidemiological results with regard to developmental toxicity [68, 72]. However, the Scientific Advisory Committee on Nutrition and the Committee on Toxicity of the UK (SACN/COT) advised to use the JECFA reference value of 1.6 μg/kg bw/week only when assessing the dietary exposure of pregnant women and women who may become pregnant within the following year [73]. Within the context of a risk–benefit analysis concerning fish consumption, SACN/COT proposed to apply an intake limit of 3.3 μg MeHg/kg bw/week to the rest of the population to protect against non-development adverse effects [73].

3.2 PCDFs, PCDDs, PCBs Next to Hg, two groups of persistent organic pollutants are considered as critical contaminants in seafood, being the polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) on the one hand and the polychlorinated biphenyls (PCBs) on the other hand. PCDDs, PCDFs, and PCBs are ubiquitous in the environment and occur at picomolar levels in foods. PCDDs and PCDFs are by-products of combustion and of various industrial processes and thus unintentionally present in the environment. In contrast, PCBs were manufactured in the past for a variety of industrial uses, notably as electrical insulators or dielectric fluids and specialised hydraulic fluids. Most countries banned manufacture and use of PCBs in the 1970s. However, past improper handling of PCBs constitutes a continuing source of these compounds in the environment. Exposure of a typical person to these persistent organic pollutants occurs primarily through foods (>90%), particularly animal fats because of the lipophilic characteristics of these substances. Bioaccumulation of dioxin-like compounds through the food chain begins at the point of consumption of contaminated plants, soil, or sediment by animals, which then are used to produce food for humans [72, 74, 75]. Last decennia, a decreasing trend of the levels of PCBs, PCDDs, and PCDFs in food items is found, mainly due to strict rules and regulations to reduce human intake of these compounds. However, the decreasing trend seems to be quite limited in the aquatic environment since these compounds seem rather stable in large reservoirs like seas and rivers [76]. As a result, seafood is currently one of the most important contributors to the total dietary intake of PCBs, PCDDs, and PCDFs [13, 76–80]. There exist 75, 135, and 209 different congeners of PCDDs, PCDFs, and PCBs, respectively, depending on the number and position of the chlorine atoms (Fig. 19.2). Only 7, 10, and 12 of the existing PCDD, PCDF, and PCB congeners, respectively, exhibit relevant dioxin-like activity. The subset of 7 PCDDs and 10 PCDFs correspond to chlorine substitution at the 2, 3, 7, and 8 positions (hereafter referred to as PCDD/Fs). The 12 dioxin-like PCBs (dl PCBs) included have either one or no chlorine substitution in the ortho position (non-ortho or mono-ortho PCBs) [72]. For these 29 dioxin-like compounds, toxic equivalency factors (TEFs) for mammals have been derived [81–83]. The TEF approach relates the toxicity of these chemicals to that of 2,3,7,8tetrachlorinated dibenzo-p-dioxin. In the TEF concept, the assumption is made that PCDD/Fs and dl PCBs have a common mechanism of action, which involves binding on the aryl hydrocarbon

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meta 3

9 8 7 6

1

O

3

O

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1

2

7

4

Qv

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8

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Qv

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para 4

ortho 2' 1'

meta 3'

4' para

3 6

O

4

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Qv

5 meta

6 ortho

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6' ortho

5' Q meta s

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Fig. 19.2 Chemical structures of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and polychlorinated biphenyls (PCBs); Qs and Qv represent chlorine substitution

receptor, an intracellular receptor protein. This binding is considered to be the necessary first step in expressing the toxicity of these compounds as well as for the assumption that the toxic effect of the different congeners is additive. Many uncertainties exist in the use of the TEF approach for human risk assessment, but pragmatically it is the most feasible approach [72]. TEFs allow determination of the toxic equivalent (TEQ) concentration of the residue. For a particular residue containing a mixture of i PCDDs, j PCDFs, and k PCBs, the TEQ is calculated according to the following equation [72]: TEQ =

 i

(PCDDi × TEFi ) +

 j

(PCDFj × TEFj ) +



(PCBk × TEFk )

k

with TEQ the toxic equivalent (pg/g) of a mixture of i PCDDs (pg/g), j PCDFs (pg/g), and k PCBs (pg/g) all with their respective TEF value (dimensionless). Exposure to a mixture of PCDD/Fs and dl PCBs causes dermal toxicity, immunotoxicity, carcinogenicity, reproductive and developmental toxicity, and disruption of endocrine functions [72]. Besides the 12 dl PCB congeners, non dioxin-like (ndl) PCBs also cause multiorgan toxicity, the mechanism of which is not known. It is, however, sure that much higher doses are needed than for the dl PCBs. Data on the occurrence of ndl PCBs in food and feed are often referred to as the sum of six or the sum of seven indicator PCBs (6 iPCBs = congeners 28, 52, 101, 138, 153, and 180 or 7 iPCBs = congener 118 + 6 iPCBs, with congener 118 being a dl PCB). In general, 6 iPCBs represent at least about 50% of the total amount of ndl PCBs in food [74]. For dioxin-like compounds, a tolerable daily intake (TDI) of 2 pg WHO–TEQ/kg bw/day is proposed by the EU [84]. This TDI is mainly based on developmental toxicity, e.g. effects on the developing male reproductive system resulting from maternal exposure to dioxin-like compounds and is also considered adequate to protect against other possible effects of dioxin-like compounds, such as cancer (non-genotoxic mechanism) and cardiovascular effects [84]. SACN/COT advised to use a TDI of 2 pg WHO–TEQ/kg bw/day to protect against developmental toxicity. However, they proposed a different guideline of 8 pg WHO–TEQ/kg bw/day [73], which should be appropriate when considered in relation to the most sensitive and relevant non-development effects of dioxin-like compounds (increased cancer risk). According to SACN/COT, this higher guideline level should be used for older women and males when considering risk–benefit aspects of seafood consumption. The reason for this is that developmental toxicity is of less concern in the older population, whereas the positive effects of seafood consumption on cardiovascular disease become more important.

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4 Opinions About the Right Balance The debate on the nutritional–toxicological dilemma of fish consumption has reached a great scientific and social interest [15–23]. Different scientists and institutions investigated this dilemma, in order to formulate a consumer advice. Some important studies are summarised below. Own research focused on the Belgian situation, aiming to formulate safe and healthy recommendations about fish consumption for the Belgian population. The results of the consumption scenario analyses showed that the recommended intake for EPA plus DHA can be reached through regular consumption of seafood, more specifically:

1. a combination of lean and fatty fish species (on average 50% of each) minimum three times a week; or 2. fatty fish species two times a week.

A consumption of three times a week fatty fish, however, can lead to an intake of dioxinlike compounds close to the TDI, which is of potential toxicological concern since also other food items, mainly of animal origin, contribute to the daily intake of dioxin-like compounds. In contrast, MeHg contamination in fish on the Belgian market does not seem to be an issue of toxicological concern, even in scenarios with elevated fish consumption frequencies [85, 86]. Hence, the Belgian consumption limits for fish determined are driven by the presence of dioxinlike contaminants, which was also concluded by Foran et al. [18] performing an analysis of the risks and benefits related to salmon consumption. A recent Spanish study performed by Domingo et al, focused on 14 fish species, frequently eaten in Spain [21]. From the benefit side, EPA and DHA were considered. From the risk side, metals as well as organic pollutants were taken into account. Domingo et al. concluded that most marine species should not mean adverse health effects for the Spanish consumers [21]. However, the type of fish, the frequency of consumption, and the meal size are essential issues for the balance of the benefits and risks of regular fish consumption. Also the Food Standard Agency (FSA) in the United Kingdom has formulated in 2004 an advice on eating oily fish and was able to recommend maximum levels at which the health benefits of preventing heart disease clearly outweigh the possible risks from dioxins. Based on the report of SACN/TOC the FSA recommends that men, boys, and women past childbearing age can eat up to four portions of oily fish a week [73]. Women of childbearing age, including pregnant and breast-feeding women and girls, are advised by the FSA to eat up to two portions of oily fish a week. However, the FSA is currently reviewing its dietary advice to consumers on fish consumption to take into account nutrition, food safety, and wider sustainability issues. A new opinion will be published at the end of 2009, in which they will choose one of the two policy options: [1] doing nothing or [2] an information campaign for consumers on how they can identify sustainably caught/produced fish. In 2006, an important scientific review paper was published evaluating the risks and benefits of fish intake [20]. Mozzafarian and Rimm concluded that “for major health outcomes among adults, based on both the strength of the evidence and the potential magnitudes of effect, the benefits of fish intake exceed the potential risks. For women of childbearing age, benefits of modest fish intake, except a few selected species, also outweigh the risks”.

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5 Another Important Aspect: Sustainability 5.1 Depletion of Natural Fish Stocks There are concerns that the increased consumption of seafood and the increased use of fish oils for enriched foods are not a sustainable solution from an ecological point of view. The worldwide increase in consumption of seafood and derived seafood products during recent decades are mainly due to recommendations that seafood is part of a healthy human diet [1], the increasing world population, higher living standards, and the overall positive image of seafood among consumers [87–89]. In 2004, total capture fisheries and aquaculture supplied the world with 106 million tonnes of seafood for human consumption, providing an apparent per capita of 16.6 kg [90]. The increase in demand and supply has led to an expansion of the fishing fleet. Together with higher fish capture efficiency, this has contributed to overfishing and the risk of depletion of some natural fish stocks. As such, seafood species like Alaska pollock, blue whiting, tuna, and mackerel became globally limited food sources [91, 92].

5.2 Aquaculture: A Valuable Alternative? As an alternative to wild-caught seafood, consumers are offered now farmed seafood. In 2004, aquaculture accounted for 43% of the total world seafood supply and the contribution of aquaculture will continue to expand, while marine capture fisheries seem to have reached a ceiling [90]. It is predicted that in 2030 aquaculture will provide half of the total amount of seafood consumed worldwide [92, 93]. Therefore, it is a challenge to develop sustainable aquaculture, which in the same time minimises bioaccumulation of contaminants and other food safety risks, as the risk of contamination by chemical and biological agents is greater in freshwater and coastal ecosystems than in open seas [94, 95].

5.2.1 Wild Versus Farmed Seafood To set both ways of seafood supply side by side, a limited comparison of wild and farmed seafood is given, considering nutritional as well as food safety aspects. The nutrient content may differ between wild and farmed seafood species, viewed the difference in their diet. Wild seafood eats plankton, small algae, small fishes, and other seafood species. Their diet is affected by environmental and seasonal changes. This will affect the proximate composition of the muscle. In aquaculture, farmed seafood is provided with a supply of nutrient-dense formulated feed, which is constant throughout the year and which enables them to deposit large reserves of lipids. Moreover, the content of the formulated feed can be changed in function of the wishes of the producer and the consumer. Different studies indicated that the lipid content of farmed fish is generally larger than that of their free-living counterparts and the levels of EPA and DHA are generally lower, when expressed relatively to total fatty acids [96–100]. But viewed their higher lipid content, the amounts of EPA and DHA provided by a given quantity of farmed fish may be higher than in the same amount of wild fish. On the other hand, cholesterol and protein levels

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are similar in farmed and in wild fish. Nettleton and Exler [98] showed that levels of different vitamins (vitamin A, C, B12, B2, B3, B5, B8, and folic acid) were similar or higher in farmed species. Cahu et al. [87 concluded that the nutritional content of farmed fish is at least as beneficial as that of wild fish and farmed fish also has advantages of freshness because the storage conditions between slaughtering and sale are more verifiable. Next, food safety problems are linked to aquaculture. Regarding the presence of environmental contaminants, the most important contaminant source for farmed seafood is their formulated feed [101, 102]. Some recent studies showed that concentrations of organochlorine contaminants are significantly higher in farmed salmon than in wild and that farmed salmon from Europe is significantly more contaminated than farmed salmon from South and North America [3, 103]. In contrast, the European Food Safety Authority (EFSA) conducted a scientific assessment of the health risks related to human consumption of wild and farmed fish and concluded that with respect to their safety for the consumer there is no difference between wild and farmed fish [104]. Nevertheless, aquaculture industries should be able to take steps to reduce contaminants in fish feed by applying purification processes and as such be able to provide the population with naturally rich dietary LC n-3 sources, being safe from a toxicological point of view. Another food safety issue related to aquaculture is the use of additives like colorants and the use of drugs [105]. However, due to the large expansion of global aquaculture, countries worldwide have implemented a large number of aquaculture regulations to control inadequate developments, for example, related to drug use [90]. Nevertheless, these current aquaculture regulations cannot guarantee sustainability, especially as most of them focus on the individual farmer and do not consider the additive or synergetic effect of multiple farms on a particular area. At the same time, farmers’ economic appraisals tend to have a narrow view, which do not include the medium- and long-term revenues and costs that may be imposed on the farming activity itself and on the rest of the society in the form of a reduced supply of ecosystem goods and services [90].

6 Conclusions A final aspect related to aquaculture is the widespread practice of feeding wild-caught seafood to farmed piscivorous seafood species, e.g. salmon. This practice decreases the availability of seafood for direct human consumption on a per capita basis [95, 106]. This leads to a paradox: aquaculture is a possible solution, but also a contributing factor to the collapse of fisheries stocks worldwide [106]. It must be said that up to now, aquaculture is still the largest consumer of fish-derived oils, and so is clearly not capable of operating in a sustainable manner [107]. So, to meet consumer demand for piscivorous fish and at the same time reduce the pressure on wild fish stocks, land-based plants—such as grains, soybeans, legumes, and blended vegetable oils— are increasingly being used as staple fish food. The disadvantage is that using this feed will lower the LC n-3 PUFA concentration compared to the wild-caught species, affecting one of the important nutritional advantages of seafood consumption [95]. However, actually different studies are running that investigate whether a combination of a diet high in vegetable oil with a diet high in fish oil only during the last weeks of the production cycle can lead to a restoration of EPA and DHA concentration to equal levels when compared to fish oil-fed counterparts [102, 107]. More research is needed and probably it will take time before such customs are used in

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practice. An alternative to this kind of combined diets can be the use of single cell oils and genetically modified plants (and animals) as sustainable sources of LC n-3 PUFAs.

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Chapter 20

Anthropogenic and Naturally Produced Contaminants in Fish Oil: Role in Ill Health Adrian Covaci and Alin C. Dirtu

Key Points • Fish oil dietary supplements are recommended to increase the intake of polyunsaturated fatty acids (PUFAs), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), renowned for their beneficial effects to human health. • Fish oil dietary supplements contain anthropogenic contaminants, such as organochlorine pesticides, polychlorinated biphenyls, polychlorinated dioxins and furans, polybrominated diphenyl ethers and mercury. Recently, a number of organobrominated compounds, such as methoxylated-PBDEs and polybrominated hexahydroxanthenes derivatives, naturally produced by marine organisms (e.g., algae and sponges) have also been identified in commercial fish oil dietary supplements. • Since fish oil dietary supplements are consumed on a daily basis, concerns are issued about the presence of various contaminants in these capsules with improvements in the preparation and purification of supplements have reduced dramatically the contaminant’s concentrations. • Fish oil dietary supplements might be a suitable alternative to fish consumption for certain groups of the population for which fish consumption advice has been issued such as pregnant women or children. • There is also a stringent need to regularly monitor the presence of “classical” and “new” contaminants together with naturally occurring compounds, in marine products destined for human consumption. Keywords Anthropogenic · Organohalogenated contaminants · Naturally produced · Beneficial health effect · Fish oil dietary supplements · Dietary intake

A. Covaci () Department of Pharmaceutical Sciences, Toxicological Center, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium e-mail: [email protected] F. De Meester et al. (eds.), Modern Dietary Fat Intakes in Disease Promotion, Nutrition and Health, DOI 10.1007/978-1-60327-571-2_20, © Springer Science+Business Media, LLC 2010

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1 Beneficial Effects of Consumption of Fish Oils Rich in n–3 Unsaturated Fatty Acids Both marine fish and fish-derived products, e.g., fish oils, contain essential long-chain polyunsaturated fatty acids (PUFAs), such as 5,8,11,14,17-eicosapentaenoic acid (EPA) and 4,7,10,13,16,19-docosahexaenoic acid (DHA), which are essential in the human diet [1]. They are needed for many metabolic functions including growth, structural maintenance, repairing of nervous tissue, cellular membrane phospholipid structure, or regulation of lipid metabolism [1–3]. Moreover, the intake of high amounts of PUFAs has been suggested to have several beneficial effects to human health, including decreasing the incidence and progression of vascular diseases, as well as reducing the symptoms of multiple sclerosis and/or osteoporosis [2, 3]. In recent years, fish oil dietary supplements (FODS) have been increasingly promoted as an alternative to fish consumption. Indeed, FODS may contain high and balanced custom-made amounts of DHA and EPA [1] and can sometimes be found in combinations with other nutritional supplements, such as vitamins, minerals, or even other PUFAs.

1.1 n – 3 Fatty Acids and Cardiovascular Diseases The evidence from prospective studies and randomized trials [4–25] suggests that ingestion of n – 3 fatty acids (especially EPA and DHA) through consumption of fish or fish oil might beneficially influence cardiovascular disease. The first studies that showed the importance of fish consumption demonstrated low rates of death from coronary heart disease (CHD) among Greenland Eskimos [26]. Therefore, many effects were reported in relation with EPA and DHA ingestion, namely preventing arrhythmias [27], lowering plasma triacylglycerols [28, 29], decreasing blood pressure [30], decreasing platelet aggregation [31, 32], improving vascular reactivity [33, 34], and decreasing inflammation [35]. Across different studies, compared with little or no intake, modest consumption of n – 3 fatty acids (250–500 mg/d of EPA and DHA) lowers relative risk by more than 25%. Higher intakes do not substantially further lower CHD mortality, suggesting a threshold effect [36]. This threshold effect explains findings among Japanese populations [18, 24] in whom high background fish intake (e.g., median 900 mg/d of EPA and DHA) is associated with very low CHD death rates (87% lower than comparable Western populations) [10, 18], and additional n – 3 PUFA intake predicts little further reduction in CHD death. When comparing different types of fish, lower risk appears more strongly related to intake of oily fish (e.g., salmon, herring, sardines), rather than lean fish (e.g., cod, catfish, halibut) [11, 16]. Fish intake may modestly affect other cardiovascular outcomes, but evidence is not as robust as for CHD death [24, 37–44]. n – 3 PUFAs may influence several cardiovascular risk factors [23, 24, 27, 42–50]. Effects occur within weeks of intake and may result in altered membrane fluidity and receptor responses following incorporation of omega-3 PUFAs into cell membranes [51, 52] and direct binding of omega-3 PUFAs to intracellular receptors regulating gene transcription [53]. The heterogeneity of the effects of fish or fish oil intake on cardiovascular outcomes is likely related to varying dose and time responses of effects on the risk factors [3]. At typical dietary

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intakes, anti-arrhythmic effects predominate, reducing risk of sudden death and CHD death within weeks. At higher doses, maximum anti-arrhythmic effects have been achieved, but other physiologic effects may modestly impact other clinical outcomes (possibly requiring years to produce clinical benefits). Yet, the heterogeneity of clinical effects may also be related to differing pathophysiologies of the clinical outcomes. Biological differences in the development of atherosclerosis vs. acute plaque rupture/thrombosis vs. arrhythmia would account for heterogeneous effects of n – 3 PUFAs on plaque progression vs. nonfatal myocardial infarction vs. CHD death. Fish may replace other foods in the diet, such as meats or dairy products. However, the increase in fish consumption is unlikely to have important health benefits, since the replaced foods are highly variable among individuals and across cultures. n–3 PUFAs most strongly affect CHD death [10, 14, 15] and are unlikely to affect appreciably other causes of mortality. Effects on total mortality in a population would therefore depend on the proportion of deaths due to CHD, ranging from one quarter of deaths in middle-age populations [54] to one half of deaths in populations with established CHD [10]. This is consistent with a meta-analysis of randomized trials through 2003 that found a nonsignificant 14% reduction in total mortality with n – 3 PUFAs [5, 10, 25, 55, 56]. When additional placebo-controlled, double-blind, randomized trials performed since 2003 were added [41], marine n – 3 PUFAs reduced total mortality by 17% (pooled relative risk, 0.83; 95% CI, 0.68–1.00; P = 0.046).

1.2 Neurologic Development DHA is preferentially incorporated into the rapidly developing brain during gestation and the first 2 years of infancy, concentrating in gray matter and retinal membranes [57]. Infants can convert shorter chain n – 3 PUFAs to DHA [58], but it is unknown whether such conversion is adequate for the developing brain in the absence of maternal intake of DHA [59]. Effects of maternal DHA consumption on neurodevelopment have been investigated in observational studies and randomized trials, with heterogeneity in assessed outcomes (visual acuity, global cognition, specific neurologic domains) and timing of DHA intake (gestational vs. nursing). In a meta-analysis of 14 trials, DHA supplementation improved visual acuity in a dose-dependent manner [60]. Results for cognitive testing are less consistent, possibly due to differences in neurologic domains evaluated [57, 59, 61]. A quantitative pooled analysis of eight trials estimated that increasing maternal intake of DHA by 100 mg/d leads to an increased child IQ by 0.13 points (95% CI, 0.08–0.18) [62]. Most trials evaluated effects of maternal DHA intake during nursing, rather than pregnancy. In a trial among 341 pregnant women, treatment with cod liver oil from week 18 until 3 months postpartum increased DHA levels in cord blood by 50% and raised mental processing scores, a measure of intelligence, at age 4 [63]. This is consistent with observational studies showing positive associations between maternal DHA levels or fish intake during pregnancy and behavioral attention scores, visual recognition memory, and language comprehension in infancy [64–66]. Thus, while dose responses and specific effects require further investigation, these studies together indicate that maternal intake of DHA is beneficial for early neurodevelopment.

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2 Toxic Contaminants from Fish Oil Dietary Supplements 2.1 Anthropogenic Contaminants Besides PUFAs, it was already shown in many studies that fish may contain a variety of persistent contaminants, such as polychlorinated dibenzo-p-dioxins and furans (PCDD/PCDFs), polychlorinated biphenyls (PCBs), or polybrominated diphenyl ethers (PBDEs). This may result in a potential increase of health risks that could counteract the beneficial effects of n – 3 PUFAs [67, 68]. In general, the concentrations of such contaminants are proportional with the position of the fish in the food chain. Therefore, fish situated at the base of the food chain usually carries lower levels of contaminants compared to predatory fish situated high on the fish chain [69]. Another important parameter related to contaminant’s concentrations in fish is the content of fat; fatty fishes (e.g., salmon, herring) contain significantly higher concentrations of persistent contaminants when compared to lean fish species [69]. The ingestion of persistent contaminants through fish consumption may lead to a wide range of toxicological and hormonal effects, including endocrine disruption, reproductive, neurobehavioral, and developmental disturbances [3, 70]. Such toxic effects on human health recorded for these contaminants made several environmental and health agencies to have already issued consumption recommendations, which range between 0.5 and 2 meals of fatty fish per month [67]. The general public is given seemingly conflicting reports about the risks and benefits of fish intake, resulting in controversy and confusion over fish and fish-derived products and their role in regard to a healthy diet [71]. Nevertheless, these contaminants persist for long periods in the environment, and thus, while levels are steadily declining, PCBs and dioxins continue to be present in low concentrations in many food items. Considering these information, it become obvious that FODS may also be a potential source of toxic contaminants, especially when the fish oil produced originates from fish caught in contaminated waters or from farmed fish fed with contaminated feed. Fish oil produced from these sources may contain markedly higher amounts of contaminants than fish originating from less polluted sites [72–74]. Since FODS are recommended to be taken on a daily basis, it is therefore important to closely monitor the levels of contaminants that might be contained by these PUFA-enriched products. Hereby, the presence of above-mentioned contaminants in fish oils may counteract the highly claimed benefits of such capsules. The following paragraphs will be focused on discussing the levels and profiles of each class of contaminants reported as present in FODS and also in relation with their acceptable norms.

2.1.1 Polychlorinated Biphenyls PCBs are synthetic organochlorine compounds previously used in industrial and commercial processes, but their manufacture and processing was prohibited in 1977 [75]. Based on exposed animal experiments and also some evidence in humans, PCBs may cause adverse human health effects, such as cancer (possibly related to effects on the aryl hydrocarbon receptor), may interfere with transcription factors affecting gene expression, may affect the immune system, and may cause neurological effects [76, 77]. Also prenatal exposure to PCBs has been associated

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with childhood neurodevelopmental deficits in several studies [78–80]. Hereby, in order to counteract the negative effects on human health by the presence of PCBs in FODS, the additional health risks would have to exceed possible benefits by more than 100-fold to meaningfully alter the present estimates of risks vs. benefits [3]. From their chemical structure, theoretically PCBs may exist in a maximum number of 209 congeners (generically listed according to the number/position of the chlorine atoms in the molecule), although only about 130 are found in commercial PCB mixtures [75]. From all possible PCBs, 12 congeners do not present any chlorine atoms on ortho-positions (non-ortho PCBs) or have only one chlorine in ortho-position (mono-ortho PCBs). These congeners present a coplanar chemical structure, having a geometrical configuration like 2,3,7,8-tetrachlorodibenzop-dioxin (2,3,7,8-TCDD), being therefore called dioxin-like PCBs (DL-PCBs). The coplanar PCBs have demonstrated a close toxicological similarity to dioxins and are thought to operate by the same general mechanism [81]. However, depending on the mixture containing PCBs used, the number of possible congeners which may be measured in fish and fish oil samples differs. In general, the profile for these contaminants consists from a smaller number of congeners, mainly tri- (CB-28), tetra- (CB-52), penta- (CB-101, 118), hexa- (CB-138, 149, 153), and hepta- (CB-170, 180) chlorinated components [75]. From above-mentioned PCB congeners, the least important are CB-28 and CB-52, which usually are measured in such samples close to the limit of quantitation of different methods applied, while the most important are CB-153, CB-118, and CB-138. Considering only the number of chlorine atoms in molecule, the profile of PCBs measured in general in FODS consists from penta- and hexa-CBs which are usually present at highest concentrations, followed immediately by hepta-CBs and at the lowest levels being usually measured tetra-CB congeners. Regarding the concentration in which PCBs are usually measured in such samples, this parameter differs according to a multitude of factors, namely year/region of sample collection, type of purification process applied on the fish oil considered, type of fish, or fish organ used for oil manufacture. A non-exhaustive summary of the available literature related to the content of PCBs, including DL-PCBs, from fish oils is presented in Table 20.1. Most of the samples included in presented studies from Table 20.1 shows that reported PCB concentrations for are below of the Belgian regulatory limit (75 ng PCBs/g), with very low levels in some samples [73, 85, 86]. There are also cases where the concentrations seem to exceed the regulatory limits for PCBs, namely for unrefined oil [87] or for samples collected in the late 1990s [82], when most probably the control of such hazardous substances was not as rigorous as it is nowadays or the refining processes were not very developed. The type of fish or fish tissue used to produce fish oils can easily influence the concentrations of contaminants in the obtained products. Therefore, oils obtained from cod liver appear to be significantly more contaminated compared with the one obtained from whole fish [73].

2.1.2 Polychlorinated Dibenzo-p-dioxins and Polychlorinated Dibenzofurans The chemical compounds included in the class of polychlorinated dibenzo-p-dioxins (PCDDs) (75 different components) and also in the class of polychlorinated dibenzofurans (PCDFs) (135 different components) are commonly referring to the term “dioxins.” They are organochlorine by-products of waste incineration, paper bleaching, pesticide production, and production

FODS (mainly cod liver oil) (Australia), N = 5 FODS (fish oil) (Belgium), N=4 FODS (mainly cod liver oil) (the United Kingdom), N=6 Fish oil (Japan), N = 41 FODS (cod liver oil), N = 7 FODS (fish oil), N = 6 FODS (unspecified) (the USA), N = 20 FODS (cod oil) (the USA), N=4 FODS (cod liver) (Italy), N = 15 FODS (Belgium), N = 27 FODS (The Netherlands), N = 17 FODS (the United Kingdom), N = 12 FODS (other countries)c , N = 13 FODS (mixed—no salmon), N = 8

Sample (origin of sample), N

Legal limit (ng/g)

– –

– –

84 (5–128)a,b

– 138 (100–224) 31 (5–47) – – 71 (25–133)b 3.9 (<0.3–150) 2.9 (<0.3–230) 4.4 (<0.3–62) 3.8 (<0.3–21) 10.6 (0.189–15.2)b

655 (5–975)a

– 108 (87–202) 34 (0–49) 50.4 (10.3–94.3)

153.3 (47.4–276.2)

86 (25–201)

12 (<0.3–57) 14 (<0.3–60)

7.6 (<0.3–22)

6.0 (<0.3–95)

24.2 (0.711–37.9)

–

– –

8.2 (0.91–19.3) – – –

–

–

19 (5–851)a,b

124 (20–744)a

–

10

DL-PCBs (pg WHO-TEQ/g)

9 (4–227)a,b

1,000

OCPs (ng/g)

9 (5–341)a

75

PCBs (ng/g)

–

–

–

– –

–

–

2.0 (0.2–4.9) – – –

–

–

–

2

PCDD/Fs (pg WHO-TEQ/g)

2005–2007 [86]

2004–2006 [85]

2004–2006 [85]

2004–2006 [85] 2004–2006 [85]

2004 [74]

2003 [84]

2000–2005 [83] 2001–2002 [73] 2001–2002 [73] 2003 [84]

1994–1995 [82]

1994–1995 [82]

1994–1995 [82]

Year (Reference)

Table 20.1 Median and concentration range (ng/g oil) of polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), and polychlorinated dibenzo-p-dioxins and furans (PCDD/PCDFs) in fish oil dietary supplements Median (range) concentrations (ng/g)

326 A. Covaci and A.C. Dirtu

– –

– 0.17 (0.02–1.1) 4.9

59.2 (4.76–250)b – – – – –

13.2 38.4 (25.6–51.3) 0.74 (0.16–33)e 210e

95.3 (36.1–170) 320 (290–340)

22 (19–43)

18.5 (16–31) 13 (0.23–17)

–

–

–

– –

b OCPs

–

9.4 (1.1–41.5)

– 1.15 (0.038–1.3)

–

–

10

DL-PCBs (pg WHO-TEQ/g)

11.1 (9.31–24.9)b

1,000

OCPs (ng/g)

25.1 (19.3–26.5)

75

PCBs (ng/g)

Median (range) concentrations (ng/g)

were recalculated in ng/g using an average density of oil of 0.924 g/mL are reported as DDTs c Denmark, South Africa, USA, France, and Sweden d No heating step in the refining process e OCPs are reported as HCHs + DDTs

a Results

FODS (mixed— including salmon), N = 6 FODS (salmon), N = 7 Shark liver oil (Japan), N = 3d Shark liver oil (New Zealand), N = 3d Shark liver oil, N = 6 FODS (mainly Pacific fish, for Switzerland), N = 6 FODS (mainly cod liver oil) (the United Kingdom), N = 32 Fish oil (cod liver oil) (Spain), N = 1 Fish oil (salmon) (Spain), N=2 Fish oil (Sweden), N = 5 Seal Oil (Sweden), N = 1

Sample (origin of sample), N

Legal limit (ng/g)

Table 20.1 (continued)

0.57 (0.09–0.86) 2.3

–

–

0.9 (0.2–8.4)

– 0.65 (0.32–0.83)

–

– –

–

2

PCDD/Fs (pg WHO-TEQ/g)

2008 [91] 2008 [91]

2007 [90]

2007 [90]

2006 [89]

2006 [87] 2006 [88]

2006 [87]

2005–2007 [86] 2006 [87]

2005–2007 [86]

Year (Reference)

20 Anthropogenic and Naturally Produced Contaminants in Fish Oil: Role in Ill Health 327

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of polyvinyl chloride plastics [92]. Their toxicity was well established through various studies [93, 94] and therefore controlling emissions of these chemicals was of a high concern. Because of monitoring programs implemented by most of the countries, total environmental releases of dioxins from all quantifiable sources decreased by 90% between 1987 and 2000 [92]. The results presented in Table 20.1 shows that in case of PCDD/Fs, median concentrations measured in different FODS collected from various locations are well below the maximum tolerable limit. Only one study reported higher concentrations of PCDD/Fs, but the value is assigned to an oil sample obtained from seal [91].

2.1.3 Organochlorine Pesticides The most important pesticides from this class which are usually measured in fish or fish oil samples are hexachlorocyclohexanes (HCHs) (usually present in their four isomers: α-, β-, γ-, δ-HCH), DDT and metabolites (DDTs), and chlordanes. Commercial DDT is actually a mixture of several closely related compounds where the major component (up to 77%) is the p,p isomer. The o,p isomer is also present in significant amounts (15%), the rest of the mixture being constituted from p,p -dichlorodiphenyldichloroethylene (p,p -DDE) and p,p -dichlorodiphenyldichloroethane (p,p -DDD). p,p -DDE and p,p -DDD are also the major metabolites and breakdown products of DDT in the environment [95]. The term “total DDT” or ΣDDTs is often used to refer to the sum of all DDT-related compounds (p,p -DDT, o,p -DDT, p,p -DDE, and p,p -DDD) in a sample. From the pesticide formulations mentioned above, DDTs are by far the most abundant OCPs measured in fish and/or FODS. In fact, together with PCBs, DDTs constitute the main chlorinated contaminants found in general in marine samples. Therefore, the results from Table 20.1 related to the content of OCPs from FODS reported in the literature will often refer to the concentrations of DDTs. Because of its ban in most of the countries, usually the main contributor to the DDTs is the principal metabolite of p,p -DDT, which is p,p -DDE. However, none of the presented studies from Table 20.1 show concentration values for DDTs higher than the EU regulatory limit (1,000 ng/g). Again, concentrations of DDTs depend on the type of fish or organ used to produce FODS. As a consequence, oil supplements obtained from cod liver showed also for DDTs the highest median concentrations compared with other products [73, 82, 85].

2.1.4 Brominated Flame Retardants Although several BFRs, such as polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecane (HBCD), are found in quantifiable levels in wildlife and humans and have been extensively investigated in the last decade, we are still lacking information on the health effects caused by these compounds [70]. In humans, they are absorbed from the gastrointestinal tract and accumulate in fatty tissues [70]. It seems that they present acute toxicity at average doses, but their health effects from chronic exposure are of more concern, especially when they are related to the exposure of developing infants and wildlife. However, based on the available data, it is known that BFRs are associated with several health effects in animal studies, including neurobehavioral toxicity, thyroid hormone disruption, and possibly cancer, only for some PBDE

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congeners [70]. Even if limited information is available in the literature, there is some evidence that BFRs can cause developmental effects, endocrine disruption, immunotoxicity, reproductive, and long-term effects, including second-generation effects, reviewed by Birnbaum and Staskal [70] and Darnerud [96]. For PBDEs, there is some evidence available for estrogenic activity [96, 97], but more studies have to be undertaken to determine if low-dose exposures have estrogenic activity in humans or other species. However, their presence in fish in general and in FODS in particular is important and their monitoring should be carefully addressed for these new persistent contaminants.

Polybrominated Diphenyl Ethers PBDEs are flame-retardant additives which are used in a wide array of household products in concentrations up to 30% by weight, typically between 2 and 6% (per weight) [98]. They are structurally related to PCBs and are produced commercially as mixtures. However, PBDE mixtures contain fewer congeners than the commercial PCB mixtures. The three commercial mixtures of PBDEs are penta-BDE, octa-BDE, and deca-BDE according to the number of bromine atoms in the dominating congeners of the mixtures. Since August 2004, the use of penta- and octa-BDE technical mixtures has been banned in the EU, followed in July 2008 by the ban on the use of deca-BDE mixture [98]. In USA, only California has banned the use of penta- and octa-BDE mixtures by the end of 2008, while other US states are currently in the phase-out legislation for PBDEs [98]. Even if PBDEs have been reported (sometimes in high levels) in marine environments [99], there are very few studies which monitored their presence in FODS. Generally, the most detected PBDE congeners in FODS are BDE 47, 99, and 100 (which usually contribute with >75% to the total PBDEs), while higher brominated congeners, such as BDE 153, 154, and 183, are in most of FODS below quantification limit [100], though reported levels of PBDEs are considerably lower than those of organochlorine contaminants, such as PCBs or OCPs [85]. This is probably due to improved selection of fish used for the FODS preparation and/or to the final purification methods used by different producers. Similar to PCBs and OCPs, the most contaminated samples were reported as FODS obtained from cod liver (Table 20.2) [73, 87, 101]. Interestingly, several FODS with an elevated PBDE content had also higher DHA content [100]. It is not clear whether this is due to the fish sources used for the preparation of FODS with high DHA content (e.g., tuna) or to the purification processes specific for DHA-enriched FODS.

Hexabromocyclododecane HBCD is the third most widely used BFR in the world and on the second place in the EU [98]. It is mostly used in extruded and expanded polystyrene foams but also is used as insulation material in construction industry. HBCD is highly efficient so that very low levels are required to reach the desired flame retardancy. Other uses of HBCD are upholstered furniture, automobile interior textiles, car cushions and insulation blocks in trucks, packaging material, video cassette recorder housing, and electric and electronic equipment [98].

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Table 20.2 Median and concentration range (ng/g oil) of polybrominated diphenyl ethers (PBDEs), hexabromocyclododecane (HBCD), and total mercury (Hg + MeHg) in fish oil dietary supplements Median (range) concentrations (ng/g) Sample (origin of sample)

PBDEs

HBCDs

Hg-MeHg

Year (Reference)

FODS (cod liver oil), N = 7 FODS (fish oil), N = 6 FODS (Belgium), N = 27 FODS (The Netherlands), N = 17 FODS (the United Kingdom), N = 12 FODS (other countries)a , N = 13 FODS (mainly Pacific fish, for Switzerland), N = 6 Cod liver oil (North Sea), N = 3

20 (15–35) 1.7 (0.8–2.6) 0.4 (<0.1–45) 0.5 (0.1–17) 0.2 (0.1–2.8) 0.4 (0.1–7.5) 0.7 (0.069– 3.8) 28 (16–32)

– – – – – – –

– – – – – – –

2001–2002 [73] 2001–2002 [73] 2004–2006 [100] 2004–2006 [100] 2004–2006 [100] 2004–2006 [100] 2006 [88]

5.4 (4–6.2)

–

Shark liver oil (Japan), N = 3b

52 (49–53)

44 (44–45)

–

<0.2

–

2004–2008 [87, 101] 2004–2008 [87, 101] 2004–2008 [87, 101] 2004–2008 [87, 101] 2004–2008 [87, 101] 1998 [108]

Shark liver oil (New Zealand), N = 3b 0.6 (0.2–0.7) Shark liver oilc , N = 6

0.2 (0.1–15)

<0.2 – (<0.2–7.3) Seal oil (Canada), N = 2 0.85 (0.8–0.9) 0.45 – (0.4–0.5) Catfish-eggs oil (Venezuela), N = 22 – – 2.16 (1.8–2.97)d FODS (fish oil), N = 3 – – 38.8 2005 [109] (9.9–123) a Denmark, South Africa, USA, France, and Sweden b No heating step in the refining process c Origin (country of production) unspecified d Results were recalculated in ng/g using a density value of 0.9 g/mL

The concentrations of HCHD in fish are usually strongly correlated with the contamination level of the area from which the samples are collected or with the proximity of industrial activity areas since there are several studies reporting high levels of HBCD in such samples [102]. Because of the increasing temporal trends of HBCD in various environmental compartments, especially in aquatic environmental samples [99], HBCD content of fish oils used to prepare FODS should also be monitored. The results presented in Table 20.2 show that the reported levels of HBCD in FODS are slightly lower compared to PBDEs measured in the same samples [101].

2.1.5 Mercury and Methyl Mercury The forms in which mercury is present in the environment are various, namely elemental (metallic) mercury (Hg0 ), inorganically bound mercury (Hg2+ ), and organically bound mercury, for example, monomethyl mercury (MeHg) or dimethyl mercury (Me2 Hg). When assessing the risk for the human health, one has to consider that organically bound mercury species are much more toxic than elemental or inorganic species [103]. MeHg is formed in aquatic systems from inorganic mercury through a methylation process by the action of anaerobic organisms. Because MeHg is formed in aquatic systems and because it is not readily eliminated from organisms, it

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is biomagnified in aquatic food chains from bacteria, to plankton, through macroinvertebrates, to herbivorous fish, and further to piscivorous fish. Therefore, the concentration of MeHg in the top-level aquatic predators can reach a level a million times higher than the level in the water [103]. There are many factors which may influence Hg concentrations in any given fish, namely fish species, the age and size of the fish, and the type of water body in which the sample was collected [103]. Once entered in human body, MeHg is readily and completely absorbed by the gastrointestinal tract and afterward it reacts through a complexation process mostly with amino acids. MeHg is a risk factor for cardiovascular disease through a variety of mechanisms potentially involving prooxidant effects via the generation of radical species and the inactivation of cellular antioxidant systems such as glutathione peroxidase and catalase [104]. Mechanistic studies indicate that MeHg can exert toxic effects on the vascular endothelium by depletion of sulfhydryls, increased oxidative stress, and activation of phospholipases [105, 106]. Nevertheless, estimation of the benefits for n – 3 FA intake vs. MeHg risks should be carefully addressed for different fish species, according to their content in toxic/nontoxic compounds [107]. Therefore, even if the toxicity of Hg and its derivatives was shown in various studies involving aquatic environment, their monitoring in FODS was not as regular as it might be expected and there are very few reports of Hg content for such supplements (Table 20.2).

2.2 Naturally Produced Halogenated Compounds Several recent studies have described the presence in marine environment of naturally produced halogenated compounds, such as methoxylated polybrominated diphenyl ethers (MeO-PBDEs) [110–112], polybrominated hexahydroxanthene derivatives (PBHDs) [113, 114], or halogenated dimethyl bipyrroles (HDBPs) [115, 116]. Their presence was already confirmed in some fish species used for the preparation of FODS [117, 118]. All mentioned classes of naturally produced compounds have been sometimes measured in concentrations higher than contaminants usually targeted in monitoring schemes, but not much is known about their occurrence, their dietary intake from fish and fish-derived products, or about the potential toxicological effects of these compounds.

2.2.1 Polybrominated Methoxylated Diphenyl Ethers MeO-PBDEs are produced by algae, bacteria, or sponges (cyanobacteria and red algae— Ceramium tenuicorne) [112] and have previously been found in various marine organisms, including fish and marine mammals [110, 111]. The presence of elevated concentrations of these compounds found in the higher levels of the marine food chain demonstrates their bioaccumulative properties. However, little is known of their potential toxicological effects. Covaci et al. [100] analyzed several FODS collected from various locations (Table 20.3), and MeO-PBDEs were found at elevated levels in most of the samples. Moreover, there was no significant correlation between PBDEs and MeO-PBDEs levels (namely between BDE 47 and 6MeO-BDE 47, one of the most abundant compounds measured in fish samples usually) showing

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that these compounds could originate from other marine sources. However, some significant correlation between individual MeO-PBDEs (6-MeO-BDE 47 and 2-MeO-BDE ´ 68) shows that it is highly plausible that these compounds have both accumulated from the similar (natural) sources. The main difference between the results within the samples was based on the origin of fish included in FOD manufacture: fish from Pacific and Atlantic Oceans showed higher levels on MeO-PBDEs, similar results being reported for marine mammals from the Southern hemisphere [110]. Table 20.3 Median and concentration range (ng/g oil) of naturally produced brominated compounds: methoxylated polybrominated diphenyl ethers (MeO-PBDEs) and polybrominated hexahydroxanthenes (PBHDs) in fish oil dietary supplements Median (range) concentrations (ng/g) Sample (origin of sample)

MeO-PBDEs

FODS (Belgium), N = 27 4.6 (<0.2–1670) FODS (The Netherlands), N = 17 9.2 (<0.2–180) FODS (the United Kingdom), N = 12 14 (<0.2–315) FODS (other countries)a , N = 13 4.1 (<0.2–230) a Denmark, South Africa, USA, France, and Sweden

PHBDs

Year (Reference)

3.8 (<1.3–98) 22.9 (<1.3–158) 2.8 (<1.3–163) 14.2 (<1.3–203)

2004–2006 [100] 2004–2006 [100] 2004–2006 [100] 2004–2006 [100]

2.2.2 Polybrominated Hexahydroxanthene Derivatives PBHDs were recently identified by Hiebl et al. [113] as two congeners in fish and shellfish. Indeed, sponges of the Cacospongia genus, reported to occur in Australia, but also in the Mediterranean Sea, have been suggested as potential natural producers of PBHDs [113, 114]. In the fish oil survey by Covaci et al. [100], concentrations of PBHDs were similar to concentrations of MeO-PBDEs (Table 20.3), and in the most samples, higher than of PBDEs. Within the two mentioned classes of naturally produced compounds, the levels of PBHDs did not correlate with MeO-PBDEs (Rs = 0.24, p > 0.01), suggesting separate (natural) sources of their presence in fish/fish oil samples [100]. Similar concentrations of PBHDs were already determined in farmed fish from the Mediterranean Sea [113], in farmed mussels from New Zealand [113, 114], but also in bird eggs from Norway [119], indicating the transfer of these compounds throughout the marine food web.

2.2.3 Halogenated Dimethyl Bipyrroles Specific sources of these compounds have not been yet identified, but radiocarbon analysis strongly suggests that halogenated dimethyl bipyrroles (HDBPs) are synthesized using a relatively recent source of carbon and thus likely have a biogenic origin [120, 121]. It was also assessed that they show persistency, have bioaccumulation potential, and are already globally distributed in marine environments. Due to similarities in physical properties and persistence, their environmental behavior has somewhat paralleled the behavior of persistent anthropogenic organohalogens, such as the higher chlorinated PCB congeners [115]. Although the geographical sources of HDBPs are poorly understood, these compounds seem to be more abundant in marine samples from the North Pacific Ocean rather than the Atlantic Ocean [122, 123]. The presence of HDBPs in FODS was not reported until now, but because of their levels in fish samples, it

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might be suggested that this is a matter of time. Moreover, it is important to report their levels in fish samples when discussion about comparison of risks/benefits of fish/FODS consumption is addressed, even if their potential toxicological effects are not yet elucidated.

3 Intake of Contaminants Through Consumption of FODS Since FODS are intended to be consumed on a daily basis, several studies have also calculated the daily intake of organohalogenated compounds from FODS. In a study by Covaci et al. [100], PUFA-rich FODS (n = 69) from 37 producers were collected in 2006 from products available for sale on the Belgian market, but also from The Netherlands, Ireland, the United Kingdom, and South Africa. Information on recommended dosage as provided on the product labels together with the EPA and DHA composition was used to calculate the daily intake in pollutants. In order to estimate the contaminant intake, daily recommended consumption of the supplements, as provided on the product labels, was multiplied by the corresponding concentrations. Intakes (ng/day) were calculated using lower bound (LB) and upper bound (UB) methods, where non-detects were replaced with a value equal to zero or LOQ, respectively. The investigated FODS contained 200–800 mg/g EPA and DHA and the recommended dosing for human consumption ranged between 1 and 3 g/day [3]. Due to the low contamination levels in the FODS analyzed in this particular survey [85, 100], FODS do not appear to increase substantially the dietary intake of PCBs: median daily intake was 29 and 42 times lower than the intake from fish consumption alone or from total diet, respectively (Fig. 20.1). Similarly, the median daily intake of PBDEs was 8 and 16 times lower than the intake from fish consumption alone or from total diet, respectively (Fig. 20.1). Although fish consumption is an important contributor to the total dietary intake of PCBs or PBDEs (Fig. 20.1), the low intake of these contaminants from FODS (<10% of that from fish) suggests that purification processes were present during the preparation of the vast majority of the investigated FODS. Since the PBDE intake from FODS covers yet a wide range of values (Fig. 20.1), some FODS brands are either produced from contaminated fish or are insufficiently purified. The low intake of PCBs and PBDEs through FODS therefore makes these supplements a suitable alternative for populations with low consumption of PUFA-rich food or for which fish consumption recommendations have been issued (e.g., pregnant women). FODS also prove to be a powerful source of EPA and DHA compared with PUFA-containing vegetables oils, such as soybean and rapeseed oil, which have approximately 10 times less EPA and do not appear to provide an effective metabolic source of DHA for the average consumer [73]. This renders FODS an efficient, relatively clean, and low caloric source of PUFAs. In the same survey by Covaci et al. [100], the presence of naturally produced halogenated compounds has been reported in FODS. Using a similar approach, it was calculated that the median daily intakes of MeO-PBDEs and PBHDs from FODS were, respectively, 3 and 6 times higher than the median intake of PBDEs (3 ng/day), respectively (Fig. 20.1). For some brands, the daily intake of MeO-PBDEs and PBHDs from FODS was even higher than the total dietary intake of PBDEs. This emphasizes that the presence of these scarcely investigated compounds should not be overlooked. Likewise, MeO-PBDEs and PBHDs showed a large variation of intake estimates, encompassing the range of PBDE values.

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1000

1010

Intake (ng/day)

690

100 47

23

24

10

10

3

MeO-BDEs intake - FODS

total intake

intake -fish

intake -FODS

total intake

intake-fish

intake-FODS

0.1

PCBs

PBDEs

1

Fig. 20.1 Dietary intake (ng/day) of PCBs and PBDEs from fish oil dietary supplements, fish consumption, and total diet. The box plots show the median, 25th and 75th percentiles, the lines give the 10th and 90th percentiles, while the dots represent the outliers. Values in the box plots represent the medians for each category. Literature data used for the daily intake of PBDEs and PCBs from fish consumption and total diet are taken from references [124–144]

An estimation of the dietary intake of brominated FODS compounds for children has also been determined [100]. For each group of compounds, the intake was lower for children than for adults due to a combination of lower amounts needed to be daily ingested and lower concentrations of brominated compounds in the FODS used for children. The dietary intake from fish and seafood has also been reported for other natural compounds, such as DBPs. The daily intake estimate for DBPs was <3.5 ng/day [115], a lower result compared to the naturally produced compounds investigated by Covaci et al. [100].

4 Decontamination of Commercial Fish Oil Supplements Previously, we showed that a large variety of both anthropogenic contaminants and naturally produced compounds are present in FODS at sometime considerable amounts. Most of the abovementioned compounds are lipophilic and therefore they are mainly retained in the fatty tissues of fish used to produce the FODS. It is thus expected that such fish oils may incorporate a large variety of contaminants. If these fish oils are used as primary products directly obtained without any purification, they might represent a real risk to human health. Fish oils are usually refined by neutralization, absorption, and distillation processes. The main refining techniques developed and published until now were focused on removing of mainly

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dioxins and DL-PCBs. The refining process is usually not an easy technique to be applied, many parameters being necessary to be rigorously optimized before its proper applicability [145]. The process optimization should consist of selecting purification parameters that would allow for maximum reduction of the toxic contaminants present in fish oil while retaining the favorable high fatty acid content. However, in many cases, the levels of contaminants following these refining processes are not adequately low for human consumption; furthermore, it is known that the removal of DL-PCBs from fish oil, particularly mono-ortho PCBs, is difficult [82, 146, 147]. The removal of contaminants from fish oil was applied using supercritical CO2 extraction (SCE) and different adsorbents [148]. It was shown that when using SCE alone the removal efficiency was higher in case of DL-PCBs (70–90% efficiency), but lower for dioxins (some of PCDD/F congeners were removed only at an efficiency of 15%). In contrast, when using different adsorbent treatments, activated carbon showed high removal efficiencies (>90%) for PCDDs and PCDFs, but low (<30%) for DL-PCBs. A combination of both of these methods was suggested to be more effective in order to reduce the total TEQ value for dioxin-like contaminants [148]. These results were confirmed in 2007 when activated carbon adsorption on the reduction of POPs in fish oil was studied based on response surface methodology [149]. PCDD/Fs showed a rapid adsorption behavior and the TEQ levels could be reduced by 99%. Adsorption of DLPCBs was less effective and depended on ortho-substitution, i.e., non-ortho PCBs were adsorbed more effectively than mono-ortho PCBs with a maximum of 87 and 21% reduction, respectively, corresponding to the DL-PCB-TEQ reduction of 73%. In order to combine the best conditions for a proper purification of fish oils, refining techniques based on countercurrent supercritical CO2 extraction (CC-SCE) and activated carbon treatment were developed [150]. This resulted in a 93% reduction in the sum of PCDD/Fs and DL-PCBs levels and by 85% reduction in the TEQ values. It was shown that CC-SCE is effective for the removal of DL-PCBs, whereas activated carbon treatment is effective for the removal of PCDD/Fs.

5 Conclusions Diets rich in n – 3 fatty acids present in fish offer a number of health benefits, from fighting heart disease to boosting immunity and neurological improvement. However, many noxious persistent contaminants, such as PCBs, OCPs, PCDD/PCDFs, and PBDEs, accumulate in fatty tissue of fish and, as a consequence, they may end up in commercial fish oils produced from these fishes. In general, the levels of contaminants measured in FODS are below the legal consumption norms. In some cases, very low contaminant levels (close to the detection limit) were measured indicating improved sourcing and advanced refining processes. Consequently, the daily intake of persistent contaminants through FODS represents only a small percentage (between 3 and 12%) of the intake resulting from consumption of fish. Another advantage is the “à la carte” preparation of FODS containing high and balanced custom-made amounts of DHA and EPA, sometimes in combination with other nutritional supplements, such as vitamins, minerals, or even other PUFAs. However, some FODS products contain high levels of contaminants and this aspect needs to be better investigated. There are a number of general factors which can be linked to the purity of the fish oil capsules.

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1. A high degree of purity has been seen in FODS prepared from the oil of fish caught in clean waters (open-ocean) compared to more polluted fish from coastal areas or closed seas. 2. Oil derived from smaller species, such as anchovy, typically contains fewer contaminants than oil from larger fish (cod or salmon). This is most probably due to the shorter life of smaller fish, which leads to a lower accumulation of contaminants. 3. In general, oil produced from fish body tends to have lower contaminant concentrations than from (cod) liver or from oil of marine mammals (e.g., seal). 4. Some companies go through a number of advanced chemical-stripping or refining processes to remove contaminants from fish oil and consequently, products from these suppliers tend to be clean. Yet, most companies selling fish oil supplements do not advertise about their processing or refining procedures, nor they do identify the source of their fish, much less what species they had tapped for its oil. 5. In general, companies that had labeled their supplements as being certified free of halogenated contaminants or methyl mercury should be given credit for their efforts to improve their products and for transparency toward the consumers. 6. There is a need for inclusion of a larger number of anthropogenic contaminants, e.g., PBDEs, but also naturally produced halogenated compounds, in monitoring schemes of marine products destined for human consumption. There is also a need for appropriate monitoring and legislation for FODS. Acknowledgments Dr. Adrian Covaci was financially supported by the Research Council of the University of Antwerp and by a postdoctoral fellowship from the Research Scientific Foundation—Flanders (FWO). Dr. Alin Dirtu acknowledges financial support from the University of Antwerp.

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106. Mazerik JN, Hagele T, Sherwani S, Ciapala V, Butler S, Kuppusamy ML, Hunter M, Kuppusamy P, Marsh CB, Parinandi NL. Phospholipase A2 activation regulates cytotoxicity of methyl-mercury in vascular endothelial cells. Int J Toxicol 2007; 26: 553–569. 107. Ginsberg GL, Toal BF. Quantitative approach for incorporating methyl-mercury risks and omega-3 fatty acid benefits in developing species-specific fish consumption advice. Environ Health Persp 2009; 117: 267–275. 108. Burguera JL, Quintan IA, Salager JL, Burguera M, Rondón C, Carrero P, Anton de Salager R, Petit de Peña Y. The use of emulsions for the determination of methylmercury and inorganic mercury in fish-eggs oil by cold vapor generation in a flow injection system with atomic absorption spectrometric detection. Analyst 1999; 124: 593–599. 109. Levine KE, Levine MA, Weber FX, Hu Y, Perlmutter J, Grohse PM. Determination of mercury in an assortment of dietary supplements using an inexpensive combustion atomic absorption spectrometry technique. J Autom Method Manag 2005; 4: 211–216. 110. Melcher J, Olbrich D, Marsh G, Nikiforov V, Gaus C, Gaul S, Vetter W. Tetra- and tribromophenoxyanisoles in marine samples from Oceania. Environ Sci Technol 2005; 39: 7784–7789. 111. Teuten EL, Xu L, Reddy CM. Two abundant bioaccumulated halogenated compounds are natural products. Science 2005; 307: 917–920. 112. Malmvarn A, Marsh G, Kautsky L, Athanasiadou M, Bergman Å, Asplund L. Hydroxylated and methoxylated brominated diphenyl ethers in the red algae (Ceramium tenuicorne) and blue mussels from the Baltic Sea. Environ Sci Technol 2005; 39: 2990–2997. 113. Hiebl J, Melcher J, Gundersen H, Schlabach M, Vetter W. Identification and quantification of polybrominated hexahydroxanthene derivatives and other halogenated natural products in commercial fish and other marine samples. J Agric Food Chem 2006; 54: 2652–2657. 114. Melcher J, Janussen D, Garson MJ, Hiebl J, Vetter W. Polybrominated hexahydroxanthene derivatives (PBHDs) and other halogenated natural products from the Mediterranean sponge (Scalarispongia scalaris) in marine biota. Arch Environ Contam Toxicol 2007; 52: 512–518. 115. Titlemier SA. Dietary exposure to a group of naturally-produced organohalogens (halogenated dimethyl bipyrroles) via consumption of fish and seafood. J Agric Food Chem 2004; 52: 2010–2015. 116. Haraguchi K, Hisamichi Y, Endo T. Bioaccumulation of naturally-occurring mixed halogenated dimethylbipyrroles in whale and dolphin products on the Japanese market. Arch Environ Contam Toxicol 2006; 51: 135–141. 117. Sinkkonen S, Rantalainen AL, Paasivirta J, Lahtipera M. Polybrominated methoxy diphenyl ethers (MeOPBDEs) in fish and guillemot of Baltic, Atlantic and Arctic environments. Chemosphere 2004; 56: 767–775. 118. Marsh G, Athanasiadou M, Bergman A, Asplund L. Identification of hydroxylated and methoxylated polybrominated diphenyl ethers in Baltic Sea salmon (Salmo salar) blood. Environ Sci Technol 2004; 38: 10–18. 119. Vetter W, von der Recke R, Herzke D, Nygard T. Natural and man-made organobromine compounds in marine biota from Central Norway. Environ Int 2006; 33: 17–26. 120. Reddy CM, Xu L, O’Neill GW, Nelson RK, Eglinton TI, Faulkner DJ, Fenical W, Norstrom RJ, Ross P, Tittlemier SA. Radiocarbon evidence for a naturally-produced, bioaccumulating halogenated organic compound. Environ Sci Technol 2004; 38: 1992–1997. 121. Reddy CM, Xu L, Eglinton TI, Boon JP, Faulkner DJ. Radiocarbon content of synthetic and natural semivolatile halogenated organic compounds. Environ Pollut 2002; 120: 163–168. 122. Tittlemier SA, Borrell A, Duffe J, Duignan PJ, Hall A, Hoekstra P, Kovacs K, Krahn MM, Lebeuf M, Lydersen C, Fair P, Muir D, O’Hara TM, Olsson M, Pranschke JL, Ross P, Stern GA, Tanabe S, Norstrom RJ. Global distribution of halogenated dimethyl bipyrroles in marine mammal blubber. Arch Environ Contam Toxicol 2002; 43: 244–255. 123. Tittlemier SA, Simon M, Jarman WM, Elliott JE, Norstrom RJ. Identification of a novel C10 H6 N2 Br4 Cl2 heterocyclic compound in seabird eggs. A bioaccumulating marine natural product?. Environ Sci Technol 1999; 33: 26–33. 124. Bakker MI, De Winter-Sorkina R, De Mul A, Boon PE, Van Donkersgoed G, Van Klaveren JD, Baumann BA, Hijman WC, Van Leeuwen SPJ, de Boer J, Zeilmaker MJ. Dietary intake of polybrominated diphenyl ethers in The Netherlands. Organohalogen Compd 2006; 68: 387–390. 125. Bocio A, Llobet JM, Domingo JL, Corbella J, Teixido A, Casas C. Polybrominated diphenyl ethers (PBDEs) in foodstuffs: Human exposure through the diet. J Agric Food Chem 2003; 51: 3191–3195. 126. Darnerud PO, Atuma S, Aune M, Bjerselius R, Glynn A, Petersson Grawé K, Becker W. Dietary intake estimations of organohalogen contaminants (dioxins, PCB, PBDE and chlorinated pesticides, e.g. DDT) based on Swedish market basket data. Food Chem Toxicol 2006; 44: 1597–1606.

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127. Darnerud PO, Eriksen GS, Johannesson T, Larsen PB, Viluksela M. Polybrominated diphenyl ethers: Occurrence, dietary exposure, and toxicology. Environ Health Persp 2001; 109(Suppl 1): 49–68. 128. Domingo JL. Human exposure to polybrominated diphenyl ethers through the diet. J Chromatogr A 2004; 1054: 321–326. 129. Harrad S, Wijesekera R, Hunter S, Halliwell C, Baker R. Preliminary assessment of UK human dietary and inhalation exposure to polybrominated diphenyl ethers. Environ Sci Technol 2004; 38: 2345–2350. 130. Kiviranta H, Ovaskainen ML, Vartiainen T. Market basket study on dietary intake of PCDD/Fs, PCBs, and PBDEs in Finland. Environ Int 2004; 30: 923–932. 131. Lind Y, Aune M, Atuma S, Becker W, Bjerselius R, Glynn A, Darnerud PO. Food intake of the polybrominated flame retardants PBDEs and HBCD in Sweden. Organohalogen Compd 2002; 58: 181–184. 132. Nakagawa R, Ashizuka Y, Hori T, Tobiishi K, Yasutake D, Sasaki K. Determination of brominated flame retardants in fish and market basket food samples of Japan. Organohalogen Compd 2005; 67: 498–501. 133. Ryan JJ, Patry B. Body burdens and food exposure in Canada for polybrominated diphenyl ethers (PBDEs). Organohalogen Compd 2001; 51: 226–229. 134. Schecter A, Päpke O, Harris TR, Tung KC, Musumba A, Olson J, Birnbaum L. Polybrominated diphenyl ether (PBDE) levels in an expanded market basket survey of US food and estimated PBDE dietary intake by age and sex. Environ Health Persp 2006; 114: 1515–1520. 135. Voorspoels S, Covaci A, Neels H. Dietary PBDE intake: A market-basket study in Belgium. Environ Int 2007; 33: 93–97. 136. Zennegg M, Kohler M, Gerecke AC, Schmid P. Polybrominated diphenyl ethers in whitefish from Swiss lakes and farmed rainbow trout. Chemosphere 2003; 51: 545–553. 137. Akutsu K, Takatori S, Nakazawa H, Hayakawa K, Izumi S, Makino T. Dietary intake estimations of polybrominated diphenyl ethers (PBDEs) based on a total diet study in Osaka, Japan. Food Addit Contam Part B Surveillance 2008; 1: 58–68. 138. Harrad S, Wang Y, Sandaradura S, Leeds A. Human dietary intake and excretion of dioxin-like compounds. J Environ Monit 2003; 5: 224–229. 139. Turrio-Baldassari L, di Domenico A, Fulgenzi A, Iacovella N, La Rocca C. Dietary intake of PCBs in the Italian population. Organohalogen Compd 1998; 38: 195–198. 140. Koizumi A, Yoshinaga T, Harada K, Inoue K, Morikawa A, Muroi J, Inoue S, Eslami B, Fujii S, Fujimine Y, Hachiya N, Koda S, Kusaka Y, Murata K, Nakatsuka H, Omae K, Saito N, Shimbo S, Takenaka K, Takeshita T, Todoriki H, Wada Y, Watanabe T, Ikeda M. Assessment of human exposure to polychlorinated biphenyls and polybrominated diphenyl ethers in Japan using archived samples from the early 1980s and mid-1990s. Environ Res 2005; 99: 31–41. 141. Zuccato E, Calvarese S, Mariani G, Mangiapan S, Grasso P, Guzzi A, Fanelli R. Levels, sources and toxicity of polychlorinated biphenyls in the Italian diet. Chemosphere 1999; 38: 2753–2760. 142. Wilhelm M, Schrey P, Wittsiepe J, Heinzow B. Dietary intake of persistent organic pollutants (POPs) by German children using duplicate portion sampling. Intern J Hyg Environ Health 2002; 204: 359–371. 143. Llobet JM, Bocio A, Domingo JL, Teixido A, Casas C, Muller L. Levels of polychlorinated biphenyls in foods from Catalonia, Spain: Estimated dietary intake. J Food Protect 2003; 66: 479–484. 144. Kiviranta H, Ovaskainenn MAL, Vartiainen T. Market basket study on dietary intake of PCDD/Fs, PCBs, and PBDEs in Finland. Environ Int 2004; 30: 923–932. 145. Usydus Z, Szlinder-Richert J, Polak-Jusuzak L, Malesa-Ciecwierz M, Dobrzanski Z. Study on the raw fish oil purification from PCDD/F and dl-PCB-industrial tests. Chemosphere 2009; 74: 1495–1501. 146. Hilbert G, Lillemark L, Balchen S, Højskov CS. Reduction of organochlorine contaminants from fish oil during refining. Chemosphere 1998; 37: 1241–1252. 147. Maes J, De Meulenaer B, Van Heerswynghels P, De Greyt W, Eppe G, De Pauw E, Huyghebaert A. Removal of dioxins and PCB from fish oil by activated carbon and its influence on the nutritional quality of the oil. J Am Oil Chem Soc 2005; 82: 593–597. 148. Kawashima A, Iwakiri R, Honda K. Experimental study on the removal of dioxins and coplanar polychlorinated biphenyls (PCBs) from fish oil. J Agric Food Chem 2006; 54: 10294–10299. 149. Oterhals Å, Solvang M, Nortvedt R, Berntssen MHG. Optimization of activated carbon-based decontamination of fish oil by response surface methodology. Eur J Lipid Sci Technol 2007; 109: 691–705. 150. Kawashima A, Watanabe S, Iwakiri R„ Honda K. Removal of dioxins and dioxin-like PCBs from fish oil by countercurrent supercritical CO2 extraction and activated carbon treatment. Chemosphere 2009; 75: 788–794.

Part V

Dietary and Pharmaceutical Approaches to Modify Fat-Induced Disease and Ill-Health

Chapter 21

Do Modern Western Diets Play a Role in Myalgic Encephalomyelitis? Basant K. Puri

Key Points • Myalgic encephalomyelitis is a debilitating neurological disease affecting 3% of the adult population of Western countries. • In children myalgic encephalomyelitis may be associated with a deficiency of ω-3 and ω-6 long-chain polyunsaturated fatty acids due to viral infection or organophosphate exposure, and exacerbated by modern Western diets. Keywords Myalgic encephalomyelitis · Chronic fatigue syndrome · Proton neurospectroscopy · Diet

1 Introduction Myalgic encephalomyelitis, also referred to as chronic fatigue syndrome, is a debilitating neurological disorder which may affect up to 3% of the adult population of Western countries when defined by rigorous criteria (the revised criteria of the Centers for Disease Control (CDC); vide infra) (1). This would mean that there might be up to 1,800,000 sufferers in the United Kingdom and up to 9 million in the United States. Major epidemics of myalgic encephalomyelitis-like illnesses have occurred in both countries, and in this chapter I shall consider whether modern Western diets might play a role in this illness. First, it is germane to consider the definition of this illness. The diagnostic criteria probably most commonly used in academic research papers are the revised CDC Criteria published in 1994 by Fukuda and colleagues (2). The authors introduced their criteria by stating that ‘The complexities of the chronic fatigue syndrome and the methodologic problems associated with its study indicate the need for a comprehensive, systematic, and integrated approach to the evaluation, classification, and study of persons with this condition and other fatiguing illnesses.

B.K. Puri () MRI Unit, Hammersmith Hospital, Du Cane Road, London, W12 OHS, UK e-mail: [email protected] F. De Meester et al. (eds.), Modern Dietary Fat Intakes in Disease Promotion, Nutrition and Health, DOI 10.1007/978-1-60327-571-2_21, © Springer Science+Business Media, LLC 2010

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We propose a conceptual framework and a set of guidelines that provide such an approach.’ In essence, there are three revised CDC criteria. First, any other cause for chronic fatigue must be excluded. Second, there should be self-reported persistent or relapsing fatigue for at least six consecutive months. Third, at least four of the following symptoms need to be concurrently present for over 6 months: impaired memory or concentration, a sore throat, tender cervical or axillary lymph nodes, myalgia, multi-joint pain, new headaches, unrefreshing sleep, and post-exertion malaise. In clinical practice, I find some of these criteria unhelpful in making a diagnosis of myalgic encephalomyelitis; the temporal locking criterion of 6 months is a case in point. Other diagnostic criteria exist, such as the Oxford Criteria for chronic fatigue syndrome and the Canadian Criteria (A Clinical Case Definition and Guidelines for Medical Practitioners: The Canadian Consensus Document) for myalgic encephalomyelitis/chronic fatigue syndrome. At the time of writing, the etiology of myalgic encephalomyelitis is unknown. While there is a school of thought within some psychiatric and psychological circles that considers it to be psychosomatic in origin, this chapter is based on the fact that there is ample, and growing, evidence that myalgic encephalomyelitis is a biological illness. Some of this evidence also points to a potentially viral (or other infectious) causation. First, it is noteworthy that many of the clinical features of epidemics of myalgic encephalomyelitis-like illnesses that have been well documented, including the Los Angeles County Hospital epidemic (United States) of 1934 and the Royal Free Hospital (London) epidemic of 1955 are consistent with viral infections (3). Second, overall, the immune system changes reported in myalgic encephalomyelitis tend to point to reduced NK-cell activity, reduced Th1-cell activity, increased Th2-cell activity, and increased Tc-cell activity (3–8). Clearly, these findings could be the result of a chronic viral infection; they are also consistent with an autoimmune response, but there is no clear evidence that autoimmune diseases are more common in myalgic encephalomyelitis. Third, direct peripheral blood measurements of long-chain polyunsaturated fatty acids has shown reduced levels of the ω-6 long-chain polyunsaturated fatty acid arachidonic acid and adrenic acid in patients with postviral fatigue compared with matched control subjects (9), while another study of patients meeting the Oxford Criteria for chronic fatigue syndrome found that patients had lower levels of the ω-3 long-chain polyunsaturated fatty acid eicosapentaenoic acid (EPA) compared with matched controls (10). These findings are consistent with viral infection, as it is known that such infections can impair the biosynthesis of long-chain polyunsaturated fatty acids from their essential fatty acid short-chain precursors in vivo (11). Fourth, the finding of upregulation of eukaryotic translation initiation factor 4G1 and neuropathy target esterase in peripheral blood mononuclear cells in chronic fatigue patients compared with normal controls is consistent with, respectively, a persistent viral infection and organophosphate exposure (12). Both viral infection and organophosphate exposure could impair the ability of cells to biosynthesize long-chain polyunsaturated fatty acids. In terms of brain chemistry, we carried out the first systematic proton neurospectroscopic study of myalgic encephalomyelitis, and both our study and the next such independent study, by Chaudhuri and colleagues, each reported a significantly raised level of choline (13, 14). Furthermore, an earlier Japanese non-systematic proton neurospectroscopy study of three children with chronic fatigue syndrome aged 11, 12, and 13 years also reported a significantly elevated level of choline (15). These results are consistent with a lack of long-chain polyunsaturated fatty acids in the brain in the myalgic encephalomyelitis patients studied, since such a

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deficiency of the fatty acid component required at the Sn2 position of phospholipid molecules would lead to an elevated level of free choline, choline being a potential polar head group at the Sn3 phospholipid position. The above results are consistent with the effects of a chronic viral infection in myalgic encephalomyelitis; such infection could inhibit the action of the enzyme delta-6-desaturase and therefore the biosynthesis of long-chain polyunsaturated fatty acids from their short-chain essential fatty acid 18-carbon precursors (11). Other factors that could lead to a deficiency in long-chain polyunsaturated fatty acids include dietary deficiency, organophosphate exposure (for which there is some evidence, as mentioned above), and chronic exposure to other factors that may inhibit delta-6-desaturase, such as high cortisol levels. In patients who are so affected, it seems probable that a change from the modern Western diet to one that is rich in ω-3 and ω-6 long-chain polyunsaturated fatty acids together with fresh fruit and whole foods (free of synthetic pesticides, herbicides, insecticides, and the like) would not be harmful and might be beneficial. It is difficult to carry out a suitable controlled clinical trial of such a dietary change. However, in 1990, Behan, Behan, and Horrobin published the results of a seminal supplementation trial in which 63 patients with post-viral fatigue entered a randomized, double-blind, placebo-controlled trial of ω-3 and ω-6 fatty acids; the long-chain polyunsaturated fatty acid ω-3 fatty acids were derived from fish while evening primrose oil was the source of the ω-6 fatty acid gamma-linolenic acid (9). The patients had been ill from 1 to 3 years after an apparently viral infection and were suffering from severe fatigue and myalgia. At the end of the 3-month trial, the patients receiving the long-chain polyunsaturated fatty acids had shown significant improvement compared with the placebo group. On the other hand, a similar 3-month study published 9 years later by a different group reported negative results in that both the active and the placebo group improved with time (10). Possible reasons for this difference might be that different diagnostic criteria were used for inclusion into the two trials (the Oxford Criteria were used in the second trial); that a different placebo was used in the two trials (liquid paraffin with linoleic acid in the first and sunflower oil in the second; perhaps there was greater beneficial action from the latter, which was meant to be a placebo); that the results of one of the two trials was a statistical outlier; that there is a subgroup of patients who are more likely to have been suffering from viral infection (which seems more likely to have been the case with the first study) and who are more likely to benefit from fatty acid supplementation; that in general a higher dose of some longchain polyunsaturated fatty acids is required; that a period of longer than 3 months is generally required for significant benefit to become apparent clinically. (This list is not meant to be exhaustive, and it should also be noted that these possible explanations are not necessarily all mutually exclusive.) One patient with a long history of myalgic encephalomyelitis was found, on treatment with a combination of non-raffinated cold-pressed evening primrose oil (which is rich in botanical triterpines which have potentially beneficial free radical scavenging, cyclooxygenase, and neutrophil elastase inhibitory properties (16)) and EPA to show not only symptom remission but also beneficial changes in brain structure (17). It is noteworthy that both the ω-3 fatty acid EPA and the ω-6 fatty acid arachidonic acid (which the body can readily biosynthesize from gamma-linolenic acid obtained from, for example, evening primrose oil) are virucidal, even against enveloped species (18, 19). The antiviral actions of interferon, which may be biosynthesized from a rich EPA supply, may also require its activation of the conversion, catalyzed by cyclooxygenase, of the ω-6 fatty acids dihomo-gamma-linolenic acid and arachidonic acid into eicosanoids (20).

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2 Conclusions Converging lines of evidence suggest that myalgic encephalomyelitis, at least in a subgroup, is associated with a deficiency of long-chain polyunsaturated fatty acids. This may be exacerbated by the modern Western diet. Conversely, there is emerging evidence that a subgroup of affected patients may benefit from supplementation with cold-pressed non-raffinated evening primrose oil and EPA-rich oils. Changes in diet, away from a modern Western diet to one that is rich in fresh fruit and whole foods (taking care to avoid synthetic pesticides, herbicides, and insecticides), are likely to be helpful, although it should be noted that such dietary changes are clearly not readily amenable to traditional randomized, double-blind, placebo-controlled trials.

References 1. Afari N, Buchwald D. Chronic fatigue syndrome: a review. Am J Psychiatry 2003; 160: 221–236. 2. Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med 1994; 121: 953–959. 3. Puri BK. Chronic fatigue syndrome: a natural way to treat M.E. London: Hammersmith Press, 2005. 4. Caligiuri M, Murray C, Buchwald D et al. Phenotypic and functional deficiency of natural killer cells in patients with chronic fatigue syndrome. J Immunol 1987; 139: 3306–3313. 5. Klimas NG, Salvato FR, Morgan R, Fletcher MA. Immunologic abnormalities in chronic fatigue syndrome. J Clin Microbiol 1990; 28: 1403–1410. 6. Skowera A, Cleare A, Blair D, Bevis L, Wessely SC, Peakman M. High levels of type 2 cytokine-producing cells in chronic fatigue syndrome. Clin Exp Immunol 2004; 135: 294–302. 7. Tirelli V, Pinto A, Marotta G et al. Clinical and immunologic study of 205 patients with chronic fatigue syndrome: a case series from Italy. Arch Intern Med 1993; 153(116–117): 20. 8. Visser J, Blauw B, Hinloopen B et al. CD4 T lymphocytes from patients with chronic fatigue syndrome have decreased interferon-gamma production and increased sensitivity to dexamethasone. J Infect Dis 1998; 177: 451–454. 9. Behan PO, Behan WM, Horrobin D. Effect of high doses of essential fatty acids on the postviral fatigue syndrome. Acta Neurol Scand 1990; 82: 209–216. 10. Warren G, McKendrick M, Peet M. The role of essential fatty acids in chronic fatigue syndrome. A casecontrolled study of red-cell membrane essential fatty acids (EFA) and a placebo-controlled treatment study with high dose of EFA. Acta Neurol Scand 1999; 99: 112–116. 11. Puri BK. Long-chain polyunsaturated fatty acids and the pathophysiology of myalgic encephalomyelitis (chronic fatigue syndrome). J Clin Pathol 2007; 60: 122–124. 12. Kaushik N, Fear D, Richards SC et al. Gene expression in peripheral blood mononuclear cells from patients with chronic fatigue syndrome. J Clin Pathol 2005; 58: 826–832. 13. Puri BK, Counsell SJ, Zaman R et al. Relative increase in choline in the occipital cortex in chronic fatigue syndrome. Acta Psychiatr Scand 2002; 106: 224–226. 14. Chaudhuri A, Condon BR, Gow JW, Brennan D, Hadley DM. Proton magnetic resonance spectroscopy of basal ganglia in chronic fatigue syndrome. Neuroreport 2003; 14: 225–228. 15. Tomoda A, Miike T, Yamada E et al. Chronic fatigue syndrome in childhood. Brain Dev 2000; 22: 60–64. 16. Puri BK. The clinical advantages of cold-pressed non-raffinated evening primrose oil over refined preparations. Med Hypotheses 2004; 62: 116–118. 17. Puri BK, Holmes J, Hamilton G. Eicosapentaenoic acid-rich essential fatty acid supplementation in chronic fatigue syndrome associated with symptom remission and structural brain changes. Int J Clin Pract 2004; 58: 297–299. 18. Horowitz B, Piet MP, Prince AM, Edwards CA, Lippin A, Walakovits LA. Inactivation of lipid-enveloped viruses in labile blood derivatives by unsaturated fatty acids. Vox Sang 1988; 54: 14–20.

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19. Sands J, Auperin D, Snipes W. Extreme sensitivity of enveloped viruses, including herpes simplex, to longchain unsaturated monoglycerides and alcohols. Antimicrob Agents Chemother 1979; 15: 67–73. 20. Karmazyn M, Horrobin DF, Manku MS et al. Interferon fever. Lancet 1977; 2: 307.

Chapter 22

The Role of Modern Western Diets in Attention-Deficit Hyperactivity Disorder Basant K. Puri

Key Points • There is a rising prevalence of attention-deficit hyperactivity disorder defining the Richardson–Puri fatty acid model of attention-deficit hyperactivity disorder, suggesting association with fatty acid changes in the modern Western diet. • Children with attention-deficit hyperactivity disorder symptomatology with daily supplementation of evening primrose oil and the ω-3 fatty acid eicosapentaenoic acid leads to beneficial changes in attention-deficit hyperactivity disorder symptomatology. • There is a case to a move away from modern Western diets, particularly in children, in order to help reduce the rising tide of attention-deficit hyperactivity disorder and related disorders. Keywords Attention-deficit disorders · Vitamins · Minerals Hand in hand with the increased consumption of modern Western diets worldwide, there is also occurring a rapid rise in the prevalence of attention-deficit hyperactivity disorder. Attentiondeficit hyperactivity disorder is now estimated to affect around 5% of school children in the United Kingdom and a higher proportion in the United States (1). In this chapter, the possibility will be discussed of there being a causative link between modern Western diets and this illness. First, it is useful to define attention-deficit hyperactivity disorder. Its cardinal features are inattention, hyperactivity, and impulsivity. According to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, Text Revision (DSM-IV-TR) of the American Psychiatric Association, examples of inattention include often failing to give close attention to details, making careless mistakes in schoolwork, work, or other activities; often having difficulty in sustaining attention in tasks or play activities; often not seeming to listen when being spoken to directly; often not following through on instructions and failure to finish schoolwork, chores, or duties at work; often having difficulty organizing tasks and activities; often avoiding or being reluctant to engage in task requiring sustained mental effort; often losing objects (such as toys, school assignments, pencils, or books) needed for tasks or activities; often being distracted by

B.K. Puri () MRI Unit, Hammersmith Hospital, Du Cane Road, London, W12 0HS, UK e-mail: [email protected] F. De Meester et al. (eds.), Modern Dietary Fat Intakes in Disease Promotion, Nutrition and Health, DOI 10.1007/978-1-60327-571-2_22, © Springer Science+Business Media, LLC 2010

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extraneous (and irrelevant) stimuli; and often being forgetful in daily activities (2). Examples of hyperactivity include often fidgeting, often leaving one’s seat in situations in which remaining seated is expected (such as during classroom teaching sessions), often running or climbing excessively in inappropriate situations, often having difficulty playing or engaging in leisure activities quietly, often being “on the go” or often acting as if “driven by a motor”, and often talking excessively, while examples of impulsivity include often blurting out answers before the corresponding questions have been completed, often having difficulty waiting in turn, and often interrupting or intruding into the conversations or activities of others (2). It may be that attention-deficit hyperactivity disorder is more common in boys than girls (it appears to be up to nine times commoner in boys in outpatient clinics), but a definite gender difference has not yet been unequivocally established. Several disorders can coexist with attention-deficit hyperactivity disorder. Such comorbid disorders include emotional disorders such as anxiety and depression. Conduct disorder may also be comorbid, as may specific learning difficulties or language difficulties including dyslexia, developmental coordination disorder, or dyspraxia may also be comorbid (1). The notion that there may be an aetiological association between Western dietary fat, with its well-known deficiency in certain long-chain polyunsaturated fatty acids, and attention-deficit hyperactivity disorder was put forward in a fatty acid model of this disease by Richardson and Puri in 2000 (3). In this theoretical paper, we suggested that at least some features of this disease may reflect an underlying abnormality of fatty acid metabolism. Clinical and biochemical evidences were discussed which suggested that a functional deficiency of certain long-chain polyunsaturated fatty acids could contribute to many of the features associated with this condition, including the possible gender difference (males are more vulnerable than females to long-chain polyunsaturated fatty acid deficiency (4)), an excess of minor physical abnormalities (these are likely to involve abnormalities in cell modelling, apoptosis, and cell migration, in which phospholipids, fatty acids, and their metabolites play an important role (5, 6)), sleep problems (polyunsaturated fatty acids and their metabolites exert a direct effect on neuronal membrane structure or indirectly on the dynamics of biochemical compounds, including complex lipids, prostaglandins, neurotransmitters, amino acids, and interleukins, necessary for the initiation and maintenance of sleep (7, 8)), allergic conditions (eczema and other atopic conditions are associated with reduced efficiency of delta-6-desaturase, an enzyme required for the first step in converting short-chain essential fatty acids into longer and more unsaturated fatty acids (9–11)), somatic complaints (fatty acids and their derivatives are involved in the regulation of immune and digestive functions (12–14)), emotional and mood disorders (the fatty acid eicosapentaenoic acid (EPA) may even be used as an effective treatment for depression and bipolar disorder (15–21)), and dyslexia (fatty acid deficiency may be a contributory factor in the development of dyslexia (22) and may have a therapeutic role (23)). Physical fatty acid deficiency signs of dry hair, dry skin, polydipsia, and polyuria are more common in children with attention-deficit hyperactivity disorder and respond to fatty acid supplementation (24). Several studies have also reported reduced fatty acid levels in this disease (3). A prediction of our fatty acid model was that dietary supplementation with key omega-3 and omega-6 long-chain polyunsaturated fatty acids would help attention-deficit hyperactivity disorder. Three such long-chain polyunsaturated fatty acids have key roles as precursors of eicosanoids (including prostaglandins, leukotrienes, and thromboxanes), namely dihomo-gamma-linolenic acid and arachidonic acid (both of which are omega-6 long-chain polyunsaturated fatty acids) and EPA (an omega-3 long-chain polyunsaturated fatty acid). Considering the omega-6 long-chain

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polyunsaturated fatty acids first, an excellent dietary source is evening primrose oil, which is rich in gamma-linolenic acid. The latter can readily undergo conversion in the body into dihomo-gamma-linolenic acid and this, in turn, is readily converted into arachidonic acid. Gamma-linolenic acid administration bypasses blockage at delta-6-desaturase (which would normally allow linoleic acid to be converted into gamma-linolenic acid); this enzyme appears to be inhibited by factors such as cortisol, viral infection, and a deficiency of micronutrients that so often accompanies the traditional Western diet which is rich in highly refined carbohydrate products such as those containing white sugar, white flour, and white (polished) rice. Sadly, all too often children in the Western world have a diet rich in such “junk” food. (Coldpressed, nonraffinated virgin evening primrose oil has the added health advantages of being rich in natural pentacyclic triterpenes (25).) Turning to the omega-3 long-chain polyunsaturated fatty acids, clearly an excellent source of EPA is indeed EPA supplementation. From EPA, the omega-3 long-chain polyunsaturated fatty acid docosahexaenoic acid (DHA) can be biosynthesized. Administrating DHA as supplementation may be problematic. Being a long molecule (with a 22-carbon backbone) with no less than six double bonds per molecule, DHA is particularly prone to lipid peroxidation, which can give rise to beta-aldehydes, which may act as potent free radicals capable of attacking cell membranes and even nuclear DNA. It should be noted, however, that natural DHA found in dietary sources is usually very safe as in Nature it tends to be associated with factors which inhibit DHA peroxidation. As will be seen below, it is probably not a coincidence that the higher the ratio of EPA to DHA in supplementation studies, the better the outcome; at one extreme, giving pure DHA in attention-deficit hyperactivity disorder has actually been found to cause a worse result than placebo (vide infra). We shall begin, however, by first considering evening primrose oil trials in attention-deficit hyperactivity disorder.

1 Evening Primrose Oil The first published randomized, double-blind, placebo-controlled trial of evening primrose oil (on its own) in hyperactive children was that of Aman and colleagues, which involved 31 children suffering from marked inattention and overactivity, who took part in a crossover study (26). Subjects received the active treatment and placebo conditions for 4 weeks each and were assessed on a variety of cognitive, motor, and standardized rating scale measures. According to the authors “Supplementation was . . . associated with significant changes on two performance tasks and with significant improvement to parent ratings on the subscales designated as Attention Problem and Motor Excess of the Revised Behavior Problem Checklist. However, a variety of eight other psychomotor performance tests and two standardized teacher rating scales failed to indicate treatment effects. When the experiment-wise probability level was set at .05, only 2 of 42 variables showed treatment effects. Baseline EFA [essential fatty acid] concentrations appeared to be unrelated to treatment response.” The second such evening primrose oil study was that of Arnold and colleagues, in which, using a Latin-square double-crossover design with random assignment to sequence, 18 boys, aged 6–12 years, suffering from attention-deficit hyperactivity disorder received 1 month each of placebo, D-amphetamine, and evening primrose oil (27). Teachers’ ratings showed a trend of evening primrose oil effect between placebo and D-amphetamine; the trend reached significance (p < 0.05) on the Conners’ Hyperactivity Factor. In respect of

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both these evening primrose oil studies, it is interesting to note that Richardson and Puri had previously suggested that it might take at least 3 months for the brain to recover from the effects of chronic fatty acid deficiency, and so these results from 1-month studies should be considered preliminary but potentially indicative of a likely therapeutic result if the evening primrose oil were to be used for longer (at least 3 months), preferably in combination with EPA (vide infra) (3). Voigt and colleagues carried out a 4-month randomized, double-blind, placebo-controlled trial of pure DHA (at a dose of 345 mg per day) in 63 children, aged 6–12 years, suffering from attention-deficit hyperactivity disorder and all receiving effective maintenance therapy with stimulant medication (28). The authors reported that “Plasma phospholipid DHA content of the DHA-supplemented group was 2.6-fold higher at the end of the study than that of the placebo group (4.85 +/– 1.35 vs 1.86 +/–0.87 mol% of total fatty acids; p < 0.001). Despite this, there was no statistically significant improvement in any objective or subjective measure of ADHD symptoms.” In fact, not only did the DHA group fare no better than the placebo group, it was found that, compared with the placebo group, supplementation with pure DHA (in the absence of any EPA) was associated with significant worsening on errors of omission (an important component of the Tests of Variables of Attention (TOVA)), which reflects inattention. Furthermore, there was a significant decrease in the level of errors on commission (another important TOVA component) in the placebo group but not in the group of children who received supplementation with pure DHA. Hirayama and colleagues carried out a study entitled “Effect of docosahexaenoic acidcontaining food administration on symptoms of attention-deficit/hyperactivity disorder— a placebo-controlled double-blind study” in which 40 children suffering from attention-deficit hyperactivity disorder, aged 6–12 years, mostly not taking concomitant medication, received either a high-DHA (and low-EPA) diet (with foods containing fish oil—fermented soybean milk, bread rolls, and steamed bread; providing 3.6 g DHA/week) for 2 months or indistinguishable control foods unfortified with DHA (the placebo group) (29). There were no significant differences between the two groups in respect of changes over the study period in attention-deficit, hyperactivity, or impulsivity symptomatology as assessed according to DSM-IV criteria; aggression assessed by both parents and teachers; visual perception (finding symbols out of a table); development of visual–motor integration; and impatience. In an echo of the previous DHA study (vide supra) showing a better improvement in the placebo group compared with the DHA group, the authors reported “However, visual short-term memory and errors of commission (continuous performance) significantly improved in the control group compared with the changes over time in the DHA group.” Finally, we consider trials which have included EPA, DHA, and gamma-linolenic acid (from evening primrose oil). Stevens and colleagues randomized 50 children with inattention, hyperactivity, and other disruptive behaviours to either a fatty acid supplementation group in which they each received a daily dose of 80 mg EPA, 480 mg DHA, 40 mg arachidonic acid, 96 mg gamma-linolenic acid, and 24 mg alpha-tocopheryl acetate, or an olive oil placebo group, for 4 months in a double-blind parallel treatment (30). Significant improvements in multiple outcomes (as rated by parents) were noted in both groups; for most outcomes, improvement in the fatty acid supplementation (active) group was consistently nominally better than that of the olive oil group; the treatment difference was significant, by secondary intent-to-treat analysis, on 2 out of 16 outcome measures: conduct problems rated by parents and attention symptoms rated by

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teachers. Fatty acid supplementation led to a greater number of participants showing improvement in oppositional defiant behaviour from a clinical to a non-clinical range compared with olive oil supplementation, and significant correlations were observed when comparing the magnitude of change between increasing proportions of EPA in the erythrocytes and decreasing disruptive behaviour as assessed by the Abbreviated Symptom Questionnaire (ASQ) for parents, and for erythrocyte EPA and DHA and the teachers’ Disruptive Behavior Disorders (DBD) Rating Scale for Attention. The authors also reported significant negative correlations between the magnitude of increase in erythrocyte alpha-tocopherol concentrations and changes in scores for all four subscales of the teachers’ DBD as well as the ASQ for teachers. These positive results in favour of fatty acid supplementation might have been even more significant if a different placebo had been used; Puri and Richardson have previously pointed out that olive oil has beneficial actions (31). In a study by Harding and colleagues entitled “Outcome-based comparison of Ritalin versus food-supplement treated children with AD/HD”, 20 children with attentiondeficit hyperactivity disorder were dichotomized to receive either methylphenidate (Ritalin) or dietary supplementation containing, amongst other nutrients, 1 g salmon oil daily (providing 180 mg EPA and 120 mg DHA) and 200 mg borage oil (rather than evening primrose oil) daily (providing 45 mg gamma-linolenic acid) (32). Subjects in both groups showed significant gains on the Intermediate Visual and Auditory/Continuous Performance Test (IVA/CPT) Full Scale Response Control Quotient, and Full Scale Attention Control Quotient. Improvements in the four sub-quotients of the IVA/CPT (Auditory Response Control Quotient, Visual Response Control Quotient, Auditory Attention Quotient, and Visual Attention Quotient) were also found to be significant and essentially identical in both groups. Richardson and Puri carried out a randomized, double-blind, placebo-controlled trial which used a higher ratio of EPA to DHA, in combination with evening primrose oil, in 41 children with both specific learning difficulties (mostly dyslexia) and above-average attention-deficit hyperactivity disorder ratings, aged 8–12 years (33). While at baseline the groups did not differ, after 12 weeks the mean scores for cognitive problems and general behaviour problems were significantly lower for the group treated with fatty acids than for the placebo group; there were significant improvements from baseline on 7 out of 14 scales for active treatment, compared with none for placebo. Group differences in change scores all favoured the fatty acid group, reaching conventional significance levels for 3 out of 14 scales. Unfortunately, in this study we used olive oil as our placebo (31). Nonetheless, we were able to conclude that the fatty acid supplementation we had used appeared to reduce attention-deficit hyperactivity disorder-related symptoms in children with specific learning difficulties. Last, Richardson and Montgomery published the first findings from the Durham–Oxford randomized, double-blind, placebo-controlled trial in developmental coordination disorder in which 117 children aged 5–12 years and suffering from this disorder and from attention-deficit hyperactivity disorder symptomatology were treated for 3 months in parallel groups followed by a one-way crossover from placebo to active treatment for an additional 3 months with either a high ratio of EPA to DHA (558 mg EPA daily and 174 mg DHA daily) combined with virgin cold-pressed, non-raffinated evening primrose oil which, unlike borage oil, is rich in botanical triterpenes (25) (providing 60 mg gamma-linolenic acid daily) or an olive oil placebo (34). The two groups were matched for attention-deficit hyperactivity disorder symptomatology at baseline. After 3 months of fatty acid supplementation, the active group showed significant improvements in 12 out of the 13 Connors’ Teacher Rating Scale compared with the placebo group, as well as significant improvements in auditory short-term memory. The authors reported that “No effect of treatment on motor skills

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was apparent, but significant improvements for active treatment versus placebo were found in reading, spelling, and behavior over 3 months of treatment in parallel groups. After the crossover, similar changes were seen in the placebo-active group, whereas children continuing with active treatment maintained or improved their progress.”

2 Conclusions There is good evidence that the prevalence of attention-deficit hyperactivity disorder is rising worldwide, particularly in the Western world, and that this disorder appears to be associated with a deficiency in certain long-chain polyunsaturated fatty acids. The Richardson–Puri fatty acid model of attention-deficit hyperactivity disorder (3) predicted that not only is attentiondeficit hyperactivity disorder associated with such deficiencies (which are largely the result of the modern Western diet) but that supplementation with EPA and evening primrose oil would be beneficial. Subsequent randomized, double-blind, placebo-controlled trials have shown that as the ratio of EPA to DHA in such supplementation increases, so also does the improvement seen in attention-deficit hyperactivity disorder symptomatology. Indeed, at one extreme, those children supplemented solely or largely with DHA (with little or no EPA) actually fare significantly worse than the placebo group on some measures. Evening primrose oil appears to have a synergistic effect with EPA; a good result is particularly seen in the case of cold-pressed, nonraffinated evening primrose oil. Given the known side-effects of conventional pharmacotherapy for attention-deficit hyperactivity disorder, it seems reasonable to suggest a change in diet away from the modern Western diet together with a trial of appropriate fatty acid supplementation first before prescribing a synthetic drug for a child or adult newly diagnosed with this disorder.

References 1. Puri BK. Attention-Deficit Hyperactivity Disorder: A Natural Way to Treat ADHD. London: Hammersmith Press, 2005. 2. Association AP. Diagnostic and statistical manual of mental disorders: DSM-IV-TR. 4th ed. text revision. ed. Washington, DC: American Psychiatric Association, 2000. 3. Richardson AJ, Puri BK. The potential role of fatty acids in attention-deficit/hyperactivity disorder. Prostaglandins Leukot Essent Fatty Acids 2000; 63: 79–87. 4. Pudelkewicz C, Seufert J, Holman RT. Requirements of the female rat for linoleic and linolenic acids. J Nutr 1968; 94: 138–146. 5. Kaufmann WE, Worley PF, Pegg J, Bremer M, Isakson P. COX-2, a synaptically induced enzyme, is expressed by excitatory neurons at postsynaptic sites in rat cerebral cortex. Proc Natl Acad Sci USA 1996; 93: 2317–2321. 6. Smalheiser NR, Dissanayake S, Kapil A. Rapid regulation of neurite outgrowth and retraction by phospholipase A2-derived arachidonic acid and its metabolites. Brain Res 1996; 721: 39–48. 7. Yehuda S, Rabinovitz S, Mostofsky DI. Essential fatty acids and sleep: mini-review and hypothesis. Med Hypotheses 1998; 50: 139–145. 8. Fagioli I, Baroncini P, Ricour C, Salzarulo P. Decrease of slow-wave sleep in children with prolonged absence of essential lipids intake. Sleep 1989; 12: 495–499. 9. Manku MS, Horrobin DF, Morse NL, Wright S, Burton JL. Essential fatty acids in the plasma phospholipids of patients with atopic eczema. Br J Dermatol 1984; 110: 643–648.

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10. Morse PF, Horrobin DF, Manku MS et al. Meta-analysis of placebo-controlled studies of the efficacy of Epogam in the treatment of atopic eczema. Relationship between plasma essential fatty acid changes and clinical response. Br J Dermatol 1989; 121: 75–90. 11. Wright S, Bolton C. Breast milk fatty acids in mothers of children with atopic eczema. Br J Nutr 1989; 62: 693–697. 12. Alexander JW. Immunonutrition: the role of omega-3 fatty acids. Nutrition 1998; 14: 627–633. 13. Holman RT. The slow discovery of the importance of omega 3 essential fatty acids in human health. J Nutr 1998; 128: 427S–33S. 14. Horrobin DF. The regulation of prostaglandin biosynthesis: negative feedback mechanisms and the selective control of formation of I and 2 series prostaglandins: relevance to inflammation and immunity. Med Hypotheses 1980; 6: 687–709. 15. Horrobin DF. The roles of prostaglandins and prolactin in depression, mania and schizophrenia. Postgrad Med J 1977; 53(Suppl 4): 160–165. 16. Horrobin DF, Bennett CN. Depression and bipolar disorder: relationships to impaired fatty acid and phospholipid metabolism and to diabetes, cardiovascular disease, immunological abnormalities, cancer, ageing and osteoporosis. Possible candidate genes. Prostaglandins Leukot Essent Fatty Acids 1999; 60: 217–234. 17. Puri BK, Counsell SJ, Hamilton G, Richardson AJ, Horrobin DF. Eicosapentaenoic acid in treatmentresistant depression associated with symptom remission, structural brain changes and reduced neuronal phospholipid turnover. Int J Clin Pract 2001; 55: 560–563. 18. Puri BK, Counsell SJ, Richardson AJ, Horrobin DF. Eicosapentaenoic acid in treatment-resistant depression. Arch Gen Psychiatry 2002; 59: 91–92. 19. Peet M, Horrobin DF. A dose-ranging study of the effects of ethyl-eicosapentaenoate in patients with ongoing depression despite apparently adequate treatment with standard drugs. Arch Gen Psychiatry 2002; 59: 913–919. 20. Murck H, Song C, Horrobin DF, Uhr M. Ethyl-eicosapentaenoate and dexamethasone resistance in therapyrefractory depression. Int J Neuropsychopharmacol 2004; 7: 341–349. 21. Frangou S, Lewis M, McCrone P. Efficacy of ethyl-eicosapentaenoic acid in bipolar depression: randomised double-blind placebo-controlled study. Br J Psychiatry 2006; 188: 46–50. 22. Richardson AJ, Cox IJ, Sargentoni J, Puri BK. Abnormal cerebral phospholipid metabolism in dyslexia indicated by phosphorus-31 magnetic resonance spectroscopy. NMR Biomed 1997; 10: 309–314. 23. Baker SM. A biochemical approach to the problem of dyslexia. J Learn Disabil 1985; 18: 581–584. 24. Sinn N. Physical fatty acid deficiency signs in children with ADHD symptoms. Prostaglandins Leukot Essent Fatty Acids 2007; 77: 109–115. 25. Puri BK. The clinical advantages of cold-pressed non-raffinated evening primrose oil over refined preparations. Med Hypotheses 2004; 62: 116–118. 26. Aman MG, Mitchell EA, Turbott SH. The effects of essential fatty acid supplementation by Efamol in hyperactive children. J Abnorm Child Psychol 1987; 15: 75–90. 27. Arnold LE, Kleykamp D, Votolato NA, Taylor WA, Kontras SB, Tobin K. Gamma-linolenic acid for attention-deficit hyperactivity disorder: placebo-controlled comparison to D-amphetamine. Biol Psychiatry 1989; 25: 222–228. 28. Voigt RG, Llorente AM, Jensen CL, Fraley JK, Berretta MC, Heird WC. A randomized, doubleblind, placebo-controlled trial of docosahexaenoic acid supplementation in children with attentiondeficit/hyperactivity disorder. J Pediatr 2001; 139: 189–196. 29. Hirayama S, Hamazaki T, Terasawa K. Effect of docosahexaenoic acid-containing food administration on symptoms of attention-deficit/hyperactivity disorder—a placebo-controlled double-blind study. Eur J Clin Nutr 2004; 58: 467–473. 30. Stevens L, Zhang W, Peck L et al. EFA supplementation in children with inattention, hyperactivity, and other disruptive behaviors. Lipids 2003; 38: 1007–1021. 31. Puri BK, Richardson AD. The effects of olive oil on omega3 fatty acids and mood disorders. Arch Gen Psychiatry 2000; 57: 715. 32. Harding KL, Judah RD, Gant C. Outcome-based comparison of Ritalin versus food-supplement treated children with AD/HD. Altern Med Rev 2003; 8: 319–330. 33. Richardson AJ, Puri BK. A randomized double-blind, placebo-controlled study of the effects of supplementation with highly unsaturated fatty acids on ADHD-related symptoms in children with specific learning difficulties. Prog Neuropsychopharmacol Biol Psychiatry 2002; 26: 233–239. 34. Richardson AJ, Montgomery P. The Oxford-Durham study: a randomized, controlled trial of dietary supplementation with fatty acids in children with developmental coordination disorder. Pediatrics 2005; 115: 1360–1366.

Chapter 23

The Role of Dietary Fat in Insulin Resistance and Type 2 Diabetes Betsy Dokken and Jackie Boucher

Key Points • The role of dietary fat in health and disease is controversial as fatty acids act as signaling molecules in a variety of metabolic pathways and dietary fat has a role in both the etiology and prevention of insulin resistance and type 2 diabetes. • Another hypothesis is that excessive caloric intake of any kind, vs. any specific dietary component, explains the strong relationship between obesity and these metabolic disorders. • Dietary fat recommendations geared toward the prevention and treatment of insulin resistance and type 2 diabetes should be evidence-based. Keywords Dietary fat · Insulin resistance · Hyperlipidemia · Obesity · Hypertension · Oxidative stress · Mitochondrial dysfunction

1 Introduction The role of dietary fat in health and disease is controversial. Fatty acids act as signaling molecules in a variety of metabolic pathways [1]. Several reports have implicated dietary fat as having a role in both the etiology [1] and prevention [2] of insulin resistance and type 2 diabetes. Others contend that simply excessive caloric intake of any kind, vs. any specific dietary component, explains the strong relationship between obesity and these metabolic disorders. This chapter will review the evidence on either side of this argument and will attempt to draw conclusions on the relationship between dietary fat and insulin resistance. In addition, we will attempt to summarize the evidence to support dietary fat recommendations geared toward the prevention and treatment of insulin resistance and type 2 diabetes.

B. Dokken () Department of Medicine, Section of Endocrinology, Diabetes and Hypertension, University of Arizona, 1656 East Mabel St, Tucson, AZ, USA e-mail: [email protected] F. De Meester et al. (eds.), Modern Dietary Fat Intakes in Disease Promotion, Nutrition and Health, DOI 10.1007/978-1-60327-571-2_23, © Springer Science+Business Media, LLC 2010

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2 Mechanistic Evidence of the Role of Dietary Fat in Insulin Resistance Dietary fat has long been implicated in the causation of the metabolic syndrome and type 2 diabetes [1]. More recently, as knowledge of the variety of fatty acids (FAs) and their effects on health and disease has improved, research has focused increasingly on the metabolic effects of specific types of dietary fat. The intake of fat in the typical Western diet includes a variety of fatty acids with different chain lengths and numbers of double bonds (% saturation). The most commonly ingested saturated FAs are palmitic acid (C16:0) and stearic acid (C18:0), while the most prevalent dietary unsaturated FAs are oleic acid (C18:1n-9) and linoleic acid (C18:2n-3) [3]. Fish, especially oily fish, is rich in very long-chain three polyunsaturated FAs, and, now more commonly recommended as part of the Western diet. Fatty fish and fish oils contain both docosahexaenoic acid (C22:6n-3) and eicosapentaenoic acid (C20:5n-3) [4]. The quality of dietary fat has been postulated to affect cellular membrane FA composition and thus function [5]. The FA composition of cellular membranes may affect membrane fluidity, permeability, and receptor affinity. In the case of insulin resistance, these alterations could impair the translocation of intracellular transporters (such as GLUT-4 in skeletal muscle and adipose tissue) to interact with docking proteins and second messengers [6]. This interference with normal insulin receptor signaling would clearly decrease whole-body insulin sensitivity. In addition, FAs acting as signaling molecules can affect a variety of pathways, including gene expression, protein expression, posttranslational modification of proteins, and enzymatic activity [7]. In skeletal muscle (the tissue most responsible for glucose disposal from the blood) both saturatedand polyunsaturated (n-6)-rich diets impair phosphorylation of insulin receptor substrate-1 (IRS-1) and protein kinase B (Akt), two critical steps in intracellular insulin signaling [8]. Taouis et al. found that diets high in polyunsaturated FAs (either n-3 or n-6) induced whole-body insulin resistance in male Wistar rats [9]. In addition, animals fed a diet rich in n-6 FA demonstrated decreased expression of the insulin receptor (IR) and IRS-1 phosphorylation in skeletal muscle, an effect that was not found in the animals fed a diet rich in n-3 FA. However, both diets decreased IR expression and IRS-1 phosphorylation in liver, and increased the expression of p85, a critical signaling moiety of the insulin signaling protein phosphatidylinositol 3 -kinase (PI3-kinase) [9] in adipose tissue. Current understanding of these signaling pathways would indicate that these high-fat diets induce actions that differentially enhance and inhibit insulin action, through a variety of mechanisms, in a variety of tissues. Clearly, a deeper understanding of the molecular signaling effects of FAs is warranted. Intracellular receptor pathways for FA signaling include the PPAR family, GPR40 [10, 11], and GPR120 [12]. As a group, these receptors are all activated by readily available FAs in the typical Western diet, but each pathway is activated by certain FAs and not others. For example, the unsaturated long-chain FA α-linolenic acid (n-3), but not the saturated medium-chain FA octanoic acid, activates the GPR120 receptor pathway and results in enhanced secretion of glucagonlike peptide-1, an insulin secretagogue [12]. The GPR40 receptor, which also promotes insulin secretion, is activated by both saturated and unsaturated FAs with a chain length of more than six [11]. Chronic activation of the GPR40 pathway has been found to impair glucose homeostasis in response to a high-fat diet [13]. These novel FA receptors have become potential targets for the discovery of new drugs (agonists or antagonists) to treat type 2 diabetes [14]. The PPAR family is activated with the highest affinity by polyunsaturated FAs, followed by medium-chain monounsaturated FAs, but not activated by long-chain monounsaturated FAs [15].

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Activation of PPARs enhances insulin sensitivity, in part, by improving the utilization of dietary fatty acids in animals fed a high-fat diet [16]. Therefore, these receptor pathways are interesting and varied targets for the investigation into the basic science of the relationship between dietary fat and insulin sensitivity, as well as for clinical nutrition trials of specific dietary FA interventions. Several physiologic hypotheses have emerged to explain the relationship between insulin resistance and fatty acid signaling and utilization; these include lipid-induced insulin resistance in skeletal myocytes (intra myocellular compartments), oxidative stress-induced insulin-resistance in a variety of tissues, and FA-induced mitochondrial dysfunction.

3 Lipid Oversupply to Skeletal Muscles Although type 2 diabetes is characterized by insulin resistance in liver and muscle, considerable evidence also points to dysfunctional lipid metabolism in adipocytes [17]. In the insulin-resistant state, adipocytes fail to respond to antilipolytic signals from insulin, which results in chronically elevated plasma FFA levels [18]. In addition to the underlying metabolic dysfunction, a high-fat diet also increases plasma FFA levels [19]. Therefore, in insulin-resistant patients on a high-fat diet, a cause–effect relationship between the dietary fat and the hyperlipidemic component of the metabolic dysfunction is difficult to determine. Altered lipid metabolism contributes to insulin resistance through a variety of cellular and molecular mechanisms. In particular, there is a strong link between muscle lipid accumulation and insulin resistance [20]. In both normal and obese subjects, intramuscular triglyceride is inversely associated with whole-body insulin sensitivity [21], inferring a causal relationship independent of obesity. In mice with normal metabolism, 3 days of a high saturated fat diet (45% of calories from palm oil) resulted in the alteration of several genes involved in a variety of critical biological processes such as energy metabolism, lipogenesis, and immune function. In skeletal muscle from these animals, cell morphology changed to a preponderance of slow fibertype protein and higher levels of protein complexes were found in the oxidative phosphorylation pathway [22]. Although these adaptations may be initially positive and increase the muscle’s ability to compensate for the increased fat and caloric intake, mitochondrial membrane phospholipids already contained more saturated fatty acids in the high-fat-fed animals than those of the control animals (fed a 10% palm oil diet) [22]. These investigators suggest that an early increase in the capacity for oxidative phosphorylation eventually downregulates these metabolic genes and leads to the defective mitochondrial dysfunction observed in insulin resistance and type 2 diabetes. Storlien et al. investigated the effects of a variety of different dietary fats on the development of insulin resistance in rats [23]. These authors found that diets high in either saturated, monounsaturated (n-9), or polyunsaturated (n-6) FAs led to severe insulin resistance (measured by euglycemic clamp). In animals fed the polyunsaturated diet, the substitution of 11% FAs from fish oils (long-chain n-3 FAs) normalized insulin action, but a similar approach using α-linolenic acid (short-chain n-3 FAs) was ineffective in treating insulin resistance. In contrast, providing a diet rich in α-linolenic acid completely reversed the insulin resistance induced in rats previously treated with a high saturated fat diet. These authors concluded that insulin sensitivity depends not only on the FA composition of the diet but also on the lipid environment in which the diets

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are presented. In addition, a diet rich in long-chain n-3 FAs from fish oil correlated strongly with insulin sensitivity [23]. In contrast to previous findings, Lee et al. found that a diet rich in n-6 polyunsaturated fat protected insulin sensitivity when compared to a diet high in saturated fat. Interestingly, both diets increased plasma FFA by 30%, but the PUFA-treated rats demonstrated an improved insulin sensitivity as compared to chow-fed rats [24]. In addition, the diet high in saturated fat was associated with higher intramuscular triglyceride than either the high PUFA diet or the regular chow diet [24].

4 Oxidative Stress Convincing experimental and clinical evidence links oxidative stress to both the development of insulin resistance and the progression of diabetes-related complications. Reactive oxygen (and nitrogen) species damage cellular membranes, and, like fatty acids, can act as signaling factors and impair proper molecular and cellular functionality [25]. In addition, high-fat feeding increases oxidative stress in animals [26] and humans [27]. Milagro et al. found that a cafeteriastyle high-fat diet induced insulin resistance and hepatic oxidative stress. Yang et al. found that lipoic acid (an antioxidant) prevents high-fat diet-induced oxidative stress in mice [28]. These authors fed mice high-fat diets with and without 0.1% lipoic acid. After 6 weeks, the animals fed the high-fat diet alone exhibited abnormal lipid profiles and impaired antioxidant defenses. Those fed the lipoic acid-supplemented high-fat diet experienced decreased lipid peroxidation, improved lipid profiles, and upregulation of free radical scavenger enzymes [28]. In humans, Devaraj et al. found that one energy-dense, high-fat (fast-food style) meal resulted in significantly elevated levels of triglyceride as well as several biomarkers of oxidative stress (plasma thiobarbituric acid reactive substances and malondialdehyde + hydroxynonenal) compared to an American Heart Association-recommended “heart-healthy” meal. In contrast, in a rabbit model, Slim et al. determined the effects of a variety of high-fat diets on oxidative stress in the liver [29]. These authors found that a diet rich in corn oil increased markers of oxidative stress to a significantly greater degree than one high in saturated (dairy) fat, leading them to conclude that high levels of polyunsaturated fat promotes oxidative stress, while high saturated fat diet decreases susceptibility to oxidative stress [29].

5 Mitochondrial Dysfunction Mitochondrial deficiency [30] and dysfunction [31] in skeletal muscle have been implicated as one of the causal factors in the insulin-resistant state. One mechanism of insulin resistance might be impaired flux of FAs into mitochondria. Bruce et al. found that overexpression of muscle carnitine palmitoyltransferase 1 (CPT1), the enzyme that controls the entry of long-chain fatty acyl CoA into mitochondria, enhanced rates of fatty acid oxidation and improved insulin sensitivity in rats with high-fat diet-induced insulin resistance [32]. These authors concluded that enhancing FA entry into mitochondria is sufficient to ameliorate lipid-induced insulin resistance in skeletal muscle.

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In contrast to previous studies that reported decreased mitochondrial mass in diabetic skeletal muscle, Hancock et al. reported that, in rats, a high-fat diet caused insulin resistance despite an increase in the number of mitochondria in muscle [33]. These authors found that a diet rich in n-3 FA from flaxseed (α-linolenic acid) as well as one high in lard/corn oil induced insulin resistance of muscle glucose transport within a few weeks [33].

6 Clinical Trials and Epidemiological Studies Evidence of the effects of dietary fat on human health is somewhat contradictory. Like most experimental studies, few clinical trials or epidemiological studies carefully measured the effects of specific types of dietary FAs on metabolic function.

7 Insulin Resistance The majority of animal studies and human observational studies have reported a relationship between total FA intake, regardless of type, and greater insulin resistance [34]. Data most consistently support an adverse effect of dietary saturated fat on insulin sensitivity more consistently than that of total fat. Most epidemiologic studies have observed that saturated fat or meat intakes are associated with either markers of insulin resistance [35–37] glucose intolerance, or type 2 diabetes [38–40]. Many of these same studies also found that polyunsaturated fat was significantly associated with improved insulin sensitivity or glucose tolerance. Studies in individuals with impaired glucose tolerance or type 2 diabetes have also found that improvements in insulin action or glucose metabolism occur when saturated fat is replaced with monounsaturated fat [41]. There is some evidence that the beneficial effects of monounsaturated fat compared to saturated fat seems to be lost in individuals who obtain more than 37% of their energy from fat [42, 43]. However, in a recent study in which fat was substituted isocalorically, insulin-resistant patients fed 38% of their energy from fat as monounsaturated fat improved fasting glucose and HOMA-IR compared to patients who ate a diet rich in saturated fat [43]. In most studies, it appears that when the proportion of dietary fat is in excess of 40% of energy from fat insulin sensitivity worsens, especially when the fat is saturated [44–46]. Trans-FAs also appear to have an impact on insulin resistance in individuals who are predisposed to it (i.e., overweight individuals or patients with diagnosed diabetes) [47]. Epidemiological evidence suggests that trans-FA intake was significantly associated with incident diabetes mellitus [48]. In a clinical trial that included subjects who were overweight or had diagnosed diabetes, the diets containing trans-FAs consistently had an adverse effect on insulin sensitivity (both fasting and postprandial blood insulin levels) [49–51]. Omega-3 (n-3) FAs appear to be associated with improved insulin sensitivity [52], however, findings have been inconsistent across studies [53]. Thus, it appears that there may be upper and lower thresholds of total dietary fat beyond specific types; however, overall, it appears that dietary prevention of insulin resistance may be best achieved by those who choose unsaturated fats (poly or mufa) over saturated fat, limit trans-fat intake, and eat a diet moderate in total fat [34, 53].

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8 Obesity It is still controversial whether dietary fat is a major determinant of obesity or not [54]. The long-term effects of food choices and dietary habits on weight gain are difficult to assess in clinical trials and observational studies [47]. However, there is recent evidence from a randomized controlled trial in monkeys that suggests that trans-FAs may increase body weight and fat accumulation, particularly in the intra-abdominal (visceral) region, over the amount predicted by caloric intake [55]. Observational evidence is consistent with the evidence from nonhuman primates. In a prospective cohort of 16,587 men who were followed for 9 years, each 2% increase in energy intake from trans-FA was associated with a 0.77 cm increase in waist circumference, after adjustment for other risk factors and lifestyle behaviors [56]. A prospective study in women had similar results; among 41,518 women who were followed for 8 years, each 2% increase in energy intake from trans-FA was associated with a 1.6 kg weight gain after similar adjustments [57]. More research is needed to confirm these findings, but data suggest that trans-FAs have important effects on weight gain and adiposity, independent of the energy contribution [47].

9 Disorders of Lipid Metabolism Recommendations for reducing total fat and replacing dietary saturated fat and trans-fat with unsaturated FAs to improve an individual’s lipid profile and hence prevent cardiovascular disease have been available for decades [58]. This, despite the fact that there is very little evidence from prospective epidemiological studies suggesting that total fat intake increases the risk of coronary heart disease or cardiovascular disease independent of dietary fat quality [59]. The diet-heart hypothesis took root based mainly on metabolic studies, such as Ancel Keys study that demonstrated that unsaturated fat lowers, but saturated fat increases serum cholesterol concentrations [60]. The biologic basis for this diet-heart hypothesis has been mainly focused on the effects of saturated fat, monounsaturated fat, and polyunsaturated fat on the lipid profile [61]. In recent years, studies of trans-fat [62] have been recognized as important. In addition, the role that dietary fat quality may play in modulating other cardiovascular outcomes, such as the effects on thrombosis, endothelial function, inflammation, obesity, and insulin sensitivity has been recognized [59]. Trans-FAs may have more deleterious effects than saturated FA on the lipid profile and other cardiovascular risk factors [59, 62]. A meta-analysis of 13 randomized controlled trials that carefully controlled intakes of trans-fatty acids in 518 individuals demonstrated that when trans-FAs are isocalorically replaced with either cis-polyunsaturated FAs, cis-monounsaturated FAs or saturated FAs, the total cholesterol:HDL-cholesterol ratio, apolipoprotein (apo) B:apoA ratio, triglyceride levels, and lipoprotein(a) levels all improved [47]. Cleary there is more epidemiological and clinical evidence on dietary FAs and disorders of the lipid metabolism than that available for any other risk factor for the metabolic syndrome. An entire chapter could be written to review this topic, thus, only summary conclusions will be discussed in the scope of this chapter. Over the past 20–30 years evidence has consistently supported the hypothesis that dietary intake of saturated FA and trans-fats increase cardiovascular risk [47, 59, 62] and that monounsaturated FAs and polyunsaturated FAs intake decrease risk. In a recent evidence analysis by the American Dietetic Association [63], the following recommendations were made:

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• In terms of major fat components and a cardioprotective diet (i.e., lowering of LDLcholesterol), the recommendation is to tailor an individual’s needs to provide a fat intake of 25–35% of calories with less than 7% of calories from saturated FAs and trans-FAs. • In terms of saturated FAs and trans-FAs, intake should be as low as possible and less than 7% of total daily calories. If individuals are at their appropriate body weight with normal LDLcholesterol or triglyceride levels and normal HDL-cholesterol levels, saturated FAs calories could be replaced by unsaturated fat and/or complex carbohydrate. Replacing saturated FAs with monounsaturated FA or polyunsaturated FA can lower LDL-cholesterol levels, although the ideal replacement percentages remain unclear. More research is needed in this area. • Trans-FAs intake should be as low as possible; individuals should aim for less than 7% of total calories from saturated fat and trans-FAs. Trans-FAs raise total cholesterol and LDLcholesterol and may decrease HDL-cholesterol. In terms of n-3 FAs and triglycerides, there is a growing body of evidence from epidemiological studies and randomized controlled trials demonstrating that long-chain n-3 fatty acids from fish reduce triglyceride levels, positively affect platelet function, and reduce risk of mortality [64]. Both n-6 and n-3 polyunsaturated FAs seem to be cardioprotective and sufficient intake of both should be encouraged [59, 64, 65].

10 Hypertension It is difficult to demonstrate a direct relationship between a specific nutrient and hypertension because of the variability different populations experience in their responses to specific nutrients/food components and the heterogeneity of the disease [66]. Very limited data are available on the specific effect of FAs on blood pressure in humans. Studies like the Seven Country Study [67], the Ireland–Boston Diet Heart Study [68], or the Lyon Heart Study [69] have reported an inverse relationship between monounsaturated FA and cardiovascular mortality, but they have not demonstrated any specific relationship between monounsaturated FAs and blood pressure. Consumption of n-3 FAs does not appear to lower blood pressure and thus, may not be beneficial for the management of hypertension [70]. This recommendation is based on the review of seven randomized clinical trials that examined the effect of n-3 fatty acid intake on blood pressure compared to other dietary fatty acids in both healthy adults and those at increased risk for cardiovascular disease (i.e., hyperlipidemia or diabetes), including individuals with prehypertension and stage 1 hypertension. None of the seven studies using n-3 FA supplements (ranging from 0.48 to 4.0 g/day for 5–12 weeks) reported a significant effect on blood pressure [41, 71–76].

11 Conclusions In conclusion, with respect to dietary fat composition, diets enriched in saturated and trans-FAs may increase insulin resistance, whereas some types of monounsaturated fat appear to improve insulin sensitivity. On the other hand, metabolic studies using diets high in PUFAs have provided conflicting conclusions on the effect of these compounds in glucose metabolism. Current

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evidence of the effects of specific types of dietary fat on insulin resistance is limited, and often times contradictory. More investigation, both basic and clinical, is needed in order for clinicians to confidently recommend a specific dietary strategy for the prevention and treatment of insulin resistance.

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Chapter 24

Strategies to Modify School-Based Foods to Lower Obesity and Disease Risk John B. Bartholomew and Esbelle M. Jowers

Key Points • School-based interventions to modify dietary practices in children are generally supported as a means to reduce obesity and to combat obesity-related disease. • The in-school dietary practices of children and how these practices have been modified through school-based interventions are discussed in this chapter. Keywords Children · Obesity · Diet · Environmental change · School lunch · Disease prevention · School interventions

1 Introduction School-based interventions to modify dietary practices in children are generally supported as a means to reduce obesity and to combat obesity-related disease. As such, this chapter will briefly describe the measurement and prevalence of overweight in children. We will then describe dietary practices of children in school and how these have been modified through school-based interventions. We will close with suggestions for application of these efforts as well as potential future directions. It is important to note that this is not a full review. Instead, we have selected a number of interventions to illustrate the broad categories of existing strategies as a guide to future intervention design.

J.B. Bartholomew () Department of Kinesiology and Health Education, The University of Texas, 1 University Station, D3700, Austin, TX 78712-1204, USA e-mail: [email protected] F. De Meester et al. (eds.), Modern Dietary Fat Intakes in Disease Promotion, Nutrition and Health, DOI 10.1007/978-1-60327-571-2_24, © Springer Science+Business Media, LLC 2010

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2 Measurement of Overweight in Children Body mass index (BMI) is a simple means to assess body size. It is calculated as weight in kilograms divided by height in meters squared, for which there are numerous on-line calculators [1–3]. While there are clear cut-points for overweight (BMI > 25 < 30) and obesity (BMI > 30) in adults, BMI is more difficult to interpret in children. Given different rates of growth, norms have been established based on the 2000 CDC growth charts. Based on these charts, children are considered overweight if they equal or exceed the 85th percentile and are considered obese if they equal or exceed the 95th percentile for their age and sex [2]. As a note of caution, although BMI is correlated with body fat percentage [4], it is not particularly useful as an indicator of overweight in individual cases. It is best used as a surveillance tool and/or to screen children for further testing. BMI measures in childhood do track into adulthood, with 50% of overweight adolescents who are classified as at or above the 95th percentile for age and gender likely to reach an adult BMI value of 30 kg/m2 or greater [5]. In this chapter, we will consider BMI and its use as a surveillance tool to categorize children as normal weight, at risk for overweight and overweight.

3 Prevalence of Overweight in Children With overweight children demonstrating metabolic complications, such as hypertension, fatty liver disease, dyslipidemia, and others that lead to early morbidity [6], as well as a majority becoming obese adults [7], overweight is a serious national issue. This is particularly troubling as the prevalence of overweight among children is increasing drastically. The National Health and Nutrition Examination Surveys (NHANES) data reveal that between 1976–1980 and 2003–2006, obesity in children aged 6–11 years has increased from 6.5 to 17% and increased from 5 to 17.6% in adolescents aged 12–19 years [8, 9]. In addition, disparities exist in rates for overweight. For example, NHANES (1999, 2000, 2001, 2002) indicated that the yearly prevalence of overweight was greater for Mexican American (22%) and African American (20%) children aged 6–11 years than for White, non-Hispanic children (14%) [10]. In addition, the proportion of adolescents from low socioeconomic status (SES) households that is overweight or at risk for overweight is two times that of adolescents from moderate to high socioeconomic status [11]. A longitudinal examination of teens from 1999 to 2004 revealed that those with a low socioeconomic status were at increased risk for overweight and were more likely to continue to be overweight or become overweight [12]. Thus, the existing research indicates that minority children and children with low socioeconomic status are at greatest risk for being overweight or obese [13]. Given that low SES children rely heavily on reduced-price breakfast and lunch for their caloric intake, schools provide an ideal target for intervention to prevent obesity in children [14].

4 Food in Schools Although there are numerous contributors [15], it is clear that childhood obesity is related to inappropriate nutritional intake. Specifically, the consumption of fat beyond recommended levels is closely related to body size [16]. With more than 84% of children eating excessive fat and more

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than 91% eating excessive saturated fat [11], the rise in childhood overweight is not surprising. In addition, diet quality declines over childhood [17, 18]. It is critical that interventions to prevent obesity must be designed to improve diet during early childhood years. Along these lines, there is a growing recognition that environmental factors contribute to diet [19, 20]. The National School Lunch Program (NSLP) is a federally assisted program that provides meals to over 101,000 schools and child care institutions [21]. The US Department of Agriculture (USDA) specifies the dietary guidelines that school meals must meet as part of the NSLP. School lunches are recommended to have no more than 30% of calories from fat, with less than 10% derived from saturated fat [21]. While federal requirements must be met, the decisions as to what foods to offer, how to prepare those foods, and when to offer them in the school menu falls on local food service personnel. In addition, these guidelines are for the aggregate offerings. As a result, any individual food item may not meet the guidelines; leaving room for calorie-dense entrées that are balanced by low-calorie vegetables (that are often ignored by children). As a result, children may consume food that is far outside of the national guidelines. The elementary school cafeteria exemplifies this challenge, with more than 75% of children exceeding the recommended level of fat in their lunch and nearly 80% of elementary schools exceeding the recommended levels of calories from fat in lunches served [22]. As a result, although children who participate in the NSLP consume more vitamins and minerals, they also consume more fat at school than at home and more fat than do non-participants—differences that remain after controlling for ethnicity, age, household income, and other demographic factors [22]. Obviously, schools are an ideal place to reach children. The US Census Bureau projects that 55 million children attended grades Kindergarten–12th during the 2006–2007 school year in public schools [23] and the Food Research and Action Center [24] reported that 30.5 million students participated in the NSLP during the 2006–2007 school year alone. Of these 30.5 million, about 18 million students received free or reduced-price lunch [24]. Thus, the potential reach in schools is awesome—the challenge is how to motivate and assist food service directors to initiate and maintain healthy changes to their menus, how to introduce healthier foods to the children in a manner in which they will select them at school, what types of policies to implement regarding competitive food sales and food fundraisers, and how to monitor the effect of these changes across time.

5 School-Based Nutrition Interventions Numerous interventions have targeted the school cafeteria to reduce fat intake. One strategy has been to ensure the availability of low-fat foods so that motivated children might select these entrées. Research is not supportive of this minimal strategy. Whitaker and colleagues [25] increased the availability of low-fat food in the elementary cafeteria, but found a significant drop in the selection of these foods [25]. Sallis and colleagues [26] increased the availability of lowfat foods with no change in total or saturated fat in the selected lunches [26]. Likewise, our data indicate that the mere addition of a low-fat entrée had no effect on the selection rates of low- or high-fat entrées among elementary school students [27]. Unfortunately, low-fat foods must compete with higher fat foods that are also offered as entrée choices. Because children prefer high-fat foods [16, 28, 29], merely offering low-fat foods appears to be insufficient to change children’s

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diet. In addition, as the preference for high-fat foods is associated with overweight [30], children with higher BMI may be particularly resistant to this intervention strategy. Another strategy has been to educate students about making healthy choices through increased health education and/or programming. One elementary school program, the Bienestar Health Program, provides various health education sessions per school year to students, including physical education and health classes, a health club, a family fun fiesta, and works with food service to motivate children to choose and eat fruits and vegetables and lower fat foods [31]. The Bienestar primary outcome is fasting capillary glucose level, with secondary outcomes including increasing fiber intake and decreasing energy intake from saturated fat. While health programming significantly affected capillary glucose level and fiber intake in intervention schools, there were no resultant differences in percentage of energy intake from saturated fat in intervention students compared to controls [31]. Thus, it appears that health promotion and a change in knowledge alone is not sufficient to instill dietary changes with regard to selecting low-fat foods [32]. A third strategy has been to train food service staff to modify recipes to make foods offered at school lower in fat content. A large randomized trial, the Child and Adolescent Trial for Cardiovascular Health (CATCH), developed an elementary school food intervention called the CATCH Eat Smart Program. The Eat Smart intervention included food service staff trainings, materials and supplies to affect menu planning, food preparation, purchasing, and promotion, with the goal to lower total fat, saturated fat, and sodium content of school meals [33]. Results of this multifaceted intervention revealed that the program significantly lowered total fat and saturated fat of school meals, compared to control schools, without sacrificing student participation [33]. In a 5-year follow-up study, CATCH-ON, both intervention and control schools demonstrated significant decreases in mean levels of calories from fat and saturated fat, although intervention schools were closer to achieving original Eat Smart goals compared to controls [34]. Though moderately successful, the barriers of implementing food preparation change are severe. This strategy is reliant on implementation by food service staff. Unfortunately, food service staff report perceived barriers with any system change including lack of time for modified meal preparation, increased cost, and student non-acceptance of those meals [35]. Thus, although modifications in food preparation are useful, it may not be practical for wide-spread dissemination. The challenge then is to motivate healthy food selection while remaining cost neutral to food service. One way to accomplish this is through pricing policy in the school. For example, middle school students appear to be more likely to select low-fat foods, fruits, and vegetables when their price is lowered to compete with higher fat options [36]. Likewise, schools have added salad bars, gardening clubs, and distribution of healthy snacks or fruits and vegetables to students free of charge [37] in order to motivate students toward selecting healthier choices. In both cases, the costs of less healthy foods and snacks can be increased to off-set the cost of the intervention. This requires no change to the regular menu items and thus not cost for training or concern for implementation by food service staff. As a result, this is a strategy with great potential in situations, like high school and middle school, where a la carte pricing is possible. This strategy is not applicable in most elementary schools where competing items are controlled and price is consistent across items. Ideally, high-fat foods would be eliminated from the school lunch menu. Unfortunately, Food Service Directors are strongly resistant to removing higher fat foods. The primary form of resistance centers on the assumption that participation rates in the NSLP will drop with the introduction of low-fat entrées. As management of the school lunch is a for-profit industry, a reduction in participation rates and their associated income is a

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threat to employment. In fact, a sizable section of the Food Service Management training specifically centers on marketing and enhancing the number of children participating in the NSLP [38]. In addition, some parents are opposed to healthy menu changes because they do not believe their child will eat the healthy items, thus leaving them without an option at school lunch. Focus groups conducted with African American and Hispanic parents of middle school students revealed that parents purchased foods their children liked, especially fast food or junk food, allowed their children to help decide what was offered for dinner, placed no restrictions on eating, and indicated concern over placing restrictions [39]. Clearly, a child’s diet will be compromised when they are the primary determinant of its content. As an example of how one might instead restrict choice, drive dietary behavior in a healthier direction, and remain cost neutral, consider a study by Bartholomew and Jowers [27] as part of the Texas Initiatives for Children’s Activity and Nutrition (Texas I-CAN!) [27]. This study utilized two schools with disproportionately high representation of low socioeconomic status and Hispanic children. Prior to the study, the district provided three entrée choices, with low-fat entrées rarely offered. Phase I of the intervention was designed as a policy change that required at least one low-fat entrée offered each school day. These items were not new recipes or vendors. Instead, we simply asked them to increase the availability of entrées that were low in fat but offered infrequently. Thus, this strategy is designed to fit within the cost profile and existing preparation methods of the school. Unfortunately, as stated previously, initial results indicated no change in behavior, with the provision of a single low-fat entrée [27]. However, in Phase II of the intervention, the policy change was modified to limit the number of offered entrées to two, with one always being low fat (< 30% of calories from fat). The selection of low-fat entrées more than doubled for the intervention schools—from 15.4 to 32.6% of selected entrées, with little change in the control school (11.3–13.8%) [27]. Modifying the ratio of low-fat to high-fat foods has the potential to significantly modify the selection of low-fat entrées at elementary school lunch. This seems to be due to differences in relative preferences. Jowers and colleagues assessed children’s preferences for the available low-fat options and found that children, regardless of ethnicity, rated low-fat entrees favorably [40]. However, further examination revealed that these absolute ratings were unrelated to the intention to select the low-fat foods at school. Instead, it was important to consider intention to select specific entrées versus other commonly offered and competing entrées [40]. Here we found that with more high-fat foods offered, children invariably found one that they preferred over the low-fat entrée. However, when low-fat entrées are equal to or outnumber high-fat entrées, more children are likely to prefer a low-fat option [40]. Low-fat options are but one example of the type of entrée that can be positioning in this manner. Regardless of the specific food, it seems that the combination of providing healthy options, while reducing traditional entrées, has great potential for success. It creates an intervention that is cost neutral and tolerable to both parents and food service directors as it allows at least limited access to traditional entrées. Thus, it appears to be a strategy that is practical to disseminate.

6 Competitive Food Sales In addition to reducing high-fat entrée options, schools often attempt to implement school-based policies that place restrictions on “competitive foods” such as the sale of a la carte items, school food fundraisers that generally include calorie-dense foods like cookies, and foods available

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during school functions. For example, a majority of middle (69%) and high (80%) schools have vending options and/or pouring contracts, where a specific soft drink company is allowed to exclusively market their products [41]. Competitive foods are not regulated by the USDA guidelines for nutritional content [42] and can be sold alongside of school entrees without being held to the standards of school meals. As a result, they provide a distracting enticement to students that make it difficult for children to choose the healthier option. In addition, school administrators send mixed messages when they promote a health intervention during the school day while offering foods of minimal nutritional value after school, at school events, or as school fundraisers. As a part of a larger policy initiative, a restriction on competitive foods could be effective in changing behavior and also increase revenue at the same time [43, 44]. The state of Texas, for example, initiated a Texas Public School Nutrition Implementation Policy which, in part, includes a restriction on foods of minimal nutritional value from being served outside of school meals, offered at school, or brought from home during certain parts of the school day depending on grade levels (vary according to elementary, middle, or high schools) [45]. These items include gum, certain types of candy, any carbonated beverages, and other similar foods. Unfortunately, there are few clinical trials of sufficient length to fully evaluate these policies. Although a review of school food and nutrition policy studies reports that while some policies are effective in changing dietary intake and choices in schools, not much is known on their effect on resultant BMI [46]. As a result, there is a need for future evaluations to measure the effect of policy change on children’s BMI.

7 Conclusions and Implications for Practice Many approaches have been identified to combat childhood obesity, including school-based nutrition interventions. The existing data seem to support a number of conclusions. First, the provision of health education alone or a simple addition of healthy, low-fat entrées is insufficient to modify behavior. Children, especially children with high BMI values, tend to prefer caloriedense foods. When given an option, they will select higher fat foods. The strategies with the most potential for success for providing healthy options within a school environment are those that also restrict access to competing calorie-dense foods. This has been accomplished through manipulating the price structure of salad bars versus snack foods and by eliminating or reducing the less healthy options that are offered. Such environmental approaches have great potential for success. Any approach, however, must be implemented by food service personnel. The concerns of food service staff need to be taken into account when proposing changes to school foods. We must work together to design dietary school interventions that address all concerns. Only then will we have strategies that can be disseminated across a wide range of schools and reach many children and adolescents.

References 1. Calculate your body mass index. National Heart Lung and Blood Institute Department of Health and Human Services. National Institutes of Health. (Accessed on Dec. 15, 2008, at http://www.nhlbisupport.com/bmi/.). 2008.

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2. Defining childhood overweight and obesity: Use of BMI to screen for overweight and obesity in children. Centers for Disease Control and Prevention. (Accessed December 12, 2008, at http:// www.cdc.gov/nccdphp/dnpa/obesity/childhood/defining.htm.). 2008. 3. BMI calculator for child and teen. Centers for Disease Control and Prevention. (Accessed December 12, 2008, at http://apps.nccd.cdc.gov/dnpabmi/Calculator.aspx.). 2008. 4. Mei Z, Grummer-Strawn LM, Pietrobelli A, Goulding A, Goran MI, Dietz WH. Validity of body mass index compared with other body-composition screening indexes for the assessment of body fatness in children and adolescents. Am J Clin Nutr 2002; 75: 978–985. 5. Whitlock EP, Williams SB, Gold R, Smith PR, Shipman SA. Screening and interventions for childhood overweight: a summary of evidence for the US Preventive Services Task Force. Pediatrics 2005; 116(1): e125–e144. 6. Cali AM, Caprio S. Obesity in children and adolescents. J Clin Endocrinol Metab 2008; 93(1): S31–S36. 7. Serdula MK, Ivery D, Coates RJ, Feedman DS, Williamson DF, Byers T. Do obese children become obese adults? A review of the literature. Prev Med 1993; 22: 167–177. 8. Obesity prevalence: trends in childhood obesity. Centers for Disease Control (CDC a). (Accessed December 11, 2008, at http://www.cdc.gov/nccdphp/dnpa/obesity/childhood/prevalence.htm.) 9. Ogden CL, Flegal KM, Carroll MD, Johnson CL. Prevalence and trends in overweight among U.S. children and adolescents, 1999–2000. JAMA 2002; 288: 1728–1732. 10. Hedley AA, Ogden CL, Johnson CL, Carroll MD, Curtin LR, Flegal KM. Prevalence of overweight and obesity among US children, adolescents, and adults, 1999–2002. JAMA 2004; 291: 2847–2850. 11. Healthy People 2010. US Washington, DC: U.S. Department of Health and Human Services. (Accessed January 26, 2009 at http://www.healthypeople.gov/Document/tableofcontents.htm#Volume2). 2000. 12. Sherwood NE, Wall M, Neumark-Sztainer D, Story M. Effect of socioeconomic status on weight change patterns in adolescents. Prev Chronic Dis 2009; 6(1): A19. Epub 2008 Dec 15. 13. Drewnowski A, Darmon N, Briend A. Replacing fats and sweets with vegetables and fruits—a question of cost. Am J Public Health 2004; 94(9): 1555–1559. 14. Georgiou C, Martin L, Long R. What third graders select and eat from school lunches when they have choices. J Child Nutr Manag 2005; 29(2). 15. Hill JO, Wyatt HR, Reed GW, Peters JC. Obesity and the environment: where do we go from here?. Science 2003; 299(5608): 853–855. 16. Lee Y, Birch LL. Diet quality, nutrient intake, weight status, and feeding environments of girls meeting or exceeding the American Academy of Pediatrics recommendations for total dietary fat. Minerva Pediatr 2002; 54(3): 179–186. 17. Lytle LA, Seifert S, Greenstein J, McGovern P. How do children’s eating patterns and food choices change over time? Results from a cohort study. AM J Health Promat 2000; 14(4): 222–228. 18. Mannino ML, Lee Y, Mitchel DC, Smickilas-Wright H, Birch LL. The quality of girls’ diets declines and tracks across middle childhood. Int J Behav Nutr Phy Activ 2004; 1(1): 5. 19. Savage JS, Fisher JO, Birch LL. Parental influence on eating behavior: conception to adolescence. J Law Med Ethics 2007; 35(1): 22–34. 20. Schwartz MB, Brownell KD. Actions necessary to prevent childhood obesity: creating the climate for change. J Law Med Ethics 2007; 35(1): 78–89. 21. National School Lunch Program (NSLP) Fact Sheet U.S. Department of Agriculture, Food and Nutrition Service. (Accessed January 27, 2009, at http://www.fns.usda.gov/cnd/Lunch/default.htm.). 2008. 22. Gleason P, Suitor C (2001) Children’s diets in the mid-1990s: dietary intake and its relationship with school meal participation. Alexandria, VA: US Department of Agriculture Food and Nutrition Service, Office of Analysis Nutrition and Evaluation; CN-01-CD1. 23. Facts for features. Back to school 2006–2007. US Census Bureau. (Accessed January 26, 2009, at http://www.census.gov/Press-Release/www/releases/archives/facts_for_features_special_editions/007108. html.) 24. Food Research and Action Center (FRAC). (Accessed January 22, 2009, at http://www.frac.org/html/federal_food_programs/programs/nslp.html.) 25. Whitaker RC, Wright JA, Finch AJ, Psaty BM. An environmental intervention to reduce dietary fat in school lunches. Pediatrics 1993; 91: 1107–1111. 26. Sallis JF, McKenzie TS, Conway TL et al. Environmental interventions for eating and physical activity: A randomized controlled trial in middle schools. Amer J of Prev Med 2003; 24: 209–217. 27. Bartholomew JB, Jowers EM. Increasing frequency of lower-fat entrees offered at school lunch: an environmental change strategy to increase healthful selections. J Am Diet Assoc 2006; 106: 248–252.

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28. Sherwood NE, Story M, Neumark-Sztainer D, Adkins S, Davis M. Development and implementation of a visual card-sorting technique for assessing food and activity preferences and patterns in African American girls. J Am Diet Assoc 2003; 103(11): 1473–1479. 29. Birch LL. Development of food preferences. Annu Rev Nutr 1999; 19: 41–62. 30. Wardle J, Guthrie C, Sanderson S, Birch L, Plomin R. Food and activity preferences in children of lean and obese parents. Int J Obes Relat Metab Disord 2001; 25(7): 971–977. 31. Trevino RP, Zenong Y, Hernandez A, Hale DE, Garcia OA, Mobley C. Impact of the Bienestar school-based diabetes mellitus prevention program on fasting capillary glucose levels. Arch Pediatr Adolesc Med 2004; 158: 911–917. 32. Lytle LA, Achterberg CL. Changing the diet of America’s children: what works and why?. J Nutr Educ 1995; 27: 250–260. 33. Osganian SK, Ebzery MK, Montgomery DH et al. . Changes in the nutrient content of school lunches: results from the CATCH Eat Smart Food Service Intervention. Prev Med 1996; 25: 400–412. 34. Osganian SK, Hoelscher DM, Zive M, Mitchell PD, Snyder P, Webber LS. Maintenance of effects of the Eat Smart school food service program: results from the CATCH-ON study. Health Educ Behav 2003; 30(4): 418–433. 35. Stang JS, Story M, Kalina B, Synder MP. Meeting the US Dietary Guidelines in school meals: current practices, perceived barriers, and future training needs. J Nutr Educ 1997; 29(3): 152–158. 36. French SA, Stables G. Environmental interventions to promote vegetable and fruit consumption among youth in school settings. Prev Med 2003; 37(6): 593–610. 37. French SA, Wechsler H. School-based research and initiatives: fruit and vegetable environment, policy, and pricing workshop. Prev Med 2004; 39(2): S101–S107. 38. Foundations for effective leadership in child nutrition programs. National Food Service Management Institute. University, MS: ET 71–07. 2007. 39. O’Dougherty MO, Story M, Lytle L. Food choices of young African-American and Latino adolescents: where do parents fit in?. J Am Diet Assoc 2006; 106: 1846–1850. 40. Jowers EM, Bartholomew JB, Callen KJ. The effects of gender and ethnicity on absolute vs. relative ratings for low-fat school lunch entrees. Matern Child Nutr 2009; 5(4): 368–376. 41. Finkelstein DM, Hill EL, Whitaker RC. School food environments and policies in US public schools. Pediatrics 2008; 122(1): e251–e259. 42. Pilant VB. Position of the American dietetic association: local support for nutrition integrity in schools. J Am Diet Assoc 2006; 106(1): 122–133. 43. Fox S, Meinen A, Pesik M, Landis M, Remington PL. Competitive food initiatives in schools and overweight in children: a review of the evidence. WMJ 2005; 104(5): 38–43. 44. Story M, Kaphingst KM, French S. The role of schools in obesity prevention. Future Child 2006; 16(1)): 109–142. 45. Texas public school nutrition policy implementation schedule: Four year plan: 2006–2010. Texas Department of Agriculture. (Accessed January 27, 2009, at http://www.squaremeals.org/fn/render/ channel/items/0,1249,2348_2360_0_0,00. html.) 46. Jaime PC, Lock K. Do school based food and nutrition policies improve diet and reduce obesity?. Prev Med 2009; 48(1): 45–53.

Chapter 25

Selenium Enigma: Health Implications of an Inadequate Supply Peter Surai, A.C. Pappas, F. Karadas, T.T. Papazyan, and V.I. Fisinin

Key Points • Selenium (Se) plays an important role in health maintenance, and optimization of Se status of the general population is an urgent task for many countries worldwide. • Low Se availability from European soils due to fertilization decreased dramatically. Se availability for plants leads to low Se concentrations in grains and in animal-derived products and ultimately in human diet. • Supplementing animal diets with Se in the form of sodium selenite or selenate does not affect substantially Se concentration in eggs, meat, and milk. • SeMet represents the major form of Se in animal-derived foods and must be provided with diets for solving Se deficiency problems through production of Se-enriched eggs, meat, and milk. Keywords Selenium · Antioxidants · Human health · Deficiency

1 Introduction Many centuries ago, Hippocrates’ observations on the relationship between health and food choices began discussions about the factors that determine our health. However, during the last decade it has become obvious that while our lifestyle, including diet, stress, smoking, medical attention, exercise, and genetics, is a major determinant of our health status, it is diet that has the pivotal role. The effect of nutrition on human health has received tremendous attention, and traditional medical teaching that diet and nutrients play only limited roles in human health is being revised. In most developed countries, nutritional practice has changed the focus from combating

P. Surai () Avian Science Research Centre, Scottish Agricultural College, Ayr, UK; Division of Environmental and Evolutionary Biology, University of Glasgow, Glasgow, UK e-mail: psurai@mail ru F. De Meester et al. (eds.), Modern Dietary Fat Intakes in Disease Promotion, Nutrition and Health, DOI 10.1007/978-1-60327-571-2_25, © Springer Science+Business Media, LLC 2010

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nutrient deficiencies to addressing nutrient requirements for maintaining good health throughout the life. Indeed, collectively, cardiovascular disease (including stroke), cancer, and diabetes account for approximately two-thirds of all deaths in the United States—close to 1.5 million people in 2001 [1, 2]. The economic costs of cardiovascular disease, cancer, and diabetes in the United States in 2003 were estimated to be $351.8 billion, $189.5 billion, and $132.0 billion, respectively [3, 4]. Three major areas of concern are the improvement of the diet, the increase of physical activity, and the reduction of prevalence of tobacco use—the major risk factors for these diseases. Considering improvement of the diet it is necessary to make sure that all nutrients, including minerals, in the diet are in optimal amounts. One of such minerals which has received tremendous attention for the last few years is selenium (Se).

2 Selenium Deficiency Se essentiality for human is proven and based on the following [5]: • Se is a component of about 25 selenoproteins identified in human body playing important roles in regulation of various physiological functions. • Se supplementation of depleted patients undergoing long-term total parenteral nutrition had favorable responses. • Se deficiency has been implicated in certain human diseases and Se supplementation was shown to be cancer protective and immunomodulatory in human. The signs and symptoms of Se deficiency closely simulate each other for animals and man. Deficiency states have been demonstrated for inhabitants of regions where Se supply is limited in protein energy malnutrition and in patients maintained on total parenteral nutrition without Se supplementation. Severe deficiency is characterized by cardiomyopathy while moderate deficiency results in less severe, myodegenerative syndromes such as muscular weakness and pain as well as a variety of other Se-associated diseases [6]. For example, a suspected Se deficiency syndrome has been demonstrated in a few patients treated with parenteral nutrition without added Se [7]. In detail, muscular pain and muscular and cardiac dysfunction have been demonstrated in some patients, but no uniform symptomatology has been described. A case of fatal cardiomyopathy caused by Se deficiency during parenteral nutrition for 6 consecutive years was also described [8]. Furthermore, a case of fulminant heart failure in a middle-aged woman with a complex medical and surgical history including documented malabsorption and Se deficiency was presented where pathological examination of the heart showed features consistent with Keshan disease [9]. Clinical manifestations of many of these disorders require contributory factors, such as stress, to precipitate symptoms which are documented for animals and implicated for humans. Se deficiency in human population is associated with two diseases (Keshan disease and Kashin-Beck disease) reported in areas of China and some other countries characterized by extremely low Se content in the soil and food. In particular, the diseases occur in a geographic belt stretching from Heilongjiang Province in northeast China to Yunnan Province in the southwest [10, 11].

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• Keshan’s disease (KD) is a cardiomyopathy, which mainly affects young children and women of child-bearing age. The disease has occurred in some areas of China where the soil is low in Se. In fact, KD was first described in Chinese medical literature more than 100 years ago, but not until 40 years after its widespread occurrence in 1935 was it discovered that Se deficiency was an important factor in its etiology. The earliest identification of this disease was in the Keshan area of the northeastern provinces of China and this gave the name to the disease. In the period between 1959 and 1970, peak KD rates exceeded 40 per 100,000 (approximately 8,500 new cases per annum) with 1,400–3,000 death recorded each year [10]. For example, KD occurred in six communities in the northwest of Lichuan County. In total, 213 people have suffered KD in the county. From those with KD, 136 recovered and 163 died. Children between the ages of 3 and 8 accounted for 83.4% of the total cases and 80% of the children affected by the disease died [10]. The acute form is characterized by sudden onset of insufficient heart function, whereas individuals with chronic disease exhibit moderate to severe heart enlargement with varying degrees of heart insufficiency. Typical manifestations are fatigue after even mild exercise, cardiac arrhythmia and palpitations, loss of appetite, cardiac insufficiency, cardiomegaly, and congestive heart failure. Pathologic changes include a multifocal myocardial necrosis and fibrosis. The coronary arteries are essentially unaffected. Additional symptoms of the disease also include coughing, difficulty on breathing, vomiting/or tendency to vomiting, chest uncomfortable, low desire for food; swollen body, severe lung enlargement, and pass out. Ultrastructural studies showed that membranous organelles, such as mitochondria or sarcolemma, are affected earliest, while the histopathological features include the following: multifocal necrosis; fibrous replacement of the myocardium; myocytolysis. It is important to note that there are other factors that affect this disease development including [5]: marginal to deficient vitamin E status; other complicating nutritional deficiencies and disbalances (e.g., protein, polyunsaturated fatty acids); presence of a cardiotoxic agent, such as a virus. It seems likely that this is the case for areas with low Se level in China where Keshan disease occurs. A series of intervention trials with Se supplementation proved to be effective in prevention of Keshan disease. As a result of Se inclusion in table salt, Se status of general population in those high-risk areas was improved, there was also improvement in general diet and as a result Keshan disease practically disappeared from endemic areas. In a large, prospective, placebocontrolled study conducted in China [12], the incidence of Keshan disease in Se-supplemented children fell from 2.2% in 1974 to 1% in 1975, to 0.32% in 1976, and in 1977 no cases of the disease were reported.

2.1 Kashin-Beck disease Kashin-Beck disease is an osteoarthropathy, a generative articular disease caused by oxidative damage to cartilage that leads to deformation of bone structure [13, 14]. The disease is endemic in Tibet and other areas of China, Siberia, and North Korea—areas where Se deficiency is also endemic. This Se-responsive bone and joint disease has been detected in children aged 5–13 years in China and less extensively in southeast Siberia. Indeed, the disease occurs during preadolescence or adolescence [15]. The disease is characterized by joint necrosis—epiphyseal

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degeneration of the arm and leg joints resulting in structural shortening of the fingers and long bones with consequent growth retardation and stunting. Affected subjects have varying degrees of joint deformation and limited joint mobility. In the most severe cases, there is necrosis of growth plates and joint cartilage. Therefore, necrotic degeneration of the chondrocytes is the most striking pathologic feature of this disease. Dwarfism and joint deformation can result from these cartilage abnormalities [13]. As mentioned above, Kashin-Beck disease occurs in areas where the availability of soil Se for crop growth is low. The Se contents of hair and of whole blood are abnormally low and the blood content of GSH-Px is reduced. The disease has been reported in white migrants to the areas of endemic disease, and clinical improvement was observed in children who move to areas where the disease is not endemic [16]. In addition to Se deficiency, a number of other etiologic factors have been suggested for this condition, including mycotoxins in grain, mineral imbalance, organic contaminants in drinking water. It has also been hypothesized that iodine deficiency and Kashin-Beck disease might be associated [17]. A spontaneous decrease in incidence from 1970 (44%) to 1980 (14%) to 1986 (1%) has been attributed to general improvements in the nutritional status of Chinese rural communities [18]. However, the efficacy of Se supplements in the prevention of Kashin-Beck disease is still controversial.

3 Meeting Selenium Requirement In 1980, the National Research Council (USA) established an estimated safe and adequate daily dietary Se intake for adults of 50–200 μg [19]. This recommendation was the first dietary standard for Se and was based primarily on data extrapolation from animal experiments because few human data were available at that time. Later balance human studies and dietary surveys in areas with different Se status helped to further clarify Se requirement. The first RDA for Se was proposed in 1989 [20]. By using the dietary Se intake needed to maximize the activity of GSH-Px in Chinese people living in KD area, it was calculated that plasma GSH-Px was maximized at Se supplementation of 30 μg/day. By adding 11 μg/day from the food it was calculated that 41 μg/day Se would provide maximum GSH-Px activity [21]. By taking into account body weight and safety factors, Se requirement was calculated to be 70 and 55 μg/day for adult men and women, respectively [5]. An intake of 40 μg/day was suggested as the minimum Se amount required for humans [22]. It should be noted that the daily requirements of elemental Se remain controversial. Thus, although dietary Se intake of 40 μg/day is considered as adequate for prevention of Keshan disease, higher intake of 50–200 μg/day [23] or even 400–600 μg/day [24] has been recommended for treating active conditions. Furthermore, Se requirement for optimal health and disease prevention needs further elucidation. Recently a human study was carried out in New Zealand by Duffield et al. [25]. In the study men and women were given Se supplements (placebo, 10, 20, 30, or 40 μg) for 20 weeks and they had an average dietary Se intake of 28 μg/day. The authors showed that GSH-Px activity reached a plateau only in the group with the maximal Se supplementation and they proposed an intake of 90 μg Se as recommended daily allowance. The Institute of Medicine (USA) used two studies (Chinese study of 1983 and aforementioned New Zealand study) to establish RDI in Se. As a result of this analysis the recommendations of the Panel was for a daily RDI of 55 μg

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for adults including men and women [26]. The British government’s defined reference nutrient intake is 75 μg/day for men and 60 μg/day for women ([27], Department of Health, 1991). The RDI suggested by other countries are as follows [11]: • The Nordic countries: 30–60 μg/d for adult males and females • The German Estimated Value for Adequate Supply: 20–100 μg/d for adults • The Australians: 85 and 70 μg/d for men and women, respectively It seems likely that increased Se status could be beneficial for general health. For example, increased Se consumption was shown to have cancer-preventing properties, immuno-modulating and anti-inflammatory actions responsible for maintenance of good health, and decreasing detrimental consequences of aging [11]. A great body of evidence indicates that European intakes of Se are falling. For example, in 1978 Se intake in Britain was 60 μg/day, 7 years later it was only 43 μg/day, and in 1990 fell to 30 μg/day. Even in 1997, average reported Se intake was only 43 μg/d [28]. Dietary intakes of Se in other countries vary considerably but in some of them intake is still lower than the RDI (Table 25.1). The decline in Se intake is reflected in decreased serum and whole blood Se concentrations. Indeed, in 1991 a French study showed a large-scale deficit in micronutrients, including Se affecting 30–40% of the healthy population [29]. This was confirmed by many other studies showing low plasma concentrations of Se. Plasma Se concentrations are decreasing progressively in the healthy European population since the 1980s, reflecting lower nutritional Se intake due to decreased nutrient Se content [30–34]. The mean plasma concentration in various European areas (40–85 μg/L) is substantially lower than the Se concentration associated with a cancer prevention activity according to the American Nutritional Cancer Prevention Study or Se levels required for maintenance of an optimal plasma GSH-Px activity [33].

4 Health-Promoting Effects of Optimal Se Status There is a great body of evidence to show health-promoting properties of Se. In fact, Se deficiency is considered to be an important factor in the development of various diseases, and optimization of Se status is of great help in disease prevention and treatment.

4.1 Cancer The most compelling evidence exists in related to cancer-protective effect of Se [35–40]. First, in epidemiological observations and prospective studies an inverse correlation between Se levels in food and blood and risk of cancer and cancer mortality were observed. Second, there are case–control studies showing that Se levels in blood, serum, hair, or toenails are lower in cancer patients than in controls. Third, laboratory animal studies showed a protective effect of various forms of Se against cancer initiation and development. Finally, there are human intervention trials showing Se supplementation to be effective means of decreasing risk of cancer.

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Table 25.1 Low daily selenium intakes in selected countries (μg/day) (Adapted from [11]∗ and [160]∗∗ ) Country μg/day Reference/year China, Keshan disease area China, Keshan disease area New Zealand, low-Se area Saudi Arabia Czech republic Poland UK Lybia New Guinea Czech republic Nepal Finland before selenium fertilization India,vegan low income Croatia Belgium Egypt Serbia Slovenia China Croatia Slovakia Belgium Brazil Egypt New Zealand Sweden France Serbia Belgium Poland Sweden UK, 1994 Turkey UK, 1995 New Zealand England Spain Germany Portugal Slovakia Sweden Denmark Germany Greece Sweden Denmark France Italy UK, 1985 Belgium

2–36 7–11 11 15 10–25 11–40 12–43 13–44 20 15–50 23 26 27 27 28–61 29 30 30 26.0–37.2 27.3–33.9 27–38.2 28.4–61.1 28.4–37.0 29 29–38 29–44 29–48 30 30 30–40 31 32 32 33 33.5 35 35 35–48 37 38 38 38–47 38–48 39.3 40 40 42 43 43 45

1985∗ 2001∗ 1984∗ 1997∗ 1996∗∗ 2000; 2003∗ 1995; 1997; 1998; 2003; 1992∗ 2005∗∗ 1992∗ 2003∗ 1988∗ 1987; 1984; 1985∗ 1997∗ 1998∗∗ 1994∗∗ 1972; 1996∗ 2001∗ 1998∗ 2002; 2000∗ 1998; 2000∗ 1996; 1998∗ 1989; 1994∗ 2004∗ 1972∗∗ 1999; 2001; 2004∗ 1991; 2000; 2003∗ 1994; 1994∗ 1995∗∗ 1993∗∗ 2003∗∗ 1989∗∗ 1997∗ 1991∗∗ 1997∗ Watson and McDonald, 2008 [162] 2000∗ 1996∗ 1989; 2000∗ 1990∗ 1998∗∗ 1993∗∗ 2000∗ 1989∗∗ 2006∗∗ 1989∗∗ 1998 ∗∗ 1988∗∗ 1985∗ 1997∗ 1994∗∗

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Table 25.1 (continued) Country

μg/day

Reference/year

France Germany France India, conventional diet Austria Italy Egypt Ireland UK, 1974

47 47 48 48 48 49 49 50 60

1991∗∗ 1989∗∗ 1994∗∗ 1997∗ 2001∗ 1991∗∗ 1999∗∗ 2002∗ 1997∗∗

It is believed that the protective effects of Se are due to its metabolism into low molecular weight seleno compounds and because of its role in the regulation and activity of Se-containing proteins or selenoproteins [11, 37]. A number of potential mechanisms are proposed for the chemopreventive effects of Se, including • • • • • • •

stimulation of apoptosis induction of cell cycle arrest activation of the tumor suppressor p53 induction of DNA repair genes enhancement of immune functions Influence on estrogen and androgen receptor expression Changes in cancer-related gene expressions

Up to date there were 10 human trials to test protective effect of Se against cancer and six of them were conducted in China, a country characterized by a number of Se-deficient regions. The main outcome of the mentioned trials is a protective effect of Se (in most cases Se-yeast) against cancer [11]. Such data provided a strong incentive to design a definitive trial for Se and vitamin E with prostate cancer as a primary end point. Hence, there are new human trials underway to further substantiate the protective effects of Se against cancer, including a SELECT trial employing 35,533 men from 427 participating sites in the United States, Canada, and Puerto Rico randomly assigned to four groups (Se, vitamin E, Se+ vitamin E, and placebo) in a doubleblind fashion between August 22, 2001, and June 24, 2004. This trial was planning to last for 12 years with a budget exceeding US $200 million [41, 42]. However, there was a potential problem with this study, since in previous studies a natural product, Se-enriched yeast, was used, while in the SELECT trial, purified SeMet is being used, and so there were some questions as to how results of this study could be extrapolated to intakes of Se through food [43]. Furthermore, pure SeMet is not a stable compound and can be easily oxidized and its protective effect can be compromised [11]. It seems likely that this was the case in this study which was prematurely stopped in October 2008 after the independent review of the results. As of October 23, 2008, median overall follow-up was 5.46 years. Hazard ratios (99% confidence intervals) for prostate cancer were 1.13 for vitamin E, 1.04 for Se, and 1.05 for Se + vitamin E vs 1.00 for placebo [42]. There were no significant differences (all P >0.15) in any other prespecified cancer end points. There were statistically not significant increased risks of prostate cancer in the vitamin E group (P = 0.06) and type 2 diabetes mellitus in the Se group. The authors concluded that Se or

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vitamin E, alone or in combination at the doses and formulations used, did not prevent prostate cancer in this population of relatively healthy men.

4.2 Cardiovascular Diseases It has been shown that increased Se status has not only cancer-protective effect but also can help the body to fight other free radical-associated diseases. In particular, dietary deficiency of Se has been incriminated in the etiology of cardiovascular diseases (CVD). In particular, Se inadequacy (through its role in selenoenzymes, thyroid hormones, and interactions with homocysteine and endothelial function) appears to be a major mediator in several pathways potentially contributing to chronic heart failure development [44]. However, the results of longitudinal studies within populations are conflicting with some investigations observing a relationship between low serum Se levels and the risk of coronary disease, while others did not. For example, 25 observational studies (14 cohort and 11 case–control studies) that measured blood or toenail Se concentrations and six randomized trials that evaluated supplements containing Se were analyzed [45]. The pooled relative risk in a comparison of the highest with the lowest Se concentration categories was 0.85 in cohort studies and 0.43 in case–control studies. In observational studies, a 50% increase in Se concentrations was associated with a 24% reduction in coronary heart disease risk. In randomized trials, the pooled relative risk in a comparison of supplements containing Se with placebo was 0.89. Arroyo et al. [46] studied Se values in 40 African-American patients with protracted, short-lived, and compensated congestive heart failure (CHF). In the protracted group 100% exhibited Se values below normal. In general, dietary Se supplement may be considered anti-atherosclerotic. Levy et al. [47] reported a case of reversible cardiomyopathy in a patient receiving Se-deficient parenteral nutrition. Another case of Se deficiency induced heart failure reversed after treatment with Se has been reported recently [48]. It is interesting to note that Se deficiency affects myocardial energy metabolism and contractile proteins [49]. Based on studies conducted on animal models, the role of Se in the antioxidant defense of cardiac muscle is described [50] and protective effect of Se against ischemia/reperfusion injury of the heart was observed [51, 52]. Selenium protects the heart against I/R injury due to its action on the redox state and deactivation of NF-κB in I/R hearts [53]. In fact, endothelial cells, which play a major role in the development of the vascular system, are dependent on selenoprotein expression for development and proper function [54]. Furthermore, Se appears to protect endothelial cells from oxidative damage which has been implicated in cardiovascular diseases, including atheroma [55, 56]. For example, in the heart of adriamycintreated rats, Se supplementation caused an increase in the total antioxidant activity, glutathione concentration, and glutathione peroxidase and catalase activities leading to a decreased generation of reactive oxygen metabolites [57]. It has been shown that selenoprotein K is a novel antioxidant in cardiomyocytes and is related to the regulation of cellular redox balance [58]. Selenoprotein W is also involved in protection of the developing myoblasts from oxidative stress [59]. It has been suggested that Se supplementation may provide an effective method for reducing oxidative damage post-cardiac ischemia reperfusion [60]. Recently, it has been shown that non-limiting Se availability counteracts the postprandial formation of the atherogenic form of LDL and provides a rationale for the epidemiological evidence of the inverse correlation between Se intake and the incidence of chronic and degenerative

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diseases [61]. Earlier it was shown that patients suffering from acute myocardial infarction exhibited lower plasma, erythrocyte, and urinary Se than the controls [62]. Similarly, it was confirmed that patients suffering from acute myocardial infarction exhibited lower plasma concentrations of Se and higher concentrations of pro-inflammatory cytokines of TNF-α and IL-6 [63]. In patients with cardiac disorders immune activation was associated with lower serum Se concentrations [64]. Significant negative correlations were found between serum Se and total cholesterol, lowdensity lipoprotein cholesterol, and high-sensitive C-reactive protein values [65]. Furthermore, Se supplementation (200 μg/day as Se-yeast for a week) improved blood fluidity by metabolic modification of lipoproteins [66] which also could be an additional protective factor against CVD development. As such, dietary Se supplementation may provide a safe and convenient method for increasing antioxidant protection in aged individuals, particularly those at risk of ischemic heart disease, or in those undergoing clinical procedures involving transient periods of myocardial hypoxia [67]. In Australia, the presence of CVD did not appear to influence Se status, with the exception of the over 81 age group, which showed a trend for a further decline in Se status with disease [68]. These findings emphasize the importance of an adequate dietary intake of Se for the maintenance of a healthy aging population, especially in terms of cardiovascular health. Atherosclerosis is accelerated in diabetic patients. This is at least partially caused by hyperglycemia and hyperinsulinemia increasing adhesion molecule expression, an important event in the initiation of an atherosclerotic lesion. It was shown that Se inhibited high glucose- and high insulin-induced expression of adhesion molecules [69]. Furthermore, it was shown that diabetic cardiomyocytes exhibited significantly increased [Zn2+ ] and [Ca2+ ] reduced glutathione; increased levels of lipid peroxidation and nitric oxide products and decreased activities of superoxide dismutase, glutathione reductase, and glutathione peroxidase [70]. Treatment of diabetic rats with sodium selenite prevented these defects induced by diabetes. It is known that nuclear factor-kappa B (NF-κB) is a protein complex and transcription factor found in cells and is involved in cellular responses to stimuli such as stress, free radicals, ultraviolet irradiation, oxidized low-density lipoprotein (LDL), and bacterial or viral antigens. Exposure of cells to stressful stimuli results in the release of NF-κB and its subsequent translocation to the nucleus of the cell. In type 2 diabetic patients, activation of NF-κB measured in peripheral blood monocytes can be reduced by Se supplementation (960 μg/day over 3 months), confirming its importance in the prevention of cardiovascular diseases [71]. Therefore, Se may be considered as a potential preventive intervention for diabetesaccelerated atherosclerosis. Indeed, Se as an essential component of a range selenoproteins plays a critical role in protecting aerobic tissues from oxygen radical-initiated cell injury, and dietary Se supplementation may provide a convenient method for increasing antioxidant protection in aged individuals, particularly those at risk of ischemic heart disease, or in those undergoing clinical procedures involving transient periods of myocardial hypoxia [67]. However, the form of Se used is a key for a success. For example, sodium selenite supplementation increases GPx-1 activity in endothelial cells and in coronary artery disease patients [72]; however, no relevant changes were observed for flow-mediated dilation or biomarkers of oxidative stress and inflammation. Clearly, the results of clinical studies suggest that an increase in the intake of Se is associated with health benefits, especially when organic form of Se is used. However, the present emphasis should be on diagnosing and treating Se deficiency, resulting from a poor diet or disease. Large high-quality randomized controlled trials and observational studies are needed across populations with different levels of Se intake [73].

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4.3 Reproductive Disorders Data are also actively accumulating to indicate that from the one hand, Se deficiency is related to reproductive disorders in human, including poor semen quality and pregnancy complications, and from the other hand, the Se dietary supplementation could potentially have prevented those changes [11]. Since hydrogen peroxide and lipid peroxides are toxic for the spermatozoa [74], GSH-Px plays an important role in protecting cell membrane lipid from peroxidation, thus maintaining the integrity of the cell. In fact, GSH-Px in the sperm is considered to be the main enzyme which removes peroxides and thereby protects cells against damage caused by free radicals and the products of lipid peroxidation in vivo [75]. Evidence has been provided indicating that Se supplementation enhances the in vitro motility and oxygen uptake of human sperm in sub-fertile males [76, 77]. In particular, 69 sub-fertile patients were recruited in Scotland and received placebo, Se alone, or Se plus vitamins A, C, and E daily for 3 months. Selenium treatment significantly increased plasma Se concentrations and sperm motility but sperm density was unaffected. Five men (11%) achieved paternity in the treatment group, in contrast to none in the placebo group [77]. In order to verify the hypothesis that Se and vitamin E could improve male fertility, nine oligoasthenoteratozoospermic men were supplemented for a period of 6 months with Se and vitamin E. Compared to the baseline period (pre-supplementation) of 4 months, statistically significant increases were observed for Se and vitamin E levels, sperm motility, percent live, and percent normal spermatozoa. These improvements are likely to be “supplementationdependent,” since all of the parameters returned to baseline values during the post-treatment period [78]. Similarly, sub-fertile men in Russia were given three courses of Se (3.5 μg/kg/day for 30 days) with positive effects on semen quality [79]. In Tunisia 28 men were supplemented daily by vitamin E (400 mg) and Se (225 μg) for 3 months. Vitamin E and Se supplementation produced a significant decrease in MDA concentrations and an improvement of sperm motility [80]. A significantly positive correlation was observed between human semen concentration of Se and sperm density, as well as sperm count, sperm motility, and viability [81]. Moreover, 8-OHdG levels in sperm DNA inversely correlated with semen Se concentrations in fertile and infertile subjects [82]. Recently a study has been conducted with 468 infertile men with idiopathic oligoasthenoteratospermia who were randomized to receive 200 μg Se orally daily (Se group of 116), 600 mg N-acetyl-cysteine orally daily (N-acetyl-cysteine group of 118), 200 μg Se plus 600 mg N-acetyl-cysteine orally daily (Se plus N-acetyl-cysteine group of 116), or similar regimen of placebo (control group of 118) for 26 weeks, followed by a 30-week treatment-free period [83]. In response to Se treatment serum follicle-stimulating hormone decreased but serum testosterone and inhibin B increased and all semen parameters significantly improved. A significant positive correlation existed between the seminal plasma concentrations of Se and semen parameters. These results indicated that supplemental Se improves semen quality. It seems likely that oxidative stress is involved in this human pathology. In particular, recent findings suggest that lipid and protein oxidation may be an important factor in the pathogenesis of preeclampsia [84]. Indeed, oxidative stress and subsequent lipid peroxidation were shown to accompany the complications of hypertension, preeclampsia, and diabetes mellitus in pregnancy [40]. It has been shown that median toenail Se concentrations in the preeclamptic subjects were significantly lower than in their matched controls. Furthermore, the authors showed that being in the bottom tertile of toenail Se was associated with a 4.4-fold greater incidence of the condition [32]. Within the preeclamptic group, lower Se status was significantly associated with

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more severe expression of disease, as measured by delivery before 32 weeks. However, an earlier study indicated that women with preeclampsia had significantly higher median leukocyte Se concentrations than normotensive controls and there was evidence of a linear increase in risk of preeclampsia with increasing concentrations of Se in leukocytes [86]. Serum levels of MDA was markedly higher (P <0.001) and serum level of Se was markedly lower (P <0.001) in PE women compared with healthy pregnant or non-pregnant women [87]. Indeed, oxidative stress associated with preeclampsia may be a consequence of reduced antioxidant defense pathways specifically involving glutathione peroxidases, perhaps linked to reduce Se availability [88]. Reduced glutathione peroxidases could be associated with increased generation of toxic lipid peroxides contributing to the endothelial dysfunction and hypertension of preeclampsia. In addition, Se supplementation during pregnancy and in the postpartum period reduced thyroid inflammatory activity and the incidence of hypothyroidism [89]. Selenium deficiency in pregnant rats leads to symptoms similar to those seen in human PE [90]. There was a significant reduction in the mean hair Se level in the recurrent miscarriage group compared with the control group (0.14 μg/g vs 0.34 μg/g; [91]). However, in an earlier study there was no association between unexplained recurrent miscarriage and reduced Se status [92]. The effect of Se supplement on pregnancy was studied in 52 pregnant women with highrisk factors of pregnancy-induced hypertension (PIH). They were given natural Se dietetic liquid (100 μg/d) for 6–8 weeks during late pregnancy, and 48 controls were given placebo. The results revealed that Se supplement on the pregnant women prevented and decreased the incidence of PIH and gestational edema [93]. It is well known that neural tube defects are important causes of infant mortality and childhood morbidity. Maternal Se deficiency during pregnancy was thought to be one of the factors responsible for fetal neural tube defects (NTDs). The relationship between Se concentration and neural tube defect occurrence in women with a second trimester termination due to fetal neural tube defects (NTDs) was investigated in the case–control study [94]. It was shown that cases had significantly lower serum Se levels (55.2 vs 77.4 μg/mL, respectively, P <0.001). However, the lowered serum and hair Se concentrations may be secondary manifestations of an abnormal pregnancy and did not contribute to its production [95].

4.4 Aging Aging is a very complex, multifactorial process, and numerous aging theories have been proposed; the most important of these are probably the genomic and free radical theories. In particular, the free radical theory of aging postulates that the production of intracellular reactive oxygen species is the major determinant of life span [96]. Numerous cell culture, invertebrate, and mammalian models exist that lend support to this half-century-old hypothesis. It has been shown that elderly individuals have a higher risk to develop trace element deficiencies due to modified dietary habits and requirements, age-related physiological changes, drug therapy, and chronic diseases leading to or associated with enhanced consumption or excretion of trace elements [97]. There is a great body of evidence indicating decreased Se status in elderly populations. For example, in aged individuals aged blood Se levels were shown to be negatively correlated with age. A study was conducted in a representative sample of non-institutionalized individuals aged ≥65 years living in southwestern France. Plasma and erythrocyte Se was measured in 239 volunteers (mean age 73.7 years). It was shown that plasma Se decreased

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significantly with age. A similar but nonsignificant trend was found for erythrocyte Se [98]. The analysis of the relationship between Se and GSH-Px activity conducted by the authors suggests that low Se values were associated with decreased GSH-Px activity. Selenium levels in plasma of healthy individuals were found to be low in the oldest group (41–69 years old) in comparison to younger people and a negative correlation between age and Se levels were found [99]. A decreasing level of Se with age was shown in Korea. In fact, the overall proportion of women having Se deficiency, with less than 80.0 μg/L of the Se concentrations in the serum, was 18.3% [100]. The serum Se levels in the young adult, middle-aged, and elderly groups were 120.6, 97.2, and 90.8 μg/L, respectively. Subjects with the lowest tertile of Se concentration had significantly higher atherogenic index and lower HDL-cholesterol levels compared to those with the highest tertile. However, only the serum HDL-cholesterol level showed the dependency on the Se status as determined by stepwise analysis, and this dependency was significant only in the subjects below the age of 40. Similar relationship between Se and age was shown in animal models as well. In an experiment conducted in Turkey male Wistar rats at ages of 1, 6, and 12 months were used. The activity of Se-GSH-Px and the level of GSH in rat erythrocytes were decreased with age and the correlation between age and Se-GSH-Px activity (r = –0.376, P <0.05) was negative [101]. Low plasma Se is independently associated with poor skeletal muscle strength in communitydwelling older adults in Tuscany [102]. Similarly, low serum Se concentrations are associated with poor grip strength among older women living in the community [103]. Furthermore, suboptimal Se status could worsen muscle functional decrements subsequent to eccentric muscle contractions [104]. In elderly people in Spain serum Se was associated with self-perceived health, chewing ability, and physical activity. In particular, subjects in the upper quartile of serum Se had more than twice as much probability of reporting good health status, good chewing ability, and of doing more than 60 min of exercise/day. Low serum concentrations of Se predict subsequent disability in activities of daily living in older women living in the community [105]. Improved Se status was associated with reduced risk of osteoporotic hip fracture in elderly subjects [106]. In elderly population, those with the lowest Se levels had a significantly higher risk of total mortality over a period of 5 years [107]. Similar conclusion was drawn from the EVA study (a 9-year longitudinal study with six periods of follow-up). During the 2-year period from 1991 to 1993 (EVA0), 1,389 men and women born between 1922 and 1932 were recruited. The effects of plasma Se at baseline on mortality were determined. During the 9-year follow-up, 101 study participants died. Baseline plasma Se was higher in individuals who were alive at the end of follow-up than in those who died during the follow-up. Therefore, mortality rates were significantly higher in individuals with low Se [108]. Similarly, it was also shown that elderly women living in the community who have higher serum Se are at a lower risk of death [109]. It seems likely that low plasma Se may be an independent predictor of mortality among older adults living in the community. For example, 1,042 men and women 65 years of age or older were investigated in the Chianti region of Tuscany in Italy [110]. Plasma Se was measured at enrollment (1998, 1999, 2000), and vital status was ascertained until May 2006. During follow-up, 237 participants (22.7%) died. At enrollment, mean plasma Se concentrations among participants who survived or died were 0.96 and 0.87 μmol/L (P <0.0001), respectively. The proportion of participants who died, from the lowest to the highest quartile of Se, was 41.3, 27.0, 18.1, and 13.5% (P <0.0001). After adjusting for age, sex, education, and chronic diseases, adults in the lowest quartile of plasma Se at enrollment had significantly higher mortality compared with those in the highest quartile.

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Indeed, the Se status of elderly is related to quality of life. For example, recent results of a cross-sectional survey of 2,000 rural Chinese aged 65 years or older from two provinces in the People’s Republic of China support the hypothesis that a lifelong low Se level is associated with lower cognitive function [111]. In fact, in elderly cognitive decline was associated with decreases of plasma Se over time. Among subjects who had a decrease in their plasma Se levels, the greater the decrease in plasma Se, the higher the probability of cognitive decline [112].

4.5 Other Diseases Furthermore, an optimal Se status is shown to be beneficial in asthma, rheumatoid arthritis, cystic fibrosis, HIV, pancreatitis, brain, and neurodegenerative disorders [11]. Lower serum Se and RBC GSH-Px activity in epileptic patients compared to healthy children may support the proposed crucial role of Se and GSH-Px activity in the pathogenesis of epilepsy [113]. The prevalence of Se deficiency was significantly higher in goitrous boys and girls than nongoitrous children in Iran [114]. Data obtained by Puchau et al. [115] suggested a possible role for Se intake in the decrease of serum complement factor 3, whose may be an early marker of metabolic syndrome manifestations and inflammatory-related features. Recently it was shown that low serum Se is independently associated with anemia among older women living in the community [116]. Selenium deficiency is a risk factor, due to the malabsorption, in celiac disease because the inflammatory damage affects the small intestine; this deficiency can modulate SeP genes expression, with consequent reiteration of inflammation and increase of mucosal damage [117]. Furthermore, increased Se status could substantially decrease negative effects of heavy metals [118].

5 Controversy Around Se Roles in Diabetes Roles of Se in diabetes development and treatment is a controversial area with animal model data supporting beneficial effect of Se while results of recent human trials showed that the Se supplementation of people having high Se status potentially could be detrimental. First, it has been suggested that enhanced production of free radicals and hyperglycemia-induced oxidative stress are central events to the development of diabetic complications [119, 120]. This suggestion has been supported by demonstration of oxidative stress in diabetic individuals suffering from complications. Indeed, chronic hyperglycemia can influence the generation of free radicals, which may lead ultimately to increased lipid peroxidation and depletion of antioxidants, and thereby enhanced oxidative stress in subjects with type 2 diabetes mellitus [121]. There are some evidences indicating lower activity of the SOD, the GPx, and the catalase in diabetes mellitus [122–124]. Therefore, it seems reasonable to expect that antioxidants could have a protective role in the improvement of diabetes. For example, a therapy with adjuvant antioxidants (100 μg of Se as sodium selenite and 600 mg of alpha-lipoic acid daily for 3 months) leads to a regression of diabetic late complications [125]. Indeed, Se was shown to play an important role in reducing the oxidative stress (plasma TBARS and serum urinary albumin

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excretion rates) associated with diabetes. The effect of oral administration of sodium selenite on streptozotocin (STZ)-induced diabetic mice was studied [126]. Diabetes caused hyperglycemia (2.8-fold increase) with a significant increase in the MDA levels (89% in liver and 83% in blood) and glutathione S-transferase (GST) activity (55%) and marked decreases in GSH levels (approximately 73% in blood and 79% in liver) in the fifth week after STZ treatment as compared to normal control animals. Treatment of STZ-induced diabetic mice with sodium selenite significantly reduced oxidative stress changing aforementioned parameters to near control values in almost all cases. Similar results have been obtained recently with the same model of STZ-induced diabetic rats [127]. It was concluded that Se augmented the antioxidant defense by increasing GSH-Px activity and this effect was more prominent when Se was supplemented as SeMet, which exerted positive effects also on glucose homeostasis. The effects of four different preparations of inactivated yeast containing various concentrations of Se and glutathione on a combined atherosclerosis and diabetes hamster model were evaluated [128]. The hamsters were supplemented with the yeast products for 3 months. The enriched yeast with the highest Se and glutathione levels reduced the weight loss induced by diabetes, inhibited an increase in plasma cholesterol and triglyceride caused by a high-cholesterol and high-fat diet, increased the time taken for oxidation of lower density lipoproteins (lag time), and inhibited the formation of atherosclerosis better than low Se/glutathione yeast supplementation. It has been shown that synthetic organo-Se compound diphenyl diselenide at high dose of supplementation (10 ppm) was protective against the development of SPT-induced diabetes in rats by exhibiting antioxidant properties [129]. Furthermore, treatment of diabetic rats with sodium selenite had beneficial effects on both antioxidant system and the ultrastructure of the liver tissue. In an experiment conducted in Turkey, both diabetic and normal rats were treated with sodium selenite (5 μmol/kg/d, intra peritoneally) for 4 week following 1 wk of diabetes induction. This treatment of diabetic rats improved significantly diabetes-induced alterations in liver antioxidant enzymes [130]. Moreover, treating diabetic rats with sodium selenite prevented primarily the variation in staining quality of hepatocytes nuclei, increased density and eosinophilia of the cytoplasm, focal sinusoidal dilatation and congestion, and increased numbers of mitochondria with different size and shape. From the one hand, lower Se levels in the biological fluids of the diabetic patients as compared with non-diabetic subjects have been shown [95, 131, 132]. For example, recently, the association between serum Se levels in patients with gestational diabetes mellitus (GDM) and glucose intolerants and compare them with those of glucose-tolerant pregnant women has been investigated [133]. Patients with gestational diabetes mellitus and those with glucose intolerants had significantly lower Se level than that of the normal pregnant women. There was also a significant inverse correlation between Se and blood glucose level. The authors concluded that Se supplementation might prove beneficial on patients with GDM and prevent or retard them from secondary complications of diabetes. On the other hand, the decrease in hyperglycemia and the improved glucose tolerance have been observed in patients supplemented with Se [134, 135]. Furthermore, the long-term administration of Se and the decrease in diabetic renal lesions have been observed in the experimental rats [136]. It has been hypothesized that Se treatment will reduce proliferation, restore physiology, and correct increased proliferation signaling of diabetic aorta [137]. Diabetes was induced by streptozotocin and rats were then treated with sodium selenate (15 μmol/kg body weight/day) for 4 weeks. The data from diabetic rats showed an increase in proliferation rate and matrix metalloproteinase activity in aortic cell cultures. There are

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significant changes in enzymatic activities rat aorta homogenates. Selenium treatment resulted in complete normalization of the above parameters to control level. The authors suggested that Se treatment of diabetics can play beneficial role in protecting vascular architecture and function against diabetes-induced pathology. Glutathione peroxidase (GSH-Px) and Se were assessed in type 2 diabetes mellitus patients with microalbuminuria (MA) (group 1), without microalbuminuria (group 2), and in control subjects (group 3; [138]). Control group showed higher serum Se concentrations as compared to the diabetic groups and two groups of diabetic patients showed similar serum Se levels. Serum activity of GSH-Px was significantly lower in group 1 as compared to groups 2 and 3. Microalbuminuria (MA) test (an early marker of renal disease) showed a positive correlation with glucose, and a negative relationship with serum Se and GSH-Px and multiple regression revealed an inverse relationship between Se or GSH-Px in serum and the results of the MA test. The authors concluded that lower Se levels and GSH-Px activities in diabetic patients may be implicated in the diabetic nephropathy. Human umbilical vein endothelial cells (HUVECs) were pretreated with Se and stimulated by high glucose or high insulin by Zheng et al. [69]. The results suggested that Se can inhibit high glucose- and high insulin-induced expression of adhesion molecules. Such antagonism is at least partially mediated through the modulation of p38 pathway. Selenium showed insulin-mimic properties in vitro and in vivo [139] restoring glucose and glycogen concentrations affected by diabetes. In particular, it has been shown that selenite treatment of diabetic mice with an effective dose is beneficial for the antioxidant system of liver and brain, although it exerts a toxic effect on the liver of normal mice [140]. Indeed, selenite treatment for diabetic mice reduced the TBARS levels in red blood cells (RBC) compared to the normal and significantly improved GSH-Px activity in RBCs compared to the diabetic control. Similarly, intraperitoneally administered vitamin E and Se to rats had significant protective effects on the blood, liver, and muscle against oxidative damage of diabetes [141]. To investigate whether sodium selenite treatment would impact on the onset of diabetes, various serum biochemical indexes were investigated in diabetic and non-diabetic conditions of non-obese diabetic (NOD) mice [142]. It was shown that Se treatment induced insulin-like effects in lowering serum glucose level in NOD mice. Se-treated mice had significantly decreased serum biochemical components associated with liver damage and lipid metabolism. Furthermore, Se treatment led to the activation of the endoplasmic reticulum stress signal and Se-treated mice were significantly relieved apoptosis of liver tissues indicated by DNA fragmentation assay in the diabetic NOD group. The authors concluded that Se compounds not only serve as insulin-like molecules for the down-regulation of glucose level and the incidence of liver damage but may also have the potential for the development of new drugs for the relief of diabetes. There was a comparative study of efficacies of inorganic and organic Se compounds in reducing glucose synthesis in hepatocytes and renal tubules which are significantly contributing to the glucose homeostasis [143]. It was shown that both selenite and methylselenocysteine inhibited renal gluconeogenesis by about 40–45% in control rabbits. Selenate did not affect this process, whereas selenomethionine inhibited gluconeogenesis by about 20% in both hepatocytes and renal tubules. In general, results indicated that Se supplementation might be beneficial for protection against diabetes-induced nephrotoxicity. Recent results of Zeng et al. [144] suggested that the hypoglycemic role of Se may relate with its inhibiting effect on augmentation of pro-inflammatory cytokines and reactive

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oxygen species/reactive nitrogen species by streptozotocin inducing in the pancreas of diabetic mice. Therefore, from aforementioned studies it can be concluded that Se may be considered as a potential preventive intervention for diabetes-accelerated atherosclerosis. However, recently, Stranges et al. [145] have reported findings from the Nutritional Prevention of Cancer (NPC) trial that show an increased risk for diabetes among participants randomly assigned to receive supplements with 200 μg of Se daily for 7.7 years compared with placebo. This effect was largely limited to participants in the top tertile of plasma Se level at baseline (>121.6 ng/mL). The author clearly indicated limitations of their findings. First, the incidence of diabetes was not a primary end point of the NPC trial. Therefore, the findings must be interpreted cautiously because they result from exploratory analyses. Second, diagnosis of type 2 diabetes was self-reported, which may have led to some misclassification (under diagnosis) at baseline or during the trial. Third, detailed information on unmeasured risk factors at baseline, such as family history of diabetes, body fat distribution, and physical activity, were lacking. Fourth, the NPC sample consisted of elderly individuals (mean age 63.2 years) from low Se areas in the eastern United States who had a history of nonmelanoma skin cancer. The generalizability of these findings to other groups may therefore be limited. Finally, the authors cannot rule out the role of chance in their findings. For example, a few more cases of diabetes in the placebo group would attenuate the main effect of Se treatment and produce null findings. It is worth mentioning that in the SELECT trial which was prematurely stopped in October 2008 there were statistically nonsignificant increased risks of type 2 diabetes mellitus in the Se group (relative risk 1.07; 99% CI 0.94– 1.22; P = 0.16) but not in the Se+ vitamin E group [42]. It could well be that oxidation products of SeMet are responsible for oxidative stress and possibly diminished protective effect of Se. Combining SeMet with vitamin E overcomes that problem and the trend for diabetes promotion disappeared. A similar conclusion was drawn by Bleys et al. [146] suggesting that in a probability sample of the US population, high serum Se levels were positively associated with the prevalence of diabetes. It is interesting that in this study mean serum Se levels in participants with and without diabetes were 126.5 and 125.7 ng/mL, respectively. Taking into account a precision of Se determination which is giving variability in a range of 1–5% (which means 1–5 ng/mL) it is clear that conclusions from such small differences have limited value. Furthermore, there are no clear mechanisms described which could without doubts explain detrimental effect of Se on diabetes development. For example, the mechanisms of such Se action suggested by Bleys et al. [147] include pro-oxidant properties of Se, its possible accumulation in pancreas, and effect of ROS on insulin resistance. However, pro-oxidant properties of Se are not characteristic for Se-yeast, Se accumulation in pancreas is not necessary to cause a toxicity, and Se-proteins can decrease ROS production and decrease insulin resistance and improve pancreatic cell function. Indeed, Se and diabetes relationship needs further study, since, a sub-study of the Health Professionals Follow-up Study found an inverse association between toenail Se levels and the prevalence of diabetes at baseline [148]. Furthermore, a study of Asian persons residing in Singapore found similar mean serum Se levels among participants with and without diabetes [149]. Taking into account the fact that Se levels in plasma of European residents are substantially lower than in American residents it would be desirable to increase Se status of Europeans and various approaches to solve this problem exist. It is always important to access Se benefit (e.g., cancer-preventing properties) against possible side effects described above and make a decision as for strategy to optimize Se status.

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6 Different Strategies to Address Se Deficiency in Human In aforementioned cancer-related trials it has been shown that, ideally, increasing Se consumption to have Se concentration in the blood >121 μg/L would be a way to address Se deficiency issues and simultaneously provide natural protection against cancer. Indeed, in the cancer-preventing trial run by Clark et al. [150] those participants with baseline Se level in plasma above 121 ng/mL did not benefit from extra Se supplementation. Therefore, there are two main approaches to address cancer-preventing properties of Se: • Pharmacological, associated with usage of Se supplements at about 200 μg/day for a long period of time. • Nutritional, based on consumption of Se-rich food to reach Se level in the blood >121 μg/L and give the body an option of effective fighting against cancer. Based on recent findings and failure of SELECT trial it seems likely that nutritional approach in future will be the main direction in Se medical applications. Since Se content in plant-based food depends on its availability from soil, the level of this element in human foods varies among regions. When considering ways to improve human Se intake, there are several potential options. These include • • • •

direct supplementation soil fertilization supplementation of food staples such as flour Production of Se-enriched eggs, meat, and milk as well as Se supplements in tablet/ capsular form

Se-containing supplements in tablet or capsular form are available through healthy shops. It is interesting to mention that over 158 million Americans regularly consume dietary supplements to maintain and/or improve their health and consumer expenditures on dietary supplements (alone) reached a reported $20.5 billion in sales in 2004, more than double the amount spent in 1994 [149]. In fact, more than 1% of the US population take Se supplements, and more than 35% take multivitamin and multimineral supplements [152] that often contain Se. Furthermore, table salt fortified with 15 mg/kg sodium selenite was used as a daily Se supplement to reduce the incidence of primary liver cancer in Se-deficient areas of China [153]. However, since Se in high doses could be toxic and selenite is not the optimal form of Se dietary supplementation, this approach is limited to the specific areas of China and did not find a great support in other countries. Soil Se availability is dependent on both Se content and soil composition. Low crop Se content owing to low soil pH is quite common situation in various countries all over the world. Furthermore, usage of synthetic fertilizers containing sulfur (S) and phosphorus (P) substantially decreases Se availability as a result of competition between these minerals at the site of Se absorption by plants. For example, in Finland the availability of soil Se for plants is poor owing to the relatively low Se concentration, low pH, and high iron content of the soil. In areas where soil Se content is low (Finland and New Zealand) sodium selenate was added to fertilizers used for both grain and forage production [11]. Therefore, since 1984 multimineral fertilizers have

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been supplemented with Se (16 mg/kg to fertilizers for grain production and 6 mg/kg to those for fodder production) in the form of sodium selenate. The supplementation affected the Se content of all major food groups with the exception of fish. As a result, there was a rapid increase in the Se content of the crops and the foodstuffs derived from animals consuming the crops, as well as the human Se status was improved. In particular, recently there was a workshop devoted to 20-year experience in Se fertilization in Finland [154]. Twenty years of research and practical applications showed the following: • Only about 10% of the added Se was utilized by plants. • Se level in grains significantly increased, and this was associated with increased Se concentrations in eggs, milk, and meat. However, variability of Se concentration in grains and animal produce is quite high. Indeed, pH soil and variability of sulfur concentration are main reasons for this. • There was no effect of the Se fertilization on rates of heart diseases and cancer in Finland. • It was difficult to prove the Se accumulation in soils after 20 years Se fertilization. The main problem was the technical difficulties with analysis as well as a high variability in the Se concentration in the soil. • There was no research on the effect of the Se fertilization on the microbial population of soil, which could be the biggest obstacle for wider usage of the technology worldwide. This approach has been successful in Finland and New Zealand, but has had limited application in other countries because of environmental issues. For example, in the, the use of Se fertilizers caused run off of the element, resulting in its accumulation in the aquatic biota [155]. Furthermore, even in Finland, simultaneous increase of total nitrogen, phosphorus, and Se levels in consecutive samples from some groundwater pools indicated leaching of Se from the fertilizers into the groundwater in certain areas [156]. As mentioned above, by adding inorganic Se into the soil there is a risk of changing microbial population of the soil which could have longterm consequences. It is a great surprise that Finish authorities went ahead with this technology in all the country without answering this important question. Indeed, it could be considered as an example when practice went ahead of science. The most recent paper by Haudin et al. [157] confirmed that Se introduced into the soil can modify its microbial population. Indeed, there is a need for more research in this area to answer those important questions before the technology could be used to improve the Se status in other countries. Supplementation of staple foods such as bread flour is another approach to improve Se status of the human population (Rayman, 1997). Alternatively, Se-enriched yeast may be used to produce bread. This approach deserves close consideration owing to its practical ability to reach wide segments of the population and previous success with other trace element deficiencies such as iron. For example, in China Se-enriched wheat flour is produced by its fortification with an Se-enriched mushroom extract [158]. In February 2005 Se-enriched bread, produced from grains grown on Se-fertilized soil, was lunched through Waitrose stores in the UK, however, it has not sold enough to stay on the shelf and was withdrawn. The firm behind the product, agritechnologist group Nutrilaw, blames a lack of consumer awareness of the role of Se in health. Indeed, customer education is an essential part of the Se-enriched product marketing. A fourth strategy is production of Se-enriched eggs, meat, and milk as “functional foods” enriched with Se already found its way to the supermarket shelves in various countries worldwide [11, 159].

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7 Conclusions Selenium plays an important role in health maintenance, and optimization of Se status of general population is an urgent task for many countries worldwide. In this respect European Se status is shown to be low. It is a result of low Se availability from European soils. Indeed, low soil pH and high concentrations of S and P due to fertilization decreased dramatically Se availability for plants. This results in low Se concentrations in grains and in animal-derived products (grains are major feed ingredients for poultry and pigs and also used in dairy and beef production) and ultimately in human diet. Supplementing animal diets with Se in the form of sodium selenite or selenate does not affect substantially Se concentration in eggs, meat, and milk. Indeed SeMet represents the major form of Se in animal-derived foods, but chickens, pigs, or cows cannot synthesize SeMet, it must be provided with diets. There are different ways of solving Se deficiency problems, but production of Se-enriched eggs, meat, and milk is considered to be most promising. In this respect production and commercialization of Se-enriched yeast is a critical step in this direction. Furthermore, warning about possible detrimental effects of Se access would not be valid for European population consuming Se-enriched eggs, meat, and milk, since they would not be able to reach that Se levels which are considered to be excessive.

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Chapter 26

Homocysteine: Role in Cardiovascular Disease Arash Sabetisoofyani, Douglas F. Larson, and Ronald Ross Watson

Key Points • Elevated plasma levels of homocysteine are associated with atherosclerosis and cardiovascular ischemic events. • Hyperhomocysteinemia (HHcy) is an independent risk factor for ischemic heart disease, stroke, hypertension, arrhythmia, and peripheral vascular disease. • Some factors induce elevation of homocysteine concentration such as mutations in the enzymes responsible for homocysteine metabolism: cystathionine β-synthase (CβS) or 5,10methylenetetrahydrofolate reductase, nutritional deficiencies in B vitamin cofactors required for homocysteine metabolism; vitamin B6 (pyridoxal phosphate), vitamin B12 (methylcobalamin), and folic acid. • Studies using animal models of genetic- and diet-induced HHcy have recently demonstrated a causal relationship between hyperhomocysteinemia, endothelial dysfunction, and accelerated atherosclerosis. Keywords Homocysteine β-synthase

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5,10-methylenetetrahydrofolate

reductase

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Cystathionine

1 Introduction Clinical study shows majority of deaths in industrial countries from cardiovascular disease (CVD). Cardiovascular diseases are determined by genetic and environmental factors and by gene–gene and gene–environment interactions [1]. Vascular diseases are commonly associated with traditional risk factors (high blood pressure, high total or low-density lipoprotein and low

R.R. Watson () College of Medicine, Sarver Heart Center, The University of Arizona, Tucson, AZ 85724, USA; College of Public Health, The University of Arizona, Tucson, AZ 85724, USA e-mail: [email protected] F. De Meester et al. (eds.), Modern Dietary Fat Intakes in Disease Promotion, Nutrition and Health, DOI 10.1007/978-1-60327-571-2_26, © Springer Science+Business Media, LLC 2010

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high-density lipoprotein cholesterol levels, high triglyceride levels, smoking, obesity, diabetes) but only 50% of CVD can be explained by classical risk factors. In the last decade other risk markers have been identified, one of them being homocysteine [2]. Up to 40% of patients diagnosed with premature coronary artery disease, peripheral vascular disease, or recurrent venous thrombosis present with HHcy [3]. The increasing interest in HHcy as a risk factor for cardiovascular diseases is based on the observation that a rare inborn metabolic error, homocystinuria, leads to severe HHcy (>150 μmol), atherosclerosis, and arterial or venous thromboembolic events in early adulthood or even in childhood [4]. Homocystinuria is a rare autosomal recessive condition marked by major alterations in the homocysteine concentrations in plasma (>100 μmol/L), which is 10 times that found in healthy subjects. The usual cause of homocystinuria is CBS deficiency, which has an incidence of 1:200,000. Other rarer causes include severe methylenetetrahydrofolate reductase deficiency and cobalamin (B12 ) processing defects [5]. McCully [5] first postulated that mildly elevated homocysteine concentrations could increase the risk of cardiovascular disease [5]. A few years later, Wilcken reported that patients with coronary artery disease (CAD) showed a high concentration of homocysteine [58]. This has led to many studies on mild hyperhomocysteinemia as a risk factor for coronary and cerebrovascular disease. The results suggested that elevation of tHcy concentration (>15 μmol) is associated with a risk of myocardial infarction, peripheral arterial disease, and venous thrombosis. Some epidemiological studies have demonstrated that increased concentrations of plasma total homocysteine (tHcy) are an independent risk factor for ischemic heart disease, stroke, and peripheral vascular disease [6–9]. However, prospective studies show that elevations in the tHcy concentration may be an important risk factor in these subjects for a recurrent CHD event. Many authors doubt whether relationship between homocysteine and CVD exists [10–13].

2 Homocysteine Metabolism Hcy is a sulfur amino acid that is formed by demethylation of methionine. Methionine, an essential amino acid, is activated to form S-adenosylmethionine (SAM). S-adenosylhomocysteine is formed when SAM donates the methyl group. S-adenosylhomocysteine is hydrolyzed to generate homocysteine and adenosine. Hcy can be degraded to cysteine through the transsulfuration pathway, which is mainly limited to cells of the liver and kidneys. The enzymes in this pathway, CβS and γ-cystathionase, are both dependent on pyridoxal-5 -phosphate, a biologically active form of vitamin B6 , as cofactor. Hcy can also be remethylated to methionine by the enzyme methionine synthase. This enzyme uses methylcobalamin (a biologically active form of vitamin B12 ) as cofactor. The methyl group for the latter reaction is donated by 5-methyltetrahydrofolate. This form of folate is produced by the enzyme 5,10-methylenetetrahydrofolate reductase. MTHFR in turn uses flavin adenine dinucleotide (a biologically active form of vitamin B2 ) as cofactor [14]. In an alternative remethylation pathway, which is also mainly restricted to the liver and kidney, betaine is used as the methyl donor by the enzyme betaine homocysteine methyltransferase. However, when methionine levels are low, Hcy is mainly metabolized via a methionine-conserving pathway.

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In most tissues, this involves remethylation of Hcy to methionine. These two pathways are coordinated by SAM, which is the sole source of methyl groups for all methylation reactions within the cell. S-adenosylhomocysteine (SAH) is rehydrolyzed thereby regenerating Hcy, which is then available to start a new cycle of methyl group transfer. Thus, high levels of Hcy are associated with reduced methylation potential, whereas folate and vitamin B12 increase this potential. Changes in the concentration of methionine in the body, particularly as a result of dietary intake of methionine, affect the rate of SAM synthesis, as well as the metabolism of Hcy. In physiological conditions, a balance between homocysteine formation and degradation is present, and about 50% is remethylated to methionine. Excess homocysteine is exported into circulation, causing elevated plasma or urine levels. In the circulation <1% homocysteine is present in the free form, while 10–20% of tHcy is present as homocysteine–cysteine mixed disulphide and homocysteine (the dimer of homocysteine), while the remaining 80–90% of homocysteine is protein bound. An overview of the homocysteine metabolism is presented in Fig. 26.1.

Fig. 26.1 Homocysteine metabolic pathways. Dietary methionine is converted to the methyl donor S-adenosylmethionine (SAM) and is demethylated to S-adenosylhomocysteine (SAH) and homocysteine [3]. In the transsulfuration pathway, homocysteine is converted to cystathionine by the enzyme cystathionine β-synthase (CβS) and the cofactor vitamin B6 (pyridoxal phosphate). Once formed from cystathionine, cysteine can be utilized in a number of cellular functions, including protein synthesis and glutathione (GSH) production. Homocysteine can also be remethylated through the folate cycle. This pathway requires the enzyme methionine synthase (MS) and vitamin B12 as well as the enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) and folic acid, which enter the cycle as tetrahydrofolate (THF). In liver and kidney, homocysteine is also remethylated by the enzyme betaine homocysteine methyltransferase (BHMT), which transfers a methyl group to homocysteine via demethylation of betaine to dimethylglycine (DMG)

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3 Determinants of Homocysteine Low levels of Hcy (5–15 μmol/L) are normally found in the plasma. Moderate elevations in the tHcy concentration refer to fasting plasma concentrations 15–30 μM, intermediate hyperhomocysteinemia refers to concentrations between 30 and 100 μM, and severe HHcy refers to concentrations >100 μM. Increasing age and male gender have been found to be associated with increased homocysteine concentrations [15]. In women, increasing Hcy is observed after menopause. Moderate HHcy is common in chronic alcoholics [16]. A recent study has reported that tHcy concentration increases after consumption of red wine and spirits, but not after consumption of beer. The beverage specificity may be due to the high amount of folate and vitamin B6 in beer and negligible amounts of these vitamins in red wine and spirits. Some diseases, end-stage renal failure, proliferative disorders, inflammatory bowel disease, and hypothyroidism, have been associated with HHcy [17–21]. Several drugs have been shown to increase plasma homocysteine, influencing folate and vitamins B6 and B12 absorption. Genetically determined functional deficiencies of enzymes in homocysteine metabolism have an extremely large impact on the tHcy concentration. In the general population, these inborn errors of homocysteine Table 26.1 Factors that influence plasma homocysteine levels [2]

Age/sex/lifestyle Increasing age Male gender Postmenopause Lack of exercise Smoking Dietary Folate deficiency Vitamin B12 deficiency Vitamin B6 deficiency Alcohol consumption Coffee intake Disease Kidney dysfunction Inflammatory bowel disease Hypothyroidism Essential hypertension Diabetes Psoriasis Cancer Kidney transplantation Drugs Folate antagonistic drugs (methotrexate, anticonvulsant, carbamazepine, fenytoine) Vitamins B12 and B6 antagonistic drugs (nitrates, theophylline, estrogenic hormones) Genetics Cystathionine β-synthase deficiency Inborn errors of folate metabolism Inborn errors of cobalamin absorption, transport, and metabolism Polymorphisms of folate and cobalamin metabolism genes

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metabolism are not important because they are too rare; homozygous CβS deficiency, which is the most common inborn error in homocysteine metabolism (prevalence 1:335,000). The principal factors that can influence tHcy levels are summarized in Table 26.1.

4 Homocysteine and the Risk of Coronary Heart Disease HHcy is a risk factor for cardiovascular, thrombotic, neurodegenerative, and pregnancyassociated diseases [22–24]. Many studies using animal models and human subjects have demonstrated that HHcy induces endothelial dysfunction [25]. Impairment of endothelium-dependent relaxation during HHcy is similar to that of other risk factors such as hypercholesterolemia and hypertension [26]. Homocysteine levels relate with functional capacity in heart failure patients [27]. In a cross-sectional study analyzing 75 end-stage renal disease patients and 57 controls, Blacher et al. [64] reported a positive correlation between Hcy and the cardiac mass index (r =0.31, p < 0.01). Hcy was also correlated with left ventricular end-diastolic diameter (LVEDD), posterior wall thickness, and the diameter of the interventricular septum. Prospective data from the community-based prospective Framingham Study [65], analyzing 2,491 adults, demonstrated an increased incidence of CHF in individuals with a Hcy level >11–12 μmol/L. In multivariate analyses controlling for established risk factors for CHF including the occurrence of myocardial infarction during the follow-up, Hcy levels above the sex-specific median value were associated with an adjusted hazard ratio for CHF of 1.93 in men and 1.84 in women. Data from the European Concerted Action Project [37], a multi center study of 750 patients with vascular disease and 800 control subjects, confirmed that HHcy is associated with an increased risk of vascular disease. This risk was independent of, but multiplicative to, other risk factors, such as smoking and hypertension, and additive to hypercholesterolemia [28]. Cesari et al. observed an inverse relation of Hcy and EF in hypertensive patients [29] Moreover, Hcy significantly predicted cardiovascular mortality in hypertensives. An independent relation between Hcy and EF has also been reported in patients with angiographically defined CAD [30]. Data from the Framingham Study revealed significant associations of Hcy with left ventricular mass and left ventricular wall thickness in women, but not in men [31]. Hyperhomocysteinemia has been observed in patients with athermanous renal artery stenosis [32] and was significantly associated with non-traditional risk factor, i.e., lower glomerular filtration rate in CAD patients [33]. Other studies reported an association between elevated plasma homocysteine levels and carotid intimal-medial wall thickness [34, 35]. A prospective study of plasma homocysteine and the risk of myocardial infarction in 14,916 US physicians revealed a relative risk for myocardial infarction of 3.4 when homocysteine levels were in the 95th percentile of control values, compared with those below the 90th percentile. This risk was independent of other CAD risk factors [36]. A meta-analysis of 16 prospective studies, with a total of 3,820 subjects, showed that 5 μmol increments in homocysteine concentration were associated with a 32% increase in MI risk and a 59% increase in stroke risk [42]. The relationship between HHcy and clinical course after percutaneous coronary angioplasty has been investigated with contrasting results. Data from 205 patients with of at least one coronary vessel indicated homocysteine as a predictive risk factor for restenosis [37].

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5 Pathogenic Mechanisms of HHcy The mechanisms by which HHcy induces endothelial dysfunction have been defined. However, one consistent finding is impairment of vasodilation mediated by nitric oxide. Nitric oxide is a vasodilator that is produced by nitric oxide synthase (eNOS) and is a major mediator of endothelium-dependent relaxation. Nitric oxide synthase (eNOS) synthesizes nitric oxide (NO) and citrulline from L-arginine. NO regulates vessel tone, inhibits platelet activation, adhesion, and aggregation, limits smooth muscle cell proliferation, and modulates endothelial leukocyte interaction. Expression of eNOS is not decreased during HHcy. HHcy decreases nitric oxide bioavailability through alternative mechanisms, such as accelerated oxidative inactivation of nitric oxide. Excess homocysteine is not totally neutralized by nitric oxide and is auto-oxidized to homocysteine, producing free radicals toxic to endothelial cells. Homocysteine-induced oxidative inactivation of nitric oxide has been observed in vitro in cultured endothelial cells, and evidence for increased oxidative inactivation of nitric oxide during HHcy has been obtained in animals using both pharmacological approaches [38–41]. Several types of reactive oxygen species (ROS)—superoxide, hydrogen peroxide, and peroxynitrite—may contribute to the oxidative inactivation of endothelium-derived nitric oxide in HHcy [42]. Another potential mechanism for endothelial dysfunction during HHcy is inhibition of nitric oxide production caused by asymmetric dimethylarginine (ADMA), an endogenous eNOS inhibitor. In human subjects, plasma levels of ADMA increase after methionine loading and elevation of plasma ADMA correlates with impairment of endothelium-dependent relaxation [43]. Elevation of ADMA in HHcy may be caused by decreased catabolism of ADMA by dimethylarginine dimethylaminohydrolases, which hydrolyzes ADMA to citrulline and methylamines [44]. Homocysteine has several other properties that may adversely affect the endothelium. The highly reactive thiol group of homocysteine is readily oxidized to form ROS, suggesting that homocysteine induces cell injury through a mechanism involving autooxidation and oxidative damage. In fact, the homocysteine-dependent transsulfuration pathway is critical in the maintenance of the intracellular glutathione pools, and the regulation of this pathway is sensitive to oxidative stress conditions. Homocysteine-induced oxidative stress may impact atherogenesis by mechanisms unrelated to auto-oxidation. Various ex vivo studies using vascular tissues have implicated HHcy in causing abnormal vascular relaxation responses by inducing the intracellular production of superoxide [45]. Superoxide is believed to react with endothelial nitric oxide to yield peroxynitrite. Both superoxide and peroxynitrite contribute to the modification of tissues, resulting in the generation of lipid peroxides and in the case of peroxynitrite, the modification of proteins by tyrosine nitration and the formation of 3-nitrotyrosine. The recent findings that heme oxygenase-1 (HO-1) and glutathione peroxidase (GPx) expression and activity are impaired in cultured vascular endothelial cells [46]. This is particularly relevant to atherothrombosis given that HHcy increases vascular dysfunction in GPx-deficient mice. Excess homocysteine may be converted to the thioester homocysteine thiolactone, and its association with LDL produces atherogenic oxidative damage to the endothelium. A recent report has shown that Hcy-thiolactone levels are elevated in human CBS- and MTHFR-deficient patients [47]. HHcy can directly impair DNA methylation, resulting in altered gene expression, which may affect both the endothelial and the smooth muscle cells of the vascular wall. Several reports suggest that homocysteine induces proliferation of the vascular smooth muscle cells, leading to luminal narrowing. Moreover, excess homocysteine may promote inflammation and

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subsequently atherosclerosis. In fact, homocysteine activates NF-κB, inducing expression of monocyte chemoattractant protein 1 and interleukin 8 [48, 49]. Given that apoptosis has been widely documented to occur in animal and human atherosclerotic lesions and that apoptotic cell death and ER stress are increased in atherosclerotic lesions from mice fed hyperhomocysteinemic diets, it is possible that homocysteine-induced ER stress could adversely affect the stability and/or thrombogenicity of atherosclerotic lesions [50]. It has been reported that homocysteine induces endothelial cell detachment and causes apoptotic cell death via a detachment-mediated process [51]. Homocysteine increases vascular intimal-medial thickness, produces endothelial cell desquamation, and increases monocyte adhesion to the vessel wall. Smooth muscle vascular cells have a redox-sensitive homocysteine receptor that regulates collagen expression. The redox state of these cells is controlled by receptors of NF-κB that are induced by homocysteine. In turn, NF-κB may contribute to the mitogenic effect of homocysteine by activating cyclin D1 expression, thereby leading to a marked increase in vascular smooth muscle proliferation. Smooth muscle cells remodel the existing and new extracellular matrix, and it has been suggested that homocysteine induces constrictive collagen remodeling. Alternatively, it was suggested that HHcy induces reduced vascular elastic compliance through diminution in the vascular elastin/collagen ratio and activation of elastinolytic gelatinase A. Also, homocysteine has been shown to block aldehyde groups in elastin, thereby inhibiting the cross-linking necessary to stabilize elastin. Consequently, a reduced elastin/collagen ratio is expected to contribute to impairment in the vascular structure and increased systemic vascular resistance. Hcy is the only thiol that suppresses the generation of other thiols, and activates the MMPs and inactivates the TIMPs, causing a decrease in eNOS bioavailability [52]. Therefore, to reduce the load by dilating the heart in the absence of eNOS, latent resident MMPs are activated [53]. This activation increases interstitial edema and degrades elastin and ultrastructural collagen. Interestingly, because elastin turnover is lower than collagen turnover, the degraded elastin is replaced with stiffer oxidized collagen (fibrosis). Consequently, LV (left ventricle) wall stress is increased, causing alterations in ECM (extra cell matrix) that induces endothelial–myocyte uncoupling and impaired diastolic relaxation.

6 Hcy and Vitamins Homocysteine can be lowered by supplementation with folate and vitamins B6 and B12 [54]. Supplementation with these vitamins is inexpensive, safe, and effective in normalizing HHcy [55]. In patients with markedly increased homocysteine levels, vitamin treatment was associated with a decrease in CVD risk in a controlled trial [56]. Some authors suggest that such a correction of elevated homocysteine levels could reduce the relative risk of CVD by approximately 10% in the general population and up to 25% in high-risk groups [57]. Recent studies suggest that homocysteine levels may increase secondary to the occurrence of CVD and/or due to the presence of atherosclerosis. HHcy may also be secondary to myocardial infarction or stroke [58, 59]. Folate is associated with an alteration in vascular reactivity without any change in homocysteine concentrations [60, 61]. In addition, B vitamins were shown to reduce homocysteine without improving endothelial dysfunction or hypercoagulability [62]. Regular fruit and vegetable intake may have only a moderate impact on elevated homocysteine levels. Some authors recommend supplementation with vitamins (e.g., 200–800 μg folate, 3–30 μg vitamin B12 , and 2–6 mg vitamin B6 )

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for patients with manifest CVD or high CVD risk (hypertension, dyslipidemia, diabetes, smoking, family history of premature atherosclerosis), with hyperhomocysteinemia (>12 μmol/L), and for populations at high risk for vitamin deficiency, in order to target serum homocysteine <10 μmol/L [63]. The American Heart Association recently states as part of its diet and Lifestyle recommendations “Available evidence is inadequate to recommend folate and other B vitamin supplements as a means to reduce CVD risk at this time.”

7 Conclusion Homocysteine is associated with a risk of cardiovascular and cerebrovascular diseases and venous thrombosis. Several cellular mechanisms have been proposed to explain the effects of HHcy on endothelial dysfunction and atherosclerosis, including induction of proinflammatory factors, oxidative stress, and ER stress. Animal models of HHcy have demonstrated a causal relationship between HHcy, endothelial cell dysfunction, and accelerated atherosclerosis. In addition, there is currently no evidence that homocysteine-lowering therapy has a beneficial effect on CVD risk. Current epidemiological evidence does not provide strong evidence that elevation in the tHcy concentration is harmful in healthy subjects. More prospective, double-blind, randomized studies, including folate and vitamin B interventions, and genotyping for polymorphisms in genes involved in homocysteine metabolism might better define the relationship between mild hyperhomocysteinemia and vascular damage. Physiopathological and follow-up studies on the evaluation of therapeutic interventions in improving atherogenic profile, lowering plasma homocysteine levels, and preventing vascular events have not yet shown uniform results. An efficacy analysis from the Vitamin Intervention for Stroke Prevention Trial, limited to patients most likely to benefit from the treatment, has shown that higher doses of B12 , in addition to other therapies, such as betaine and thiols, will lead to optimal reduction of tHcy. Larger population studies might probably help in demonstrating that lower plasma homocysteine levels, due to folate and vitamins B6 and B12 oral supplementation, may lead to a lower rate of coronary and cerebral ischemic. However, whether lowering Hcy levels by administration of folate and vitamins B6 and B12 is associated with any significant decrease in vascular risk remains the subject of ongoing debate.

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53. Di Simone N, Maggiano N, Caliandro D, Riccardi P, Evangelista A, Carducci B, Caruso A. Homocysteine induces trophoblast cell death with apoptotic features. Biol Reprod 2003; 69: 1129–1134. 54. Mujumdar VS, Aru GM, Tyagi SC. Induction of oxidative stress by homocyst (e) ine impair endothelial function. J Cell Biochem 2001; 82: 491–500. 55. Hunt MJ, Aru GM, Hayden MR, Moore CK, Hoit BD, Tyagi SC. Induction of oxidative stress and disintegrin metalloproteinase in human heart end-stage failure. Am J Physiol 2002; 283: L239–L245. 56. Starkekbaum G, Harlan J. Endothelial cell injury due to copper-catalyzed hydrogen peroxide generation from homocysteine. J Clin Invest 1986; 77: 1370–1376. 57. Visioli F, Smith A, Zhang W, Keaney JF Jr, Hagen T, Frei B et al. Lipoic acid and vitamin C potentiate nitric oxide synthesis in human aortic endothelial cells independently of cellular glutathione status. Redox Rep 2002; 7: 223–227. 58. McCully KS, Wilson RB. Homocysteine theory of arteriosclerosis. Atherosclerosis 1975; 22: 215–227. 59. Ueland PM, Refsum H, Beresford SA, Vollset SE. The controversy over homocysteine and cardiovascular risk. Am J Clin Nutr 2000; 72(2): 324–332. 60. Egerton W, Silberberg J, Crooks R, Ray C, Xie L, Dudman N. Serial measures of plasma homocyst (e) ine after acute myocardial infarction. Am J Cardiol 1996; 77(9): 759–761. 61. Verhoef P, Stampfer MJ, Buring JE, Gaziano JM, Allen RH, Stabler SP et al. Homocysteine metabolism and risk of myocardial infarction: relation with vitamins B6, B12, and folate. Am J Epidemiol. 1996; 143(9): 845–859. 62. Hirsch S, Ronco AM, Vasquez M, de la Maza MP, Garrido A, Barrera G et al. Hyperhomocysteinaemia in healthy young men and elderly men with normal serum folate concentration is not associated with poor vascular reactivity or oxidative stress. J Nutr 2004; 134(7): 1832–1835. 63. Hirsch S, de la Maza P, Mendoza L, Petermann M, Glasinovic A, Paulinelli P et al. Endothelial function in healthy younger and older hyperhomocysteinemic subjects. J Am Geriatr Soc 2002; 50(6): 1019–1023. 64. 64.Blacher J, Demuth K, Guerin AP et al. Association between plasma homocysteine concentrations and cardiac hypertrophy in end-stage renal disease. J Nephrol 1999; 12: 248–255. 65. Sundstrom J, Sullivan L, Selhub J et al. Relations of plasma homocysteine to left ventricular structure and function: the Framingham Heart Study. Eur Heart J 2004; 25: 523–530.

Chapter 27

Dietary Plant Extracts to Modify Effects of High Fat Modern Diets in Health Promotion Stefano Togni

Key Points • In healthy populations, a correct diet can prevent typical deficiency diseases, which almost disappeared in advanced Western societies; however, some forms of “non-deficiency malnutrition” are now well known and easily understandable, especially in high-fat modern diets. • Plant polyphenols and plant extracts in general may be employed as an effective tool to achieve an optimized nutrition. Keywords High-fat diets · Dietary plant extracts · Polyphenols · Optimized nutrition

1 Introduction: Diet and Our Health Why do we eat? The question may sound trivial; nevertheless, it is definitely a relevant one at the beginning of a chapter on nutrition and on the relationship between health and diet. We eat to keep our bodies in equilibrium or homeostasis, we eat to live, and living as everybody knows involves the balance between the intake of a certain supply of energy and the expenditure for the production of an amount of work. In addition to basal needs, nutrition is necessary to do our day-to-day functions, for example, to maintain the reproductive capability and last but not least to keep up our mood and social capabilities. Finally, we eat or, as we may say, we adopt a specific diet to try to avoid or reduce the risk of diseases, whenever and as far as we can. Looking at the etymology of the word “diet” in the dictionary, we find that it originates from a Greek word with the meaning of “life, lifestyle, way of living.” But the crucial point is that no diet exists that is capable of meeting all of the above-mentioned goals at the same

S. Togni () Indena SpA, Viale Ortles, 12, Milano, 20139 MI, Italy e-mail: [email protected] F. De Meester et al. (eds.), Modern Dietary Fat Intakes in Disease Promotion, Nutrition and Health, DOI 10.1007/978-1-60327-571-2_27, © Springer Science+Business Media, LLC 2010

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time for everyone. Just as an example, if the Mediterranean diet, on the one hand, is acknowledged to reduce the cardiovascular risk, on the other hand, it would not exactly fit the needs of an alpine mountaineer. Psychic as well as physical capabilities are nutritionally dependent, and to achieve best capability for athletic activities, an optimized daily nutrition is necessary. Athletes must adapt diet to the intensity of their physical burden and to changing environment conditions. The concept of a correct diet was developed in the twentieth century following a widened understanding of the biochemical processes involved in metabolism. The identification of the mechanisms and pathways of metabolism has defined the rules, indicating an optimal intake for proteins, fats, carbohydrates, as well as for vitamins, minerals, and other essential nutrients. Intake of the indispensable quantities (which have been determined on the basis of a careful evaluation of the needs, calculated on the average of normal, representative subjects) can certainly prevent all forms of deficiency diseases, that is, diseases directly connected to the lack of a specific dietary element. Basic knowledge and the consequent dietary indications have then resulted in the virtual disappearance of any typical deficiency diseases at least in the advanced Western societies—even if for some vitamins, in particular age groups such as elderly people, some benefits are still obtained from supplementation. The typical nutritional deficiencies causing scurvy, beriberi, and pellagra are now almost unknown in developed countries. For example, in Japan, the decline in the thiamine deficiency disease beriberi from a death rate of 25/100,000 in 1930 to 1/100,000 in 1955 was dramatic. In the United States, the niacin–tryptophan deficiency disease pellagra increased during the depression of the 1930s and then dropped rapidly and disappeared. In recent decades, in several countries, improvements in nutrition have brought rapid declines in mortality [1]. On the other hand, there is a growing awareness that even when the diet is not responsible for deficiencies, yet it may be involved in or even be the direct cause of the onset of diseases. To some extent the diet can be responsible for the speeding up of the ageing process. Some forms of “non-deficiency malnutrition” are quite well known and easily understandable, especially in high-fat modern diets increasing obesity in Western and newly developed countries being a clear example of the situation (Fig. 27.1). From undernutrition and deficiency we have shifted to overnutrition and malnutrition typical of high-fat modern diets, which anyway is still a form of malnutrition in all respect. But the problem is certainly still more complex.

2 The Response to Stress and “Nutrigenomics” All compounds we ingest, both nutrients and xenobiotics, affect in some way and to some extent our genetic expression. Such effect can usually be referred to as a “metabolic adaptation” to a specific sets of nutrients, but it may also be the reaction to substances perceived by the cells as extraneous or stressors. And it does not necessarily need to be a xenobiotic to elicit such “reactivity,” as nutrients may also activate such a response [2, 3]. Every individual responds in a unique way, whether the response is a healthy metabolic adaptation to the diet or a stress response [4]. Our cells, in fact, react differently to what we eat, according to each individual’s genetic set. Just like other responses to the environment, every individual has a particular way of responding to stimuli: exposure to sun may induce in some people a skin tanning, if less sensitive, in other it

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Levels of obesity in selected countries* 90 80 70

Percentage

Men

Women

60 50 40 30 20 10 0

Nauru

Samoa

USA

Chile

Germany

South Africa

Morocco

China

Fig. 27.1 The percentage of adults with obesity in industrialized and developing countries. Source: World Health Organization (2006) Global Health Atlas (http://apps.who.int/bmi/index.jsp)

may produce reddening. And all the responses to external factors, diet included, are determined largely by our own genetic profile. If we knew everything about our genes, and how they are overexpressed or underexpressed by the intake of specific nutrients and xenobiotics, we could reach a situation where we could be able to design a diet optimized for each individual and personalized to obtain the best results from its effect on health preservation. Optimal nutrition is, undoubtedly, a key factor that affects the physiological as well as the psychological functions of an individual. But an optimal nutrition for one person may not be an optimal nutrition for his relatives, his neighbors, or his friends. This casts doubts on all general dietary recommendations, because nutritional advices that could provide important benefits for large groups of the population may, conversely, prove to be unhealthy or even dangerous for other individuals. It has also been shown that some people respond dramatically to therapeutic diets, whilst others do not respond at all. Clearly for the non-responders, it is a waste of time coping with a change in diet, whereas for the hyper-responders, it is well worth the effort. Genetic screening could make it possible to match the right diet or food with the right individual. Nutrigenomics is the study of the molecular relationships between nutrition and the expression of genes, with the aim of extrapolating how such subtle changes can affect human health. This novel branch of science focuses on the effect of nutrients on the genome, the proteome, and the metabolome. By determining the mechanism of the effects of nutrients or the effects of a nutritional regime, nutrigenomics tries to define the relationship between specific nutrients and diets and human health. Although still in its infancy, nutrigenomics has been associated with the idea of personalized nutrition based on genotype [5]. “Nutrigenomics” might be an ugly neologism, but this science promises, in next decades, to help minimize the occurrence of chronic degenerative diseases and cancers through optimal nutrition, which can even be applied to the individual once the individual’s response to nutrients and xenobiotics is known.

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Although the majority of practical applications of nutrigenomics are just beginning to emerge, it is already clear that certain individuals with particular gene variants will have increased needs of specific nutrients in their diet, which will also result in changing the translation of the information in their genes. The impact of this dietary change on an individual’s gene expression may be an improvement in their potential disease prevention over a lifetime. Just as an example, one gene that has received considerable attention and around which there has been a great deal of research is the gene coding for the enzyme methylenetetrahydrofolate reductase (MTHFR). A certain variation of one nucleotide in the gene (i.e., single-nucleotide polymorphism, SNP) has been associated with the decreased ability of the body to metabolize folate. As a result, an individual with this polymorphism could experience high level of homocysteine in the blood (hyperhomocysteinemia), a condition associated with an increased risk for coronary artery disease. Individuals screened with this MTHFR gene variation may benefit from increased dietary intake of pyridoxine, folic acid, B12 . Through a better understanding of nutrition and genetic expression, we can be able to modulate the cell metabolism and to prevent the “stress reaction,” which is a sort of “cell response to an insult.” The stress reaction seems to be involved in most chronic degenerative diseases, where nutrition, in facts, plays a specific role. This detrimental type of response is then typically the target of natural substances—usually belonging to the family of polyphenols—able to modulate its magnitude (for example, by controlling the activation of production of oxidants) and consequences, for example, apoptosis.

3 Optimal Nutrition and “Nutraceuticals” If to date the possibility of attaining complete diet personalization should be considered no more than a goal that can only be achieved in the future with great efforts, the concept of optimal nutrition is already virtually applicable to populations or homogeneous groups. The concept of optimal nutrition arises from the convergence of information from basic biomedical science with epidemiologic data. The objective is to define the optimal consumed amount of a given diet component, on the basis of the observed reduction of the risk of a disease resulting from its consumption, which is supported by experimental evidence of the mechanism of action. This concept is an important evolution from the traditional principle, according to which the dose was defined by prevention of a deficiency syndrome and could be applied only to essential nutrients. Just as an example, a certain dose of vitamin C helps to prevent scurvy, which would strike all those who consume a lower dose, while higher dose could help reduce the risk of cardiovascular diseases or cancers, but only in those individuals who are particularly sensitive and subjected to some risk elements. In this case, the subject of the analysis can no longer be of the individual but of a population. Another major aspect of the concept of optimal nutrition concerns the importance that can, or better must, be devoted to some substances composing the diet, which are not typically nutrients and whose lack in the diet does not necessarily involve a deficiency syndrome. There also exists a semantic problem for these substances (of essentially botanical origin), because the term that defines them exactly—“phytochemical products”—is generally used to identify some pesticides, and we can imagine the consequences in terms of understanding. Another clumsy, albeit functional, neologism used to identify these compounds is “nutraceuticals,” an expression arising from the fusion of nutrients and pharmaceuticals.

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These are compounds, however, that may potentially have a great impact on the diet wholesomeness. The whole culture supporting the need of consuming more fruit and vegetables, green tea, or red wine—just to quote a few of the most popular examples—is the culture of these nutraceuticals. And this culture has been increasingly validated by concurrent information coming from epidemiology and biomedicine. Specific substances have been isolated, and studied in vitro, from wine, tea, vegetables, and have been found to possess such biological properties in vitro, so as to support the epidemiological concept of the greater healthfulness of diets consisting of foods that contain these substances. In any case, the concept of the difference in individual sensitivity should always be applied to all these substances and their mechanisms of action, which are quite often linked to the cell stress reaction to an insult. This is consistent with the fact that the result is of statistical nature and can be observed only in a population. Nutraceuticals can be active as such, and in this sense they seem to behave essentially like drugs, or as elements of a certain diet. Consuming different types of substances (with some of them having “protective” properties) simultaneously, in a single meal, increases the protective value attainable through separate consumption between meals, with the protection resulting from any possible harmful effects of other components of the meal being opposed immediately [6]. Interesting implications ensue from all this, generally in line with tradition and popular wisdom. Salad is traditionally combined with a usual meat dish containing fats, in the same way as sauerkraut is eaten with sausages or similar food, and tomatoes or paprika, onions, and carrots are added to stew and goulash during cooking. In the Eastern culture, fat and proteinaceous food is accompanied by green tea, while in our culture it is accompanied preferably by red wine. In all these associations, it is not hard to recognize a possibly harmful element—lipid oxidation products from meat, whose generation can be initiated by myoglobin—combined with a protective element, such as polyphenols and vitamin C. Thus protection takes place both during digestion and following absorption of the meal components.

4 The Role of Food Polyphenols The prevalence of aging-related diseases such as diabetes and cardiovascular disorders is dramatically increasing not only in the Western countries but all over the world. For example, incidence of diabetes is estimated to double by 2030 [7], while cardiovascular disorders appear to be more severe in developing countries, where mortality due to cardiovascular disease is increasing dramatically, in the wake of economic development and lifestyle changes [8]. From an epidemiological point of view, nutrition plays an important role in the pathogenesis of the most common diseases, but it also has to be considered that edible plants can concretely contribute to improve human health. Natural products in various forms have been used since the most ancient times for the treatment of pathological conditions or for health benefits all over the world. The use of plants has been reported in several ancient books dating back to thousands of years in Chinese, Indian, Egyptian, Greek, and Latin cultures, and many preparations are still used in several countries. All these considerations on nutraceuticals and optimal nutrition find a relevant example precisely in the case of vegetable polyphenols, which are not essential dietary elements (except for vitamin E, which is a particular type of essential hydroquinone), but their consumption has

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been found to be related to a reduced risk of chronic degenerative diseases and, perhaps, cancer. Polyphenols are widely distributed in plants and growing epidemiological evidence suggests the existence of a negative correlation between consumption of polyphenol-rich foods or beverages and the incidence of certain diseases. For example, grape polyphenols were demonstrated to play a key role in the prevention of cardiovascular disease and their multiple mechanisms of action for cardiovascular disease prevention were elucidated [9] (Fig. 27.2). Several thousand polyphenols are found in nature, in almost all edible plants. As a rule, both popular tradition and modern biomedicine agree on the benefits derived from consumption of these substances. Daily consumption of these substances may amount to grams and, on the whole, justifies the healthful recommendation to consume fruit and vegetables, which are also important for their supply of vitamins, mineral salts, and essential fatty acids. Of the many favorable biological activities of different polyphenols, supported by a mechanism of action documented in vitro, we can mention their high antioxidant capability, inhibition of production of reactive oxygen species, protease inhibition, and finally control of the cell signaling systems involved in apoptosis. The antioxidant capability, unquestionable and quite marked in vitro, has been taken into consideration because of the oxidative damage existing in chronic degenerative diseases (atherosclerosis and dementia from neurodegeneration). This generated the syllogism that a good antioxidant must protect. For instance, it has been suggested that flavonoids might protect antithrombotic endothelial factors NO and prostacyclin from breakdown owing to their superoxide scavenging effect [10]. Today this concept is questioned, however, because the plasma or tissue concentrations of the different polyphenols are too low, in terms of both absorption and subsequent metabolism, to support a real antioxidant effect. One interesting observation recognizes the above-mentioned role of polyphenols as food antioxidants during digestion; according to this hypothesis, any food containing oxidized lipids could be “cleaned up” in the stomach when it is eaten together with antioxidants. In this context, of the various polyphenols, procyanidins

Fig. 27.2 Mechanism of action of grape seed polyphenols on atherosclerosis

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seem to be particularly interesting, as they can cause antioxidant oxidation reduction reactions even at such an acidic pH as that of the stomach, thus suggesting the usefulness of concurrent consumption of polyphenols with food [11]. Protease inhibition by different polyphenols, in particular those of green tea, is of major importance, as it both prevents thrombosis, due to plaque rupture, and opposes the metastatic capability of tumors, as well as slows down skin ageing. Apoptosis control by polyphenols, through multiple influences on the signal transfer pathways leading ultimately to the modulation of the DNA transcription, could then play an extremely important role in preventing chronic degenerative diseases.

5 A standardized approach to dietary antioxidant treatment of chronic diseases with plant polyphenols: the example of grapes and olives A general overview of the most commonly known and employed plants in phytotherapy comprises plants of various origin. The most used plants in cardiovascular and dismetabolic disorders are the ones containing a high amount of polyphenols, an antioxidant molecule that has been confirmed as active in counteracting radical scavenging-related diseases. Within this group of plants, grapes (Vitis vinifera L.) and olives (Olea europaea L.) are the pillars of the Mediterranean diet and have been the object of much research. Plant extracts from these plants are now becoming more and more popular as nutraceutical tools.

5.1 Vitis vinifera L. Grapes contain gallic acid, catechins, epicatechins, and proanthocyanidins (also combined as dimers, trimers, oligomers, and polymers). The chemical characterization of plant extracts is crucial not only for the identification of active ingredients but also to guarantee safety and consistency of the extract. Proanthocyanidins, which are oligomers or polymers of polyhydroxy flavan-3-ol units (Fig. 27.3), are the major polyphenols in red wine as well as in grapes and grape seeds in particular. A V. vinifera-standardized extract (or grape seed extract, GSE) has been shown to reduce atherosclerosis in rabbits submitted to a cholesterol-rich diet by protecting from aortic lesions caused by moderate hypercholesterolemia [12]. The same extract has been shown effective in counteracting the oxidative stress in human volunteers [13]. In diabetic patients, GSE improved the general oxidative stress situation as well [Indena, data on file]. Increasing evidence shows that grape seed proanthocyanidins (GSPs) contained in grape seed extract possess remarkable health protective effects since they contribute to cardioprotection and to the decrease of the atherosclerotic risk through mechanisms that overwhelm their “antioxidant effects”. Several may be the mechanisms and besides the antioxidant effects they induce alterations in cell membrane receptors, intracellular signaling pathway proteins, and modulation of gene expression. The preventive anti-atherosclerotic action of GSPs has been widely studied and demonstrated in the animal. The anti-atherosclerotic action of oral GSP administration was

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Fig. 27.3 A representative structure of procyanidins, the main component of proanthocyanidins. “n” means the number of catechin units. n ≥ 1, procyanidin oligomer

studied in cholesterol-fed rabbits and found in vivo to be much stronger than that of probucol, a well-known anti-hyperlipidemic drug [14, 15]. Evidence for a vasorelaxing effect linked to an endothelial NO release and subsequent increase in cAMP in the vascular smooth muscle cell has been provided by the work of Fitzpatrick et al., which unequivocally demonstrated that single isolated procyanidins were able, although in a different degree, to elicit the expression of endothelial NO synthase (NOS) [16]. Similar lines of evidence were reached by Mendes et al. working with GSPs in rat isolated aortic rings [17]. Hence GSPs induce the synthesis and release of nitric oxide by the vascular endothelium, which in turn promotes vasorelaxation, reduces platelet aggregation, and limits the flow of atherogenic lipoproteins into the artery wall. GSPs inhibit proliferation and migration of vascular smooth muscle cells by interfering on platelet-derived growth factor (PDGF) receptor signaling through the phospatidylinositol 3 -kinase (MAPK) pathways. Hence, the link between GSP administration and nitric oxide release due to activation of inducible NO synthase (i-NOS) is well established [18]. Although it has been claimed that GSPs elicit anti-platelet activity, only recently their antithrombotic effect has been demonstrated, in vitro using a shear stress-induced thrombosis test and in vivo by a laser-induced thrombosis test in the mouse carotid artery [19]. Intravenously or orally administered GSPs significantly inhibited the laser irradiation-induced thrombus formation in the carotid artery (p <0.01), while in vitro after oral administration the platelet reactivity to shear stress was inhibited. Oxidative stress plays an important role in the development of atherosclerosis as stated in the so-called “oxidation theory”: oxidized LDL is rapidly taken up by macrophages, converting the macrophages into foam cells that serve as precursors of fibrous plaques. Proanthocyanidins are able to inhibit LDL oxidation both in vitro and in vivo [20] and in addition decrease plasma triglycerides and cholesterol accumulation in the aorta of ovariectomized guinea pigs [21]. These results suggest that GSP intake in the ovariectomized guinea pigs alters hepatic cholesterol metabolism, which may affect LDL extraction rate and results in less accumulation of cholesterol

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in the aorta. These findings have been confirmed by a recent study in which it has been demonstrated that administration of GSPs lowered plasma triglycerides, free fatty acids, apolipoprotein B, LDL cholesterol, and non-HDL/non-LDL cholesterol levels [22]. Hence GSPs improve the atherosclerotic risk index in the post-prandial state, as already observed by Natella and colleagues inducing in the liver the overexpression of CYP-7A1 (suggesting a cholesterol elimination via bile acids) and the transcription factor SHP, a nuclear receptor claimed as key regulator of lipid homeostasis at transcription level [23]. GSPs may reduce levels of plasma cholesterol in hypercholesterolemic human subjects [24]. Inhibition of the inflammatory response in atherosclerosis inflammatory mechanisms play a central role in all phases of the development of atherosclerosis [25] and proanthocyanidins have been shown to mediate several anti-inflammatory reactions involved in the development of cardiovascular disease (CVD), i.e. they are implicated in the modulation of the monocyte adhesion in the inflammatory process of atherosclerosis. GSP extract was able to mediate the TNF-α-induced expression of vascular adhesion molecule-1 (VCAM-1) playing a pivotal role in the inflammatory response [26]. Anyway, care must be taken when interpreting the anti-inflammatory effects of procyanidins in cellular systems; this may result from the adherence of the procyanidin molecules to the cellular surface as well as from the absorption of the molecule into the cell. Any observed effect of a procyanidin-rich fraction may therefore be due either to cellular surface interaction or to the absorption of the low molecular weight compounds present in the fraction. Anyway, in a recent study by Kalin et al. the effect of GSP administration was investigated in systemic sclerosis patients with elevated expression of soluble adhesion molecules including ICAM-1, VCAM-1, Pand E-selectin and found that the grape seed extract significantly attenuated the increased expression of these adhesion molecules [27]. Hence, GSPs could reduce the inflammatory response in systemic sclerosis patients. It has also been demonstrated that GSPs exhibit inhibitory properties on the respiratory burst of activated neutrophils and on the release of granule enzymes myeloperoxidase, β-glucuronidase, and elastase in activated human neutrophils [28]. Proanthocyanidins strongly inhibit superoxide generation at sub-micromolar level and prevent the release from calcium ionophore-activated neutrophils of the key enzymes in a dose-dependent fashion. These results demonstrate that proanthocyanidins efficiently restrain the inflammatory response of activated neutrophils in vitro and whenever adsorbed in vivo they can prevent the oxidative discharge at the sites of the adhesion. The estimated GSP dietary intake is around 57 mg/day, which is twice the amount of other flavonoids present in our food [29], and this suggests that these compounds are important contributors to the potential beneficial health effects of dietary flavonoids. To produce a biological effect in vivo, it is imperative that sufficient concentrations are reached in target tissues. However, with the aid of new analytical techniques (LCMS, LC-MS/MS), it has been clearly demonstrated that the monomeric and the dimeric fraction of proanthocyanidins are bioavailable in vivo [30], although to a limited extent. It has been shown that after oral administration of proanthocyanidin B2 in rats, the dimer is absorbed and excreted in urine with the portion of the proanthocyanidin B converted to (–)-epicatechin, which undergoes post-ingestion conjugation and methylation [31]. In a more recent study, GSP administration by gavage (1 g/kg body weight) was detectable in urine after 4 h of ingestion as sharp peaks corresponding to procyanidin dimers B1, B2, and B4 and also to the trimer C2 and one unidentified trimer (T). All these procyanidins were detected in microgram amount, much less than the levels of the urinary metabolites [(+)-catechin/(–)-epicatechin] that were excreted in the first 4 h of ingestion [32].

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We cannot exclude that once low molecular weight proanthocyanidins, or their fermentation products, have crossed the intestinal barrier, they can reach the liver and give rise to significant amounts of bioactive phenolic acids metabolites, which are readily absorbed and can contribute significantly to the health protective effects observed for anthocyanidin-rich food [33]. This is in line with other studies which demonstrate that high molecular weight proanthocyanidins, stable under the acidic conditions of the stomach in vivo [34], pass unaltered through the small intestine where they are degraded into small bioactive phenolic acids, i.e., 3,4-dihydroxyphenylacetic, 3,4-dihydroxyphenylpropionic, and 3,4-dihydroxyphenylvaleric acids, by the colonic microflora in the cecum and in the large intestine [35]. From the brief overview of the different actions/effects of GSPs in the field of atherosclerosis prevention we can conclude that these compounds, acting at different levels of the atherosclerotic cascade, can behave as an effective biological tool in reducing the risk of vascular diseases. Basically, the effects stem from their antioxidant activity (chain-breaking and preventive antioxidants, metal-chelating properties, endogenous antioxidant regeneration and sparing, and so on), but as far as the research works on these compounds are enlarging, it becomes clear that they act through a far more complicated network of mechanisms, very likely involving several factors at the transcriptional level.

5.2 Olea europaea L. (Olive) Olive oil has been traditionally endorsed with healthful and even medicinal properties. As far as the cardiovascular system is concerned, the protective properties of olive oil have been, until recently, exclusively attributed to its high monounsaturated fatty acid (MFA) content, mostly in the form of oleic acid [18:1 (n-9)]. Indeed, monounsaturated supplementation leads to enhanced resistance of LDL to oxidation [36], hence lowering one of the risk factors for coronary heart diseases (CHDs). However, several observations argue against the hypothesis of oleic acid as the exclusive responsible factor for the lower rates of CHD of the Mediterranean area. For example, the effects of MFA on circulating lipids and lipoprotein have not been fully clarified [37]. Also, oleic acid is one of the predominant fatty acid in largely consumed animal foods such as poultry and pork. Thus, contrary to the common belief, the percentage of oleic acid in the Mediterranean diet as a whole is only slightly higher than that of other kinds of Western diets, e.g., the North American one [38]. It is therefore unlikely that oleic acid is exclusively accountable for the healthful properties of olive oil. Unlike most vegetable oils, olive oil is not extracted by solvents but rather obtained from the whole fruit by means of physical pressure, without the use of any chemical. As a result, in addition to several “minor” constituents, such as vitamins (α- and γ-tocopherols and carotenoids), phytosterols, pigments, terpenic acids, and squalene, extra virgin olive oil can be distinguished from other vegetable oils by its contents of phenolic compounds, usually termed polyphenols. As previously demonstrated, the importance of an appropriate polyphenol intake in the maintenance of human health is being increasingly recognized and the contribution of olive oil phenolics is being actively investigated. The first experiments on the biological activities of olive oil phenolics started over a decade ago, thanks to the availability of oleuropein (OE) and hydroxytyrosol (HT) (Fig. 27.4). The experimental model employed (chemically induced oxidation of LDL) was then considered a good mimic of what was supposed to take place in vivo. Both hydroxytyrosol and

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Fig. 27.4 Oleuropein and hydroxytyrosol chemical structure

oleuropein are potent in vitro inhibitors of LDL oxidation, as demonstrated by the evaluation of several markers. The antioxidant activities of hydroxytyrosol and oleuropein were further investigated and confirmed by the use of metal-independent oxidative systems, which indicated that these compounds are potent free radical scavengers [39]. In particular, both HT and OE effectively scavenge superoxide anion. The free radical-scavenging properties of olive oil phenolics have been confirmed over the past few years by several groups in various experimental models. Relevant to the development of atherosclerosis, a scavenging effect of hydroxytyrosol and oleuropein was also demonstrated with respect to hypochlorous acid, which is a potent oxidant species produced in vivo by activated neutrophils at the site of inflammation; evidence is rapidly accumulating that the formation of chloramines via the myeloperoxidase-catalyzed formation of HOCl and subsequent chlorination of apoB-100 is responsible for LDL modification and peroxidation [40]. Most studies of olive oil phenolics focus on their cardioprotective potential. However, there is epidemiological evidence of lower incidence of certain cancers (breast, colon) in the Mediterranean area [41]. As DNA mutation plays a key role in carcinogenesis, it is important to investigate the chemopreventive properties of olive oil minor constituents in ad hoc models. Low concentrations of hydroxytyrosol, i.e., 50 μM, are able to scavenge peroxynitrite and therefore are able to prevent ONOO-dependent DNA damage and tyrosine nitration. In conclusion, hydroxytyrosol is endowed with chemopreventive potential, which is being confirmed in clinical trials (see below). In addition to their antioxidant actions, the activities of olive oil phenolics on enzymes have also been tested in a variety of cellular models (i.e., platelets, leukocytes, and macrophages) relevant to human pathology. Most olive oil phenolics are amphiphilic and possess the ability to modulate enzymes such as cyclo- and lipo-oxygenases, NAD(P)H oxidase, and nitric oxide synthase, which are involved in key functions of those cells. Hydroxytyrosol inhibits (a) chemically induced in vitro platelet aggregation, (b) the accumulation of the proaggregant agent thromboxane in human serum, (c) the production of the pro-inflammatory molecules leukotrienes by activated human leukocytes, and (d) arachidonate lipoxygenase activity, with IC50 s in the 10–5 M range, just like other NSAIDs and aspirin. These observations strongly suggest that the effects of olive oil phenolics on human health go beyond mere antioxidant properties. Olive phenolics also inhibit endothelial activation and the related expression of adhesion molecules, hence decreasing the consequences of inflammation, namely the recruitment of circulating cells (monocytes/macrophages). The first step toward demonstrating in vivo effects of polyphenols, including those of olive oil, is to assess their bioavailability. In 2000, it was demonstrated that olive oil phenolics are

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dose dependently absorbed by humans and that they are excreted in the urine as glucuronide conjugates [42]. Further studies elucidated the metabolic pathways of hydroxytyrosol and oleuropein, which form elevated quantities of homovanillyl alcohol and homovanillic acid [43]. In addition to the elucidation of metabolic pathways that follow absorption, research is focusing on the possible in vivo activities of olive oil phenolics. While some evidence has been obtained from animal experiments, human studies are scarcer. The first, albeit limited, evidence of in vivo antioxidant activity was published in 2000 [44] when a moderate, but significant, decrease in F2-isoprostane excretion by healthy volunteers who ingested phenol-rich olive oils was reported. Other cardioprotective activities of hydroxytyrosol investigated in humans include its antithrombotic potential, as evaluated through a reduced production of thromboxane B2 by whole blood [45]. Finally, the chemopreventive capacity of HT is starting to be studied in vivo. Two studies report lower DNA damage after consumption of HT-rich olive oils [46]. To date, approximately a dozen randomized, crossover, and controlled studies have been published, and most of them suggest healthy effects of phenols from olive oil [47]. In all of the studies a toxic activity of hydroxytyrosol was excluded, even at high doses [48]. However, in view of the potential future formulation of nutraceuticals, consolidation of these data is mandatory. In conclusion, human evidence is accumulating and many data are promising and strongly suggestive of specific roles played by polyphenols in human health.

6 Conclusions Some final notes need to be done on standardization. In order to obtain biologically reproducible data in terms of safety and efficacy, botanical extracts must contain the same active ingredients over time; it also has to be stable and devoid of unpredictable toxicity or side effects. Standardization is the procedure that aims to minimize product variability, and it is a hard task to achieve on botanical extracts. It requires strict control of the plant material and the manufacturing process, with the identification of the critical steps, and continuous process controls. Good agricultural practices (GAPs) need to be applied to the cultivation of the biomass; this allows the plant to be collected at the peak of the balsamic period and to avoid a variety of problems connected with the use of contaminants, species cross-contamination, the use of different botanical varieties, etc. Once the biomass is collected, it undergoes desiccating processes that, once again, have to be conducted under optimal conditions in order to minimize enzymatic and microbial degradation. The aim of the extract standardization is the reproducibility of all the chemical components including the unknown ones. Process controls include the monitoring of grinding, extraction, purification, and drying, and this allows the production of botanical products with constant and reproducible composition. A standardized approach to dietary antioxidant treatment is an open field where edible plants, in the form of standardized extracts, can contribute to optimize nutrition. In this perspective, standardized products obtained from well-known plants such as tea, grape, bilberry, and olive tree have already been investigated. It is also worth mentioning that additional edible plants from the rich traditional portfolio of Western and Eastern countries, when properly investigated, could also contribute to maintain healthy physiological functions and reduce the risk of some

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of the major pathologies. In this context, cardiovascular and dismetabolic disorders are taking a major toll in industrialized countries, and their prevention could be addressed with a strategy that involves, inter alia, dietary compounds also.

References 1. McKeown T. The Modern Rise of Population. New York: Academic Press, 1976. 2. Clarke SD, Abraham S. Gene expression: nutrient control of pre- and posttranscriptional events. FASEB J 1992; 6: 3146–3152. 3. Clarke SD et al. Regulation of hepatic gene expression by dietary fats: a unique role for polyunsaturated fatty acids. In: Berdanier, CD, Hargrove, JL, (eds.), CRC Press Reviews. Boca Raton, Florida: CRC Press, 1992. 4. Ottley C. Individual variability in the nutrition response: key issues from the Nutrition Society Summer Meeting, Kings College London, 7–10 July 2003. Trends Food Sci Technol 2004; 15(5): 280–281. 5. Campión J et al. Genetic manipulation in nutrition, metabolism, and obesity research. Nutr Rev 2004; 62: 321–330. 6. Fuhrman B et al. Consumption of red wine with meals reduces the susceptibility of human plasma and low-density lipoprotein to lipid peroxidation. Am J Clin Nutr 1995; 61: 549–554. 7. Wild and Associates. Global prevalence of diabetes. Diabetes Care 2004; 27: 1047–1053. 8. Howson CP et al. Control of Cardiovascular Diseases in Developing Countries: Research, Development, and Institutional Strengthening. Washington DC: National Academy press, 1998. 9. Stoclet JC et al. Vascular protection by dietary polyphenols. Eur J Pharmacol 2004; 500: 299–313. 10. Gryglewski RJ et al. On the mechanism of antithrombotic action of flavonoids. Biochem Pharmacol 1987; 36: 317–322. 11. Gorelik S. A novel function of red wine polyphenols in humans: prevention of absorption of cytotoxic lipid peroxidation products. FASEB J 2008; 22: 41–46. 12. Ursini F et al. Optimization of nutrition: polyphenols and vascular protection. Nutr Rev 1999; 57(8): 241–249. 13. Nuttall SL et al. Mini-review. Antioxidant therapy for the prevention of cardiovascular disease. QJM Int J Med 1999; 92(5): 239–244. 14. Yamamoto A. A Unique Antilipidemic Drug—Probucol. J Atheroscler Thromb 2008; 15(6): 304–305. 15. Yamakoshi J et al. Proanthocyanidin-rich extract from grape seeds attenuates the development of aortic atherosclerosis in cholesterol-fed rabbits. Atherosclerosis 1999; 142: 139–149. 16. Fitzpatrick DF et al. Vasodilating procyanidins derived from grape seeds. Ann NY Acad Sci 2002; 957: 78–89. 17. Mendes A et al. Vasorelaxant effects of grape polyphenols in rat isolated aorta. Possible involvement of a purinergic pathway. Fundam Clin Pharmacol 2003; 17(6): 673–681. 18. Shao Z et al. Cytotoxicity induced by grape seed proanthocyanidins: role of nitric oxide. Cell Biol Toxicol 2006; 22(3): 149–158. 19. Sano T et al. Anti-thrombotic effect of proanthocyanidin, a purified ingredient of grape seed. Thromb Res 2005; 115(1–2): 115–121. 20. Shafiee M et al. Grape and grape seed extract capacities at protecting LDL against oxidation generated by Cu2+ , AAPH or SIN-1 and at decreasing superoxide THP-1 cell production. A comparison to other extracts or compounds. Free Radic Res 2003; 37: 573–584. 21. Tosca L et al. Grape polyphenols decrease plasma triglycerides and cholesterol accumulation in the aorta of ovariectomized guinea pigs. J Nutr 2003; 133: 2268–2272. 22. Del Bas JM et al. Grape seed procyanidins improve atherosclerotic risk index and induce liver CYP7A1 and SHP expression in healthy rats. FASEB J 2005; 19: 479–481. 23. Natella F et al. Grape seed proanthocyanidins prevent plasma postprandial oxidative stress in humans. J Agric Food Chem 2002; 50(26): 7720–7725. 24. Yilmaz Y et al. Health aspects of functional grape seed constituents. Trends Food Sci Technol 2004; 15(9): 422–433. 25. Blake GJ, Ridker PM et al. Inflammatory bio-markers and cardiovascular risk prediction. J Int Med 2002; 252(4): 283–294.

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26. Khanna S et al. Upregulation of oxidant-induced VEGF expression in cultured keratinocytes by a grape seed proanthocyanidin extract. Free Radic Biol Med 2001; 31(1): 38–42. 27. Kalin R. Activin, a grape seed-derived proanthocyanidin extract, reduces plasma levels of oxidative stress and adhesion molecules (ICAM-1, VCAM-1 and E-selectin) in systemic sclerosis. Free Radic Res 2002; 36(8): 819–825. 28. Carini M et al. Procyanidins from Vitis vinifera seeds inhibit the respiratory burst of activated human neutrophils and lysosomal enzyme release. Planta Medica 2001; 67(8): 714–717. 29. Gu L et al. Concentrations of proanthocyanidins in common foods and estimations of normal consumption. J Nutr 2004; 134(3): 613–617. 30 Holt RR et al. Procyanidin dimer B2 [epicatechin-(4ß-8)-epicatechin] in human plasma after the consumption of a flavanol-rich cocoa. Am J Clin Nutr 2002; 76(4): 798–804. 31. Baba S et al. Absorption and urinary excretion of procyanidin B2 [epicatechin-(4β-8)-epicatechin] in rats. Free Radic Biol Med 2002; 33: 142–148. 32. Tsang C et al. The absorption, metabolism and excretion of flavan-3-ols and procyanidins following the ingestion of a grape seed extract by rats. Br J Nutr 2005; 94: 170–181. 33. Merken HM et al. Kinetics method for the quantitation of anthocyanidins, flavonols, and flavones in foods. J Agric Food Chem 2001; 49(6): 2727–2732. 34. Rios LY et al. Cocoa procyanidins are stable during gastric transit in humans. Am J Clin Nutr 2002; 76: 1106–1110. 35. Deprez S et al. Polymeric proanthocyanidins are catabolized by human colonic microflora into lowmolecular-weight phenolic acids. J Nutr 2000; 130: 2733–2738. 36. Bonanome A et al. Effect of dietary monounsaturated and polyunsaturated fatty acids on the susceptibility of plasma low density lipoproteins to oxidative modification. Arterioscler Thromb 1992; 12: 529–533. 37. Mensink RP et al. Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials. Am J Clin Nutr 2003; 77(5): 1146–1155. 38. Dougherty RM et al. Lipid and phospholipid fatty acid composition of plasma, red blood cells, and platelets and how they are affected by dietary lipids: a study of normal subjects from Italy, Finland, and the USA. Am J Clin Nutr 1987; 45(2): 443–455. 39. Visioli F et al. Free radical-scavenging properties of olive oil polyphenols. Biochem Biophys Res Commun 1998; 247(1): 60–64. 40. Carr AC et al. Oxidation of LDL by myeloperoxidase and reactive nitrogen species: reaction pathways and antioxidant protection. Arterioscler Thromb Vasc Biol 2000; 20(7): 1716–1723. 41. Trichopoulou A et al. Cancer and Mediterranean dietary traditions. Cancer Epidemiol Biomarkers Prev 2000; 9(9): 869–873. 42. Visioli F et al. Olive oil phenolics are dose-dependently absorbed in humans. FEBS Lett 2000; 468(2–3): 159–160. 43. Miro-Casas E et al. Tyrosol and hydroxytyrosol are absorbed from moderate and sustained doses of virgin olive oil in humans. Eur J Clin Nutr 2003; 57(1): 186–190. 44. Visioli F et al. Olive oils rich in natural catecholic phenols decrease isoprostane excretion in humans. Biochem Biophys Res Commun 2000; 278(3): 797–799. 45. Leger CL et al. A thromboxane effect of a hydroxytyrosol-rich olive oil wastewater extract in patients with uncomplicated type I diabetes. Eur J Clin Nutr 2005; 59(5): 727–730. 46. Salvini S et al. Daily consumption of a high-phenol extra-virgin olive oil reduces oxidative DNA damage in postmenopausal women. Br J Nutr 2006; 95(4): 742–751. 47. Covas MI. Olive oil and the cardiovascular system. Pharmacol Res 2007; 55(3): 175–186. 48. Soni MG et al. Safety assessment of aqueous olive pulp extract as an antioxidant or antimicrobial agent in foods. Food Chem Toxicol 2006; 44(7): 903–915.

Chapter 28

Don’t Diet: Adverse Effects of the Weight Centered Health Paradigm Lily O’Hara and Jane Gregg

Key Points • Basic tenets of the weight-centered health paradigm include the following: weight is within the control of the individual; weight is caused by a simple imbalance between an individual’s energy intake and energy usage; methods for successful and sustained weight loss include focusing specifically on changing eating and physical activity patterns; and losing weight to achieve “healthy weight” status will result in better health. • Critics of the weight-centered health paradigm contend that the tenets are scientifically inaccurate and focusing on body weight is ineffective as a means to improve health or control body weight. • The attitudes, behaviors and practices arising from the paradigm are harmful to health and well-being and are associated with the paradigm which includes dissatisfaction, dieting, discrimination and death. Keywords Diet · Dieting · Weight-centered health · Health at every size

1 Introduction The issue of increasing weight in Australia and other Western countries has been the subject of intense scientific, political and media attention in recent years [1–4]. Health authorities now refer to “obesity” as an “epidemic”, and the consequences of “obesity” are regarded as being medically, psychologically and economically problematic [3]. Governments around the world have responded to this situation by investing significant resources in “anti-obesity” public health and health promotion policies and programmes. The dominant message from health authorities is that being “overweight” is unhealthy, and that “overweight” people should lose weight in order to improve their health. This placement of

L. O’Hara () Public Health, School of Health and Sport Sciences, University of the Sunshine Coast, Sippy Downs, QLD, Australia e-mail: [email protected] F. De Meester et al. (eds.), Modern Dietary Fat Intakes in Disease Promotion, Nutrition and Health, DOI 10.1007/978-1-60327-571-2_28, © Springer Science+Business Media, LLC 2010

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body weight at the focal point of health programmes is referred to as the “weight-centered health paradigm” [5, 6]. This chapter critiques the weight-centered health paradigm and examines the problems associated with viewing health through the lens of body weight.

2 The Ideal “Healthy” Body In recent years, the health sector has increasingly contributed to the definition of the “ideal” body. The aesthetically ideal body in contemporary Western societies is described as lean and any visible fat is regarded as visually ugly [2]. Health professionals have joined forces with the purveyors of this ideal aesthetic body in eschewing body fat, such that pursuing the “ideal” body is now regarded as not just an aesthetic imperative but also a health imperative. Fat is not simply regarded as undesirable to look at; it is touted as being incredibly bad for your health [1, 3, 4]. This assessment has primarily stemmed from epidemiological studies that have shown statistical associations between body mass index (BMI) and a range of morbidity and mortality outcomes [7, 8]. Weight is now presented to the public as an independent cause of disease and death, and terms such as “epidemic” and “obesity”, once the sole domain of public health and medical discourse, are now in common everyday use in the community. This is primarily due to the escalating coverage of this issue in the popular media. A recent study on trends in reporting on obesity in Australian and New Zealand newspapers demonstrated a significant increase in coverage in the 10 years from 1996 to 2005 [9, 10]. In 1996, 40 newspaper articles included the term “obesity”: on average one article every 9 days. By 2000 this had risen to 339 articles, by 2002 there were 1,438 and in 2005 there were 2,734 articles or 7.5 articles per day. This represents a 50-fold increase of reporting on “obesity” in a 10-year period (Fig. 28.1). In response to this increasing focus on weight by health scientists and the general media, international, national and state taskforces, summits and forums have been convened, and public

Fig. 28.1 Number of articles that include the term “obesity” in major Australian and New Zealand daily newspapers during 1996–2005. Reproduced from Health Promotion Journal of Australia (2006) with permission from the Australian Health Promotion Association

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health and health promotion policies and programmes have been developed to address the “epidemic of obesity”. The placement of weight at the centre of health policies and programmes has been termed the “weight-centered health paradigm” [5, 6, 10].

3 Tenets of the Weight-Centered Health Paradigm There are six basic tenets of the weight-centered health paradigm [5, 6, 11]: (1) Weight is mostly volitional and within the control of the individual; (2) Weight is caused by a simple imbalance between an individual’s energy intake and energy usage; (3) The current health status of the individual can be assessed and future health status can be predicted based on their BMI; (4) Excess body weight causes disease and premature death; (5) Methods for successful and sustained weight loss are well known to science and include focusing specifically on changing eating and physical activity patterns; and (6) Losing weight to achieve “healthy weight” status will result in better health. The tenets of the weight-centered health paradigm are promulgated by the World Health Organization (WHO), governments around the world, the industrial complex comprising pharmaceutical and weight loss companies, health and medical researchers and practitioners, professional bodies such as the International Obesity Taskforce and individual private interests.

4 Evidence of the Weight-Centered Health Paradigm “Obesity” is being presented as an issue of global concern, and the term “globesity” has been used [12] to illustrate this notion that everyone everywhere is at risk of becoming too fat [5]. The WHO World Health Statistics 2006 report states that, where the data are available, the following countries (in order of decreasing prevalence) have 10% or more of children under 5 years of age that are “overweight”: Albania (22%), Ukraine (20%), Comoros (14%), Uzbekistan (14%), Bosnia and Herzegovina (13%), Serbia and Montenegro (13%), Georgia (13%), Lesotho (12%), Kiribati (11%), Algeria (10%) and Armenia (10%) [12]. With respect to adult “obesity” the top 10 fattest populations in the world in order of decreasing prevalence are Nauru (75% of the population “obese”), Cook Islands (63%), Samoa (60%), Marshall Islands (46%), Micronesia (44%), United Arab Emirates (33%), Bahrain (29%), Kuwait (29%), Jordan (26%) and Fiji (24%). New Zealand adults are the 14th fattest in the world (23% “obese”); the United States comes in at 20th (21%), Australia at 35th (15.1%) and Canada at 37th (14.9%) [12]. Recent reports in the United States, Canada and Australia have each claimed that their country is the fattest in the world, or warned that it is at imminent risk of becoming so [9]. However, with prevalence rates of adult “obesity” for these countries only a fraction of those of Nauru, such

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claims have been criticised as being based more on “fat-phobia” rather than on actual data [5, 11, 13–16]. Billions of government health dollars are being allocated to the “obesity epidemic”. The overarching weight-centered health policies and programmes of the WHO [17] and the governments of Australia [18], Canada [19], New Zealand [20], the United Kingdom [21] and the United States [22, 23] all address the issue of “obesity” through strategies focused exclusively on diet and physical activity. These countries represent the dominant “anti-obesity” voices in the Englishspeaking world and all have developed weight-centered public health policies and programmes (Table 28.1). All of these policies and programmes have an exclusive focus on the dual strategies of increasing physical activity levels and improving nutritional status. In some cases the physical activity and nutrition policies and programmes that have been developed in recent years have been singularly predicated on the impact that they will have on the “epidemic of overweight and obesity”. Table 28.1 Weight-centered health policies and programmes for selected countries Scope Organisation Policy or programme Worldwide

World Health Organization

Australia Canada New Zealand

Department of Health and Ageing Health Canada Ministry of Health

United Kingdom

Department of Health

United States

Department of Health and Human Services

Global strategy on diet, physical activity and health [67] Healthy weight 2008 [68] Guide to healthy eating and physical activity [69] Healthy eating—healthy action. Oranga Kai—Oranga Pumau [70] Choosing a better diet [71] Choosing activity [71] Surgeon general’s call to action to prevent and decrease overweight and obesity [72] Small step [73]

5 Concerns About the Weight-Centered Health Paradigm An increasing number of researchers, health practitioners and activists are questioning the evidence for operating within a weight-centered health paradigm and suggest that it is scientifically inaccurate, ineffective, and harmful to health [5, 6, 11, 14–16, 24–26]. Significant evidence demonstrates that, when other factors such as physical activity are accounted for, weight is a very poor predictor of health outcomes [7, 8, 27–29]. A growing body of evidence suggests that the weight-centered health paradigm is ineffective at controlling body weight [30, 31]. At the population level, despite the dominance of the weightcentered health paradigm and the massive increase in coverage in the media, it appears as though average body weight has increased 3–5 kg within a generation [14]. The weight-centered health paradigm holds that this increase is due to an excess of energy in over energy out. However, there are other possible reasons for such an increase in average body weight. Paradoxically, it has been proposed that the very act of focusing on body weight as problematic may have inadvertently contributed to average weight gain through the promotion of dieting and other forms of weight control [32–34].

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Dieting is highly ineffective with a 90–95% long-term failure rate [30, 31]. Diet failure often results in higher weights than before the diet [32–34]. One of the biggest studies to demonstrate this effect was carried out by Field et al. [32], who conducted a prospective study of over 16,000 adolescents aged between 9 and 14 years. The Growing Up Today Study (GUTS) assessed dieting behaviour to control weight, binge eating, dietary intake and body mass index (BMI) over a 3-year period. Over 9,000 participants remained in the study for the entire period. Participants were classified as “frequent dieters”, “infrequent dieters” or “nondieters” based on their frequency of reported dieting to lose weight or keep from gaining weight. Frequent dieters were those who reported dieting on 2–7 days a week. Participants that reported dieting less than once a month to once a week were classified as infrequent dieters. Nondieters were used as the reference group with which infrequent and frequent dieters were compared. At the 3-year follow-up period, adolescents that were frequent or infrequent dieters had gained significantly more weight than dieters. This was the case for both boys and girls. The authors of the study controlled for potential confounding factors of BMI, age, physical development, physical activity, inactivity, caloric intake and height change over the period. Therefore, the weight gain experienced by the adolescents in this study could reasonably be ascribed to the practice of dieting behaviours. Stice et al. [34] conducted a smaller but longer study on the same issue. This prospective study of 496 adolescent girls involved the completion of a baseline assessment at 11–15 years of age and four annual follow-ups. The outcome of interest was weight gain that moved participants into the “obese” category. Self-reported dietary restraint, radical weight-control behaviours, depressive symptoms and perceived parental obesity all predicted movement into the “obese” category after controlling for a range of potential confounding factors. Girls that were already “obese” were excluded from this analysis because the researchers were specifically interested in examining factors that predicted weight gain, rather than factors that were associated with being fat to begin with. A study on the determinants of weight gain amongst first year university students by Lowe et al. [33] examined a range of dieting behaviours and practices. After controlling for BMI, dieting for weight loss strongly predicted weight gain over the course of the first year at university. Participants who reported currently dieting to lose weight gained twice as much weight (5.0 kg) as former dieters (2.5 kg) and three times as much weight as never dieters (1.6 kg). These longitudinal studies demonstrate that dietary restraint and radical weight-control behaviours actually result in weight gain, including for those that start off in the “healthy weight” category. These findings contradict the assertion by Hill that dieting is associated with fatness simply because fat people are more likely to diet [35]. Johnston and Omichinski [36] postulate that attempts to lose weight focus on concepts of deprivation, control and self-rejection and the consequences of these concepts on emotional and physical health status. They also propose that these consequences lead to repeated weight loss and regain, ultimately resulting in higher weight than ever. Another mode by which focusing on body weight can actually lead to an increase in body weight is through the uptake of physical activity. Exercise can increase fat and body weight in 25–30% of women [37]. If exercise is promoted for weight loss, then for a substantial proportion of the female population in particular, the result will not only been seen as ineffective but actually counterproductive.

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6 Harmful Effects of the Weight-Centered Health Paradigm Perhaps the most important concern about the weight-centered health paradigm is that it may actually be harmful to people and society. The range of harms associated with the weightcentered health paradigm includes dissatisfaction, dieting, disordered eating, discrimination and death.

6.1 Dissatisfaction Dissatisfaction with one’s body is extremely prevalent in Western cultures [38, 39]. It is increasing in women as the “fat is bad for your health” message becomes more pervasive [40] and is also evident at much younger ages [41, 42]. Despite body dissatisfaction generally being recognised as harmful, some “obesity” researchers have proposed inducing greater body dissatisfaction amongst “overweight” and “obese” people as a means to induce weight loss [43]. The major behavioural impact of body dissatisfaction is uptake of weight-control practices. The most common weight-control practice is dieting [44]. Dieting for weight control has become so common that it is regarded as normative behaviour [44]. The majority of American adolescents are dieting to lose weight [44, 45]. On any given day 30% of Australian women are on a diet because of their desire to conform to health expectations about being the right size [46], and many girls have started seriously dieting by the age of 14 years [47].

6.2 Dieting Dieting has a range of negative psychological and physiological effects. Dieting has been demonstrated to lead to negative cognitive effects such as preoccupation with food, which in turn impacts on working memory [48]. Dieting has also been demonstrated to increase physiological risk factors for disease such as hypertension [32, 49]. As discussed above, dieting is a strong predictor of weight gain, independent of BMI. This creates a paradox whereby the one thing that dieters are trying to reduce or avoid (“excess” body weight) is increased by the very behaviour that is used to try and decrease it. In other words, dieting is actually counterproductive to weight loss [32–34, 50–52]. Weight gain is not necessarily an independent health risk factor, but repeatedly gaining and losing weight, or weight cycling, is strongly associated with negative health outcomes. Numerous studies have demonstrated morbidity and mortality associations with weight cycling [53–59]. Most of these studies demonstrated relationships between weight cycling and cardiovascular or metabolic risk factors [53, 54, 56, 57, 59]. A small number of other studies have focused on the relationship with osteoporosis [55, 60]. For example, a 28-year study of Norwegian men and weight cycling demonstrated that elderly men whose weight had fluctuated more than four times over the course of the study were almost three times as likely to receive a forearm fracture than men who had never weight cycled [60]. Nguyen et al. [55] also focused on weight cycling and osteoporosis and found that low bone mass density and weight cycling were both independent risk factors for all-cause mortality, irrespective of initial BMI.

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6.3 Disordered Eating The weight-centered health paradigm also contributes to a broader spectrum of weight-related behaviours that are classified as disordered eating. Disordered eating behaviours include fasting, fad dieting, use of diet pills, diuretics or laxatives, vomiting and smoking for appetite control. These behaviours are practiced by almost two-thirds of American girls in Grade 9 and over a quarter of boys in Grade 9 [61]. The most severe forms of disordered eating such as anorexia nervosa and bulimia nervosa are well recognized as affecting between 1 and 3% of the general population, respectively, but with disproportionate rates amongst young women [5, 44, 46, 61].

6.4 Discrimination Discrimination based on body size is a widespread phenomenon and has been referred to as the last socially acceptable form of discrimination [62] or the last bastion of prejudice [63]. Discrimination is an outcome of body size oppression and like all other forms of oppression, body size oppression is a human rights issue that negatively impacts on all members of society [64]. Evidence of systematic bias against people of larger body weights has been demonstrated by doctors [65, 66], nurses [67], dietitians [68], exercise scientists [69], physical educators [70, 71], teachers [72, 73], employers [74–77] and adoption agencies [78]. Bias and discrimination are present across the lifespan [79] in children [80–83], adolescents [84, 85] and even parents [86]. Up to 40% of fat adults (BMI over 35) have experienced overt discrimination based on their body size [87].

6.5 Death Death is the ultimate poor health outcome ascribed to the weight-centered health paradigm. Losing and regaining large amounts of weight—the “yo-yo syndrome” [49]—has been consistently linked with increased mortality as evidenced in the Framingham and other large-scale studies [55–57, 88]. Deaths from anorexia nervosa are 12 times higher than for any other cause of death for females aged 15–24 years and 200 times greater than the suicide rate for the general population [5]. Finally, critics of the weight-centered health paradigm report that a small but increasing number of young people have died from suicide as a direct result of bullying about body size [89].

7 Conclusion The weight-centered health paradigm is hard on people and soft on health problems. Focusing on “overweight” and “obese” people does not help to address the broader social and economic issues that influence people’s lives. Health promotion strategies need to move away from the “O words” (“overweight” and “obesity”) and from blaming individuals for their body weight [90].

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There is a need for a more compassionate approach to health that is based on sound scientific evidence of health gain and no health harm. A promising alternative paradigm is the Health at Every Size paradigm, which shifts the focus away from weight towards health. It supports processes that enhance the health of all people, irrespective of their body size or weight [15, 91, 92]. The weight-centered health paradigm has become a dominant paradigm throughout the developed world. There are six basic tenets of the weight-centered health paradigm: weight is mostly volitional and within the control of the individual; weight is caused by a simple imbalance between an individual’s energy intake and energy usage; the current health status of the individual can be assessed and future health status can be predicted based on their BMI; excess body weight causes disease and premature death; methods for successful and sustained weight loss are well known to science and include focusing specifically on changing eating and physical activity patterns; and losing weight to achieve “healthy weight” status will result in better health. Critics of the weight-centered health paradigm contend that the tenets are scientifically inaccurate; focusing on body weight is ineffective as a means to improve health or control body weight; and the attitudes, behaviours and practices arising from the paradigm are harmful to health and well-being. The harms associated with the paradigm include dissatisfaction, dieting, discrimination and death. An alternative paradigm for addressing health for people of all sizes is Health at Every Size.

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Chapter 29

Physical Activity in Diet-Induced Disease Causation and Prevention in Women and Men Scott Going and Melanie Hingle

Key Points • Obesity, with its comorbidities, has emerged as a major public health problem in the USA and around the world and excess visceral and intramuscular fat is strongly linked to increased risk of cardio-metabolic perturbations. • Exercise promotes lean tissue and enhances fat loss, however, the level of energy expenditure needed for significant weight loss is daunting for most people. • Physical activity improves insulin sensitivity and glucose oxidation and enhances lipid uptake, transport, utilization, and oxidation which help to lower the risk of metabolic disorders and disease with health benefits accruing at modest levels of exercise energy expenditure. • Just as exercise may modify the effects of dietary choices, post-exercise meal composition may modify the metabolic effects of exercise with more research on the interactions of diet and exercise warranted. • Despite the uncertainties, there is little doubt that regular physical activity offers a number of powerful health benefits that may ameliorate diet-induced chronic disease risk in men and women. Keywords Adiposity · Visceral fat · Ectopic fat · Physical activity · Exercise · Diet · Chronic disease

1 Introduction Currently, over 60% of deaths worldwide are attributed to heart disease, stroke, diabetes, and cancer [1]. While age, sex, and genetic susceptibility are considered significant factors determining chronic disease risk, occurrence is also highly dependent on the presence of the major lifestyle

S. Going () Department of Nutritional Sciences, The University of Arizona, 2549 N Santa Rita Ave, #1, Tucson, AZ 85719, USA e-mail: [email protected] F. De Meester et al. (eds.), Modern Dietary Fat Intakes in Disease Promotion, Nutrition and Health, DOI 10.1007/978-1-60327-571-2_29, © Springer Science+Business Media, LLC 2010

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risk factors, including poor diet quality and over nutrition, and a lack of habitual physical activity (PA). Over the past few decades, social changes have taken place that have contributed to significant decreases in leisure- and work-related energy expenditure. Similarly, there have also been changes in food consumption patterns, significant amounts of household food budgets are now spent outside the home where the majority of plentiful, cheap, and readily available foods are not the dietary staples essential for good health (i.e., vegetables, fruits, whole grains, legumes, plant-based oils), but rather energy-dense, highly processed foodstuffs whose intake has been associated with poorer health outcomes. Chronic perturbations in energy balance brought on by a sedentary lifestyle and poor diet quality appear to be at the very foundation of the obesity epidemic and its associated comorbidities—type 2 diabetes and cardiovascular disease (CVD). While obesity is not necessary for the development of either of these two diseases, excess adiposity has been identified as a significant mediator of the relationship between health behaviors and CVD/type 2 diabetes; therefore obesity is considered by many authorities as industrialized nations’ most pressing health challenges [1]. However, just as physical inactivity and unhealthy dietary practices increase risk of obesity, morbidity, and premature death, modest improvements in either or both of these may mitigate established disease processes and, in some instances, greatly reduce disease risk or prevent disease from occurring altogether. Epidemiologic, animal, clinical, and metabolic research findings have repeatedly demonstrated that both habitual PA and prudent diet play independent and significant roles in disease prevention and health promotion. In the following pages, we present evidence for the effects of PA on obesity and obesityrelated risk factors of chronic disease as well as discuss the possible synergistic effects of PA plus diet as a means to further reduce risk. We conclude with recommendations based on the current evidence.

2 Adiposity At a fundamental level, obesity results when caloric intake exceeds caloric expenditure. Interestingly, not all available data support the notion that obese individuals consume more calories than lean persons (as caloric intake per unit of lean body mass appears to be similar across levels of obesity and is essentially the same as lean individuals) [2–5]. However, fat intake (as a percentage of total calories) has been associated with increased adiposity in male and female adults, and as a result, many interventions have focused on decreasing fat intake rather than calories per se [3]. Discrepancies in reported relationships and the effects of interventions on body weight, body composition, and risk factors likely reflect the difficulties inherent in accurately measuring diet and PA, as well as numerous other factors (e.g., genotype, adherence to the exercise or diet intervention, initial body weight and composition, magnitude of caloric restriction and nutrient adequacy of the diet, type of exercise and different combinations of diet and exercise) [6, 7] that influence individual response to intervention. Changing behavior and sustaining a healthy lifestyle is a difficult undertaking and both exercise and diet interventions have suffered from poor long-term adherence. While the optimal exercise “dose” is not established, recent studies suggest weekly levels of energy expenditure exceeding 2,000 kcal may be needed to achieve significant weight loss [8, 9]. Such a high level of exercise is daunting for most persons, particularly for sedentary, overweight, or obese persons

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who may need to exercise for several months to become fit enough to sustain a level of intensity that burns a significant number of calories [10]. Further, results of meta-analyses have shown only small average reductions in body weight with exercise [11, 12], although certainly individual losses may be large. These small losses are often discouraging for persons who are focused primarily on weight (rather than body composition) and who expect rapid results. For sedentary persons, caloric restriction is a much more effective approach to obtaining faster initial weight loss, which in turn may reinforce positive behavior changes. Although the addition of exercise to caloric restriction would be expected to improve weight loss, most data show only a modest increase (2–3 kg) in the actual amount lost [13]. Nevertheless, dieting without any exercise may have undesirable consequences; for example, as body weight decreases, energy expenditure also declines resulting in a weight loss plateau. This increase in the economy of energy expenditure following weight loss may be attributed to reductions in resting metabolic rate, lower energy cost of physical activity, and lower total thermic effect of food (TEF), all of which contribute to total daily energy expenditure [14–16]. The decline in resting metabolic rate (the largest component of daily energy expenditure) is largely a consequence of loss of fatfree mass, which accounts for 60–80% of the total RMR variance [17]. The energy cost of PA necessarily declines with weight loss, as it takes less energy to move a smaller body mass, and the thermic effect of food is less when less food is eaten. Exercise may counter the potentially deleterious effects of caloric restriction, depending on the degree of restriction, although conflicting results have been reported. Clearly, each bout of exercise expends calories during the activity. Whether physical activity significantly affects postexercise energy expenditure remains uncertain, although some evidence suggests that intense, prolonged exercise may elevate energy expenditure significantly beyond the exercise period itself [18–20]. The chronic effects of regular exercise on TEF, the energy cost of PA, and on total energy expenditure likewise lack consensus [21]. While exercise protects fat-free mass and promotes the loss of fat mass [22], it may not prevent the decline in RMR during weight loss, which is more closely related to the rate of weight loss [23]. Long-term habitual exercise has likewise not been found to increase RMR beyond its effect on fat-free mass [24]. However, independent of its effect on energy expenditure and body weight, PA may affect muscle fiber type, capillary density, substrate utilization, and metabolism in other beneficial ways [25]. Exercise also appears to have an important role on weight maintenance after weight loss, as surveys of individuals who report successful long-term weight loss typically cite regular physical activity as a key behavior [26, 27]. Studies on the importance of exercise for maintaining lost weight show that starting or maintaining exercise following weight loss is associated with better weight maintenance, lower fat mass and percent body fat, and higher RMR when compared to not exercising [22, 28–33]. Maintenance of even a modest weight loss (5–10%) is sufficient to improve glycemic control, normalize blood pressure, and improve the lipid profile [34]. This level of weight reduction can be achieved and maintained by lowering fat intake and increasing PA in the absence of a formal diet effort and without attempting to achieve an “ideal” body weight, for which the scientific community has yet to arrive at a consensus.

3 Fat Distribution An increase in the visceral fat depot is widely regarded as a significant link between excess adiposity, dyslipidemia, insulin resistance, and increased risk of type 2 diabetes. The predominant

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hypothesis posits that increased visceral fat leads to increased free fatty acid flux and the inhibition of insulin action in insulin-sensitive tissues. However, in recent years, numerous studies have also established the role of adipose tissue as an endocrine gland [35]. Secreted by adipose tissue, leptin, interleukin-6, angiotensin II, adiponectin, and resistin all appear to have potent effects on the metabolism of distant tissues, suggesting an alternative link between excess adiposity and impaired metabolism [36]. The development of obesity also leads to significant lipid deposits within and around other tissues and organs (e.g., liver, skeletal muscle, heart, blood vessels, and the pancreatic insulinsecreting beta cell). This is known as ectopic fat storage [37] and is thought to represent the failure of the adipose tissue mass to adequately expand [38] to accommodate an increased energy influx. Increases in ectopic fat, together with intra-abdominal (visceral) fat, contribute to risk of diabetes and CVD. Several studies have demonstrated that the degree of lipid infiltration into skeletal muscle and liver highly correlates with insulin resistance [39, 40]. In animals fed a high-fat diet, ectopic fat deposits within and around the heart impair both systolic and diastolic functions and may promote heart failure over time. Accumulation of fat around blood vessels (perivascular fat) may affect vascular function in a paracrine manner, as perivascular fat cells secrete relaxing factors, proatherogenic cytokines, and smooth muscle cell growth factors. Further, high amounts of perivascular fat could mechanically contribute to the increased vascular stiffness seen in obesity. Finally, accumulation of fat in the renal sinus may limit the outflow of blood and lymph from the kidney, which would alter intrarenal physical forces and promote sodium reabsorption and arterial hypertension. Considered in toto, ectopic fat increases the risk of insulin resistance and diabetes, and fat storage in key target organs of cardiovascular control may impair their functions, contributing to the increased prevalence of CVD in obese subjects. The importance of fat distribution to metabolic health risk has generated considerable interest in how various fat depots may respond to PA interventions. Some studies suggest visceral fat may be particularly labile, although relatively few studies have been designed to determine whether abdominal obesity is preferentially reduced. Ohkawara et al. [41] and Kay and Singh [42] have recently summarized evidence from studies of the effects of exercise on visceral fat [41, 42]. Visceral fat has been shown to be reduced with exercise, either in proportion to total weight loss or at a faster rate; in some studies, visceral fat was reduced even in the absence of significant weight loss [43] or reduction in waist circumference [42]. Few studies have been designed to address the dose–response effect of exercise on visceral fat, although the limited evidence from systematic reviews suggests a dose–response relationship between aerobic exercise and visceral fat reduction in obese subjects without metabolic-related disorders [41, 44]. Based on their review, Ohkawara et al. [41] suggest that at least 10 metabolic equivalents per hour per week (METsh/w) in aerobic exercise, such as brisk walking, light jogging, or stationary cycling, is required for visceral fat reduction. These results are consistent with results from the STRRIDE study [45], one of the few prospective dose–response studies, which showed that modest exercise resulted in decreases in abdominal subcutaneous and visceral fat. Prospective studies of the effects of exercise on ectopic fat are also lacking. Lower prevalence of fatty liver in active persons suggests exercise may influence liver composition [46]. Similarly active persons tend to have greater muscle density and less muscle fatty infiltration [47]. Interestingly, endurance-trained athletes have elevated intramuscular triglycerides (IMTG) similar to obese persons, without the associated insulin resistance. The apparent “metabolic paradox” suggests it is not the expansion of the IMTG stores that is harmful but rather the balance between fatty acid

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availability, uptake, and oxidation, where the low turnover of the IMTG pool and over-spilling fatty acid moieties are harmful to lean tissues and are instrumental in the development of insulin resistance [38, 48].

4 Insulin Sensitivity and Lipid Metabolism Although the exact mechanism and optimal dose remain to be elucidated, numerous studies have documented the efficacy of exercise for improving the balance between skeletal muscle fatty acid uptake and oxidation, thereby preventing lipotoxicity and the development of skeletal muscle insulin resistance [49–51]. Endurance exercise has been studied more frequently than other modes of activity [52]. Following endurance training, skeletal muscle insulin sensitivity is increased via increases in GLUT4 protein concentrations and increased activities of both glycogen synthase and hexokinase [53, 54]. Some studies have shown that placing sedentary adults on an endurance exercise program improves insulin sensitivity while increasing IMTG concentrations [55, 56] similar to endurance-trained athletes. In these studies, the improved insulin sensitivity in the presence of increased IMTG concentration is likely the result of more efficient lipid turnover as the muscle becomes more adept at lipid uptake, transport, utilization, and oxidation [39, 52]. Indeed, Menshikova et al. [57] showed improvements in mitochondrial biogenesis and electron transport chain activity in older persons after 12 weeks of endurance training, while Bruce et al. [58] showed similar results in obese persons (although their IMTG remained relatively unchanged). These results suggest the capacity for lipid oxidation is increased with training. The increase in IMTG noted in some studies suggests greater free fatty acid (FFA) delivery and uptake must also be occurring [59, 60]. This most likely represents an adaptation to the increased metabolic demands of exercise which, when coupled with increased FFA delivery (an expected response), would help explain increased IMTG concentrations. The improvement in insulin sensitivity despite increased IMTG is likely related to reductions in deleterious lipid metabolites from increased lipid flux [61, 62]. In the study by Bruce [58], obese persons who trained experienced reductions in the intramyocellular lipid intermediates DAG and ceramide. Reductions in concentrations of lipid metabolites may partly explain the improvements in GLUT4 translocation and activities of hexokinase and glycogen synthase. There is also some evidence that endurance exercise reduces susceptibility of skeletal muscle to lipid peroxidation [39], which could lead to further improvements in mitochondrial function. Last, the anti-inflammatory effects of exercise are well known [63]; studies have shown that exercise reduces concentrations of TNF-α (an inflammatory cytokine), which may in part explain the increases in GLUT4 expression. Resistance exercise may offer unique benefits not seen with endurance exercise training. Although aerobic exercise increases capillary density and skeletal muscle mitochondrial biogenesis, enhances translational stability of key proteins involved in insulin signal transduction, and improves blood flow to the muscles [53], it does not substantially affect skeletal muscle hypertrophy and muscle strength. Because resistance training increases skeletal muscle mass [64], it can augment whole-body glucose disposal capacity [65–67]. Indeed, studies have shown that even a single bout of resistance exercise can improve insulin sensitivity for up to 24 h [50, 66, 68]. These benefits may be due to reduced IMTG stores [50]. This may seem contradictory to studies

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showing increased IMTG with endurance training. However, it is important to distinguish between a single bout and multiple bouts of exercise. Although still somewhat controversial [49], IMTG appear to be an important source of fuel during exercise, and hence a single bout of either resistance or endurance exercise would be expected to decrease IMTG concentration [69, 70]. The enhanced turnover observed with endurance exercise is an adaptation to the metabolic demands of the body. Unfortunately, few studies on the metabolic demands of resistance exercise have been reported.

5 Physical Activity and Fitness Attenuate Obesity and Chronic Disease Risk Substantial observational evidence suggests that physical activity can protect against the development of chronic disease and increase longevity [71]. Early studies on cardio-respiratory fitness and obesity indicated that moderate to high levels of fitness (an objective and reproducible measure related to physical activity) attenuated the mortality risk of obesity [72]. More recent studies have examined the combined effects of physical activity or cardio-respiratory fitness and obesity on various disease endpoints [73]. Although the results have been inconsistent for various disease endpoints, populations, and exposures, an independent effect of PA on mortality and morbidity is often found after controlling for obesity as a confounder or in obesity-stratified subgroup analysis. More recent studies have used joint stratification analysis to more closely examine the interrelationship of PA or cardio-respiratory fitness and obesity on health outcomes [71]. In these studies, PA or fitness attenuates and sometimes eliminates the effect of obesity on all-cause and CVD mortality. Indeed, in studies with the Aerobics Center Longitudinal Study, obese and fit individuals had a lower risk of mortality than normal weight unfit individuals [72]. Similarly, studies of the effects of PA or cardio-respiratory fitness on morbidity showed that PA or fitness and obesity were independent contributors to incident CVD [74–76], type 2 diabetes [77–79], and hypertension [80, 81]. In all studies, obese and unfit or sedentary individuals had the greatest morbidity, and obese but fit or active generally had decreased morbidity than non-obese and unfit or sedentary.

6 Benefits of Exercise Versus Diet with and Without Weight Loss When evaluating the role of PA and its ultimate health effects in the treatment of obesity, the interaction between diet composition, calorie restriction, and exercise must be considered. Carbohydrate intake ultimately limits the endurance of aerobic exercise and its contribution to total weight loss. When dietary carbohydrate is severely restricted, sufficient time for ketoadaptation (2 weeks or longer) must be allowed, after which a moderate level of continuous sub-maximal aerobic exercise can be performed [82]. Adequate protein (∼1.2 g/kg ideal body weight/day) must also be provided to preserve lean body mass to support exercise. The severity of caloric restriction also appears to affect the role of exercise. Weight training and endurance exercise during a very low-calorie diet do not increase weight or fat loss nor preserve fat-free mass [83]. However, in some studies, weight training during more modest caloric restriction produces

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greater weight and fat loss as well as increases in lean body mass [84]. Similarly, in overweight postmenopausal women, the addition of both aerobic and anaerobic exercise to a high-protein, low-calorie diet preserved lean body mass and increased aerobic capacity, fat loss, and absolute RMR [85]. In the absence of PA, improvement in metabolic parameters also is observed with energy restriction, for example, reduced inflammation in obese individuals with type 2 in diabetes or insulin resistance [86, 87]. The majority of studies of weight loss through exercise or diet have not demonstrated whether benefits are due to exercise per se, diet, weight loss, or their combined effects. Ross and colleagues [43, 88, 89] have completed studies designed to test the independent effects of exercise, diet, and weight loss. In these studies, participants were randomized to diet-induced weight loss, exercise-induced weight loss, exercise without weight loss, or a comparison group. Weight loss induced changes in total body fat, abdominal subcutaneous fat, and intra-abdominal (visceral) fat. Abdominal and visceral fat were also reduced with exercise without weight loss in obese men [43] and women [88]. In obese men, average improvement in glucose disposal was similar in both weight loss groups and significantly greater in weight loss groups compared to control and exercise without weight loss. In obese women, compared to controls, insulin sensitivity improved with exercise without weight loss. Janssen et al. [89] compared the effects of aerobic or resistance exercise combined with caloric restriction versus caloric restriction only on body composition and metabolic risk factors in obese women [89]. In all groups weight loss was associated with reduced total, intra-abdominal subcutaneous, and visceral fat. Fasting and IGTT (impaired glucose tolerance test) insulin, total cholesterol, LDL cholesterol, and apolipoprotein B also decreased within each group and the improvement was not enhanced by the addition of exercise. Visceral fat was the only variable related to metabolic risk factors both before and after treatment. In contrast, Cox et al. [90] reported energy restriction and vigorous aerobic exercise independently and additively reduced IGTT glucose and insulin concentrations. Meals ingested after exercise are known to impact the metabolic response to the exerciseinduced energy deficit. While a single session of exercise can increase insulin sensitivity for hours or days, increased availability of carbohydrate blunts this effect [91, 92]. For example, restoring energy balance by re-feeding energy and CHO during 6 days of moderate intensity exercise resulted in no improvement in insulin action whereas exercise with energy deficit resulted in a decline in fasting leptin, lower hepatic glucose during glucose infusion, and improved insulin action [93]. Horowitz et al. [94] examined the effects of post-exercise energy deficit on substrate availability and oxidation without reducing carbohydrate availability by feeding high- and lowfat meals [94]. Despite identical blood glucose and insulin levels, plasma fatty acid and glycerol concentrations were elevated 3 to 4-fold during energy deficit compared with energy balance, and carbohydrate metabolism was 40% lower in the morning after the exercise and meal. In related studies, the addition of fat calories to meals after exercise did not alter glucose tolerance, despite increases in IMTG, as long as carbohydrate ingestion was unchanged [95], and overnight lipid infusion after exercise did not change post-exercise insulin sensitivity [96]. In contrast, in sedentary subjects, acutely increasing systemic fat availability, IMTG concentration, and positive energy balance induce insulin resistance. Thus, it seems exercise may play an important role in mediating the relationship between increased fatty acid availability and insulin sensitivity. Further work is needed to fully elucidate the independent and combined effects of energy restriction, diet composition, physical activity, and weight loss on health.

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7 Conclusions and Recommendations While the exact mechanisms of action and optimal doses for specific outcomes remain uncertain, there is little doubt that regular physical activity offers a number of powerful health benefits that may ameliorate diet-induced chronic disease in men and women [97]. Current PA recommendations to prevent weight gain are 1,200–2,000 kcal per week of energy expended (this is to prevent a weight gain of more than 3% in most adults) [98]. PA will enhance weight loss if diet restriction is modest but not severe (i.e.,
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67. Miller WJ, Sherman WM, Ivy JL. Effect of strength training on glucose tolerance and post-glucose insulin response. Med Sci Sports Exerc 1984; 16: 539–543. 68. Fluckey JD, Hickey MS, Brambrink JK, Hart KK, Alexander K, Craig BW. Effects of resistance exercise on glucose tolerance in normal and glucose-intolerant subjects. J Appl Physiol 1994; 77: 1087–1092. 69. Guo Z, Burguera B, Jensen MD. Kinetics of intramuscular triglyceride fatty acids in exercising humans. J Appl Physiol 2000; 89: 2057–2064. 70. Watt MJ, Heigenhauser GJ, Dyck DJ, Spriet LL. Intramuscular triacylglycerol, glycogen and acetyl group metabolism during 4 h of moderate exercise in man. J Physiol 2002; 541: 969–978. 71. Lee DC, Sui X, Blair SN. Does physical activity ameliorate health hazards of obesity?. Br J Sports Med 2009; 43: 3–4. 72. Lee CD, Blair SN, Jackson AS. Cardiorespiratory fitness, body composition, and all-cause and cardiovascular disease mortality in men. Am J Clin Nutr 1999; 69: 373–380. 73. LaMonte MJ, Blair SN. Physical activity, cardiorespiratory fitness, and adiposity: contributions to disease risk. Curr Opin Clin Nutr Metab Care 2006; 9: 540–546. 74. Li TY, Rana JS, Manson JE et al. Obesity as compared with physical activity in predicting risk of coronary heart disease in women. Circulation 2006; 113: 499–506. 75. Hu G, Tuomilehto J, Silventoinen K, Barengo N, Jousilahti P. Joint effects of physical activity, body mass index, waist circumference and waist-to-hip ratio with the risk of cardiovascular disease among middle-aged Finnish men and women. Eur Heart J 2004; 25: 2212–2219. 76. Weinstein AR, Sesso HD, Lee IM et al. The joint effects of physical activity and body mass index on coronary heart disease risk in women. Arch Intern Med 2008; 168: 884–890. 77. Weinstein AR, Sesso HD, Lee IM et al. Relationship of physical activity vs body mass index with type 2 diabetes in women. JAMA 2004; 292: 1188–1194. 78. Rana JS, Li TY, Manson JE, Hu FB. Adiposity compared with physical inactivity and risk of type 2 diabetes in women. Diabetes Care 2007; 30: 53–58. 79. Sui X, Hooker SP, Lee IM et al. A prospective study of cardiorespiratory fitness and risk of type 2 diabetes in women. Diabetes Care 2008; 31: 550–555. 80. Hu G, Barengo NC, Tuomilehto J, Lakka TA, Nissinen A, Jousilahti P. Relationship of physical activity and body mass index to the risk of hypertension: a prospective study in Finland. Hypertension 2004; 43: 25–30. 81. Rankinen T, Church TS, Rice T, Bouchard C, Blair SN. Cardiorespiratory fitness, BMI, and risk of hypertension: the HYPGENE study. Med Sci Sports Exerc 2007; 39: 1687–1692. 82. Phinney SD, Horton ES, Sims AH, Hanson JS, Danforth JE, Lagrange BL. Capacity for moderate exercise in obese subjects after adaptation to hypocaloric ketogenic diet. J Clin Invest 1980; 66: 1152–1161. 83. Donnelly JE, Pronk NP, Jacobsen DJ, Pronk SJ, Jakicic JM. Effects of a very-low-calorie diet and physicaltraining regimens on body composition and resting metabolic rate in obese females. Am J Clin Nutr 1991; 54: 56–61. 84. Ballor DL, Katch VL, Becque MD, Marks CR. Resistance weight training during caloric restriction enhances lean body weight maintenance. Am J Clin Nutr 1988; 47: 19–25. 85. Svendsen OL, Hassager C, Christiansen C. Effect of an energy-restrictive diet, with or without exercise, on lean tissue mass, resting metabolic rate, cardiovascular risk factors, and bone in overweight postmenopausal women. Am J Med 1993; 95: 131–140. 86. Goodpaster BH, Kelley DE, Wing RR, Meier A, Thaete FL. Effects of weight loss on regional fat distribution and insulin sensitivity in obesity. Diabetes 1999; 48: 839–847. 87. Henry RR, Gumbiner B. Benefits and limitations of very-low-calorie diet therapy in obese NIDDM. Diabetes Care 1991; 14: 802–823. 88. Ross R, Janssen I, Dawson J et al. Exercise-induced reduction in obesity and insulin resistance in women: a randomized controlled trial. Obes Res 2004; 12: 789–798. 89. Janssen I, Fortier A, Hudson R, Ross R. Effects of an energy-restrictive diet with or without exercise on abdominal fat, intermuscular fat, and metabolic risk factors in obese women. Diabetes Care 2002; 25: 431–438. 90. Cox KL, Burke V, Morton AR, Beilin LJ, Puddey IB. Independent and additive effects of energy restriction and exercise on glucose and insulin concentrations in sedentary overweight men. Am J Clin Nutr 2004; 80: 308–316. 91. Cartee GD, Young DA, Sleeper MD, Zierath J, Wallberg-Henriksson H, Holloszy JO. Prolonged increase in insulin-stimulated glucose transport in muscle after exercise. Am J Physiol 1989; 256: E494–E499.

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92. Kawanaka K, Han DH, Nolte LA, Hansen PA, Nakatani A, Holloszy JO. Decreased insulin-stimulated GLUT-4 translocation in glycogen-supercompensated muscles of exercised rats. Am J Physiol 1999; 276: E907–E912. 93. Black SE, Mitchell E, Freedson PS, Chipkin SR, Braun B. Improved insulin action following short-term exercise training: role of energy and carbohydrate balance. J Appl Physiol 2005; 99: 2285–2293. 94. Horowitz JF, Kaufman AE, Fox AK, Harber MP. Energy deficit without reducing dietary carbohydrate alters resting carbohydrate oxidation and fatty acid availability. J Appl Physiol 2005; 98: 1612–1618. 95. Fox AK, Kaufman AE, Horowitz JF. Adding fat calories to meals after exercise does not alter glucose tolerance. J Appl Physiol 2004; 97: 11–16. 96. Schenk S, Cook JN, Kaufman AE, Horowitz JF. Postexercise insulin sensitivity is not impaired after an overnight lipid infusion. Am J Physiol Endocrinol Metab 2005; 288: E519–E525. 97. Haskell WL, Lee IM, Pate RR et al. Physical activity and public health: updated recommendation for adults from the American College of Sports Medicine and the American Heart Association. Med Sci Sports Exerc 2007; 39: 1423–1434. 98. Donnelly JE, Blair SN, Jakicic JM, Manore MM, Rankin JW, Smith BK. American College of Sports Medicine Position Stand. Appropriate physical activity intervention strategies for weight loss and prevention of weight regain for adults. Med Sci Sports Exerc 2009; 41: 459–471. 99. Sacks FM, Bray GA, Carey VJ et al. Comparison of weight-loss diets with different compositions of fat, protein, and carbohydrates. N Engl J Med 2009; 360: 859–873.

Subject Index

Note: Locators followed by ‘f’ and ‘t’ refer to figures and tables respectively.

A ACAT inhibitors, 228 Adiposity, 444–445 exercise, effect of, 445 optimal exercise “dose,” 444 weight maintenance after weight loss, 445 ADMA, see Asymmetric dimethylarginine (ADMA) Aerobics Center Longitudinal Study, 448 AFB1, 277 on polymorphonuclear leukocyte (PMN) chemotaxis and chemiluminescence (CL), 295 Aflatoxins, 275, 277, 282, 289, 297 Agriculture, 48, 57, 97 Animal fat, 58, 115, 220, 311 Animal model obesity, genes involved in, 194t Anthropogenic and naturally produced contaminants in fish oil beneficial effects of consumption of fish oils rich in n–3 unsaturated fatty acids, 322 neurologic development, 323 n–3 fatty acids and cardiovascular diseases, 322–323 decontamination of commercial fish oil supplements, 334–335 intake of contaminants through consumption of FODS, 333–334 toxic contaminants from fish oil dietary supplements anthropogenic contaminants, 324–331 naturally produced halogenated compounds, 331–333 Anthropogenic contaminants, 324, 336 brominated flame retardants, 328–330 hexabromocyclododecane, 329–330

polybrominated diphenyl ethers, 329 mercury and methyl mercury, 330–331 organochlorine pesticides, 328 polychlorinated biphenyls, 324–325 polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans, 325–328 “Anti-obesity” public health, 431 voices, 434 Antioxidants, 10, 86, 173, 237, 259, 289–290 food lipids and, 251–253 antioxidants and food quality, 265–267 free radicals and reactive oxygen and nitrogen species, 253–255 lipid peroxidation in food and its consequences, 261–265 meat consumption and cancer, 260–261 three levels of antioxidant defense, 255–260 trends in food industry, 267–269 Anxiety, 7–8, 75 Apoptosis, 279 distinguishable from necrosis, 290 “programmed cell death” or, 290 Aquaculture, 314 wild versus farmed seafood, 314–315 Asian paradox, see Social class, food intakes and risk of coronary artery disease in developing world Aspergillus, 276–278 Asymmetric dimethylarginine (ADMA), 410 Atherosclerosis, 109, 157 inflammation in process of, 161–162 saturated fat intake and, 114–115

F. De Meester et al. (eds.), Modern Dietary Fat Intakes in Disease Promotion, Nutrition and Health, DOI 10.1007/978-1-60327-571-2,  C Springer Science+Business Media, LLC 2010

455

456

Attention-deficit hyperactivity disorder, role of modern western diets Abbreviated Symptom Questionnaire (ASQ), 355 allergic conditions, 352 Attention Problem and Motor Excess of the Revised Behavior Problem Checklist, 353 conduct disorder, 352 Conners’ Hyperactivity Factor, 353–354 definition, 351 dihomo-gamma-linolenic acid and arachidonic acid, 352 Disruptive Behavior Disorders (DBD) Rating Scale for Attention, 355 dyslexia, 352 “effect of docosahexaenoic acid containing food administration on symptoms of ADHD, placebo-controlled double-blind study,” 357 emotional and mood disorders, 352 emotional disorders, anxiety and depression, 352 fatty acid supplementation, 354 Full Scale Attention Control Quotient, 355 hyperactivity, examples of, 351 Intermediate Visual and Auditory/Continuous Performance Test (IVA/CPT) Full Scale Response Control Quotient, 355 physical fatty acid deficiency, 352 sleep problems, 352 somatic complaints, 352 Tests of Variables of Attention (TOVA), 354 Attention Problem and Motor Excess of the Revised Behavior Problem Checklist, 353 Auditory Attention Quotient, 355 Auditory Response Control Quotient, 355 B Beauvericin, 275, 282 Beneficial health effect, 216 Bienestar Health Program, 374 Bile acid absorption inhibitors, 228 Bioactive compounds, 231 Biological effects of mycotoxin, 276 Biomarkers, effect of lifestyle factors on, 13f Blood lipids, 207–208 changes after low-carbohydrate diet rich in saturated fat, 111t composition via dairy products, modification of, 208–210 influence of saturated fat on, 110–111 Body composition, 121–122

Subject Index

Bodyweight, saturated fat and, 115 Buffalo meat from East Africa vs. beef fillet in UK, 103f Butter, 216 C Calorie-dense foods, 375–376 Cancer, 91 CLA and, 127–128 meat consumption and, 260–261 partially hydrogenated fats in, 91 Cardiac structural and functional changes in genetically modified models of obesity, 199 alternations in cardiac structure and function, 201 genes, 200–201 Cardiovascular disease, 43 burden in Asia, 47–48 blood pressure variability, 51 coronary artery disease, 51–52 hypertension, 48–50 type 2 diabetes mellitus, 51 health-promoting effects of optimal Se status, 383–386 and its management, cholesterol and, 228–229 link between obesity and, 194 n–3 Fatty Acids and, 322–323 role of homocysteine, see Homocysteine, role in cardiovascular disease Cardiovascular health, partially hydrogenated fats in, 89–91 “Cardiovascular incapability,” 155, 158, 161 statins for anti-inflammatory actions of statins, 162–164 antioxidative effects of statins, 166 effects of statins on myocardial protection, 169 effects of statins on neovascularization, 168 effects of statins on platelets activation and thrombogenesis, 166–168 inflammation in process of atherosclerosis, 161–162 oxidative stress in atherogenesis, 165–166 statins’ actions for carotid artery endothelial dysfunction, 157–159 vascular endothelial function evaluation and effect of statins, 159–160 vascular smooth muscle dysfunction and statin, 160–161 Cardiovascular incapability parameters, 159t Cardiovascular mortality, 188–189 Cardiovascular protection, 236

Subject Index

Carotid artery disease, 154 prevention by lipid lowering, 157 promotion of disease in, see Dietary fat intake Carotid artery vasospasm, 159 CATCH, see Child and Adolescent Trial for Cardiovascular Health (CATCH) CATCH Eat Smart Program, 374 CATCH-ON, 374 CD36, 238–239 CDC, see Centers for Disease Control (CDC) Centers for Disease Control (CDC), 345 CETP inhibitors, 228 Child and Adolescent Trial for Cardiovascular Health (CATCH), 374 Children measurement/prevalence of overweight in, 372 school-based nutrition interventions Children’s Activity and Nutrition (Texas I-CAN!), 375 See also School-based foods to lower obesity and disease risk Children’s Activity and Nutrition (Texas I-CAN!), 369 Cholesterol, 8, 10, 154–155, 185, 216–217 cardiovascular disease, and its management, 228–229 Cholesterol-lowering drugs, 230 trials, 230 Cholesterol-lowering nutraceuticals, 230–231 CD36 and α-Tocopherol, 238–239 organosulfur compounds, 234–235 other dietary products, 239 phytoestrogens, 233 phytosterols, 234 plant proteins, 235–237 polyphenols, 231–233 tocopherols, 237–238 Chronic disease, 74 physical activity and fitness attenuate obesity and, 448 prevalence of risk factors in relation to social class, 53t Chronic fatigue syndrome, see Myalgic encephalomyelitis CLA, alteration of human body composition and tumorigenesis by isomers of, 121–122 CLA and cancer, 127–128 CLA and human body composition, 122–127 potential adverse effects of specific CLA isomers, 128–129 Cobalamin (B12) processing defects, 406 Coenzyme Q10, 11 Cognitive health, partially hydrogenated fats in, 90–91

457

Cognitive impairment, 7, 23 Columbus concept, 8 Comfort foods, 75 Competitive food sales, 375–376 calorie-dense foods, 375–376 restriction on competitive foods, 376 See also School-based foods to lower obesity and disease risk Complexation processes, 219–220 Conjugated linoleic acid (CLA), 121–122, 133 alteration of human body composition and tumorigenesis by isomers of, 121–122 and cancer, 127–128 effects of isomers on body weight and composition in human subjects, 123t–125t and human body composition, 122–127 potential adverse effects of specific isomers, 128–129 Conners’ Hyperactivity Factor, 353–354 Coronary angiography, 164f Coronary artery disease, 51–52 prevalence of, 50t Coronary disease, in Indian women, food intakes and social class, 55t Coronary heart disease and homocysteine, risk of European Concerted Action Project, 409 Hcy correlations, 409 hyperhomocysteinemia, 409 increased risk of vascular disease, associated with, 409 Coronary mortality, 112 Coronary risk factors, 52 prevalence of, 53 Cystathionine β-synthase, 408 See also Homocysteine, role in cardiovascular disease D Dairy products, 206–207 saturated fat, 221 Deadly quartet, see Metabolic syndrome Depression, 20, 22, 174 “Designer” meat, 266 DHA, see Docosahexaenoic acid (DHA) Diabetes, 252 noninsulin-dependent diabetes (NIDD), 135 Se roles in, 391–394 GDM, 392 Glutathione peroxidase (GSH-Px) and Se in type 2 diabetes, 393 insulin-mimic properties in vitro and in vivo, 393 oxidative stress, reduction of, 410

458

Diabetes (cont.) preventive intervention for diabetes-accelerated atherosclerosis, 394 Se-proteins, pancreatic cell function improvement, 394 Se treatment of diabetics, benefits, 393 STZ, treatment of, 392 type 2, 51 prevalence, 49t saturated fat and, 115 Diagnostic and Statistical Manual of Mental Disorders, fourth edition, Text Revision (DSM-IV-TR), 351 Diet during childhood years, 373 DHA presence in, 307–308 effect of school environment on, 35 EPA presence in, 307–308 exercise versus, see Exercise guidelines in schools, 346 and our health, 417–418 concept of correct diet, 418 disappearance of nutritional deficiencies, 418 Mediterranean diet, 418 presence of EPA and DHA in, 307–308 in schools to lower obesity and disease risk, see School-based foods to lower obesity and disease risk Dietary antioxidant treatment, 423 of chronic diseases with plant polyphenols, 423 Dietary energy derived from wild and domestic beef carcass, 100t Dietary fat in insulin resistance and type 2 diabetes clinical trials and epidemiological studies, 363 disorders of lipid metabolism, 364–365 diet-heart hypothesis, 364 recommendations, by American Dietetic Association, 364–365 hypertension, 365 inverse relationship between monounsaturated FA and cardiovascular mortality, 365 insulin resistance, 363 omega-3 (n-3) FAs, 363 lipid oversupply to skeletal muscles, 361–362 altered lipid metabolism, 361 dietary fats on development of insulin resistance on rats, 361 diet rich in n-6 polyunsaturated fat, 362 mechanistic evidence in the role of dietary fat, 360–361 commonly ingested saturated FAs, 360 intracellular insulin signaling, 360

Subject Index

intracellular receptor pathways for FA signaling, 360 PPAR family, 360 quality of dietary fat, 360 mitochondrial dysfunction, 362–363 diet rich in n-3 FA from flaxseed, 363 impaired flux of FAs into mitochondria, 362 obesity, 364 controversies, dietary fat, 364 oxidative stress, 362 “heart-healthy” meal, 362 lipoic acid-supplemented high-fat diet, 362 Dietary fat intake, 155–156 guidelines to physician, nurses, and health, 169–170 adverse events of statin therapy, 171–174 remaining safe, 171 safe use of statins, 170 and increasing consumption of meals at fast food restaurants, 33–34 and lipid lowering, 155–156 statins for cardiovascular incapability anti-inflammatory actions of statins, 162–164 antioxidative effects of statins, 166 effects of statins on myocardial protection, 169 effects of statins on neovascularization, 168 effects of statins on platelets activation and thrombogenesis, 166–168 inflammation in process of atherosclerosis, 161–162 oxidative stress in atherogenesis, 165–166 statins’ actions for carotid artery endothelial dysfunction, 157–159 vascular endothelial function evaluation and effect of statins, 159–160 vascular smooth muscle dysfunction and statin, 160–161 statins in clinical trials, 157 therapeutic intervention coenzyme Q10, 174 L-Carnitine, 174–175 lipid lowering versus statin therapy in carotid artery disease, 175–176 Dietary fiber, 36 Dietary guidelines, 65t Dietary intake, 19–20 Dietary plant extracts to modify effects of high-fat modern diets diet and our health, 417–418 concept of correct diet, 418

Subject Index

disappearance of nutritional deficiencies, 418 Mediterranean diet, 418 dietary antioxidant treatment of chronic diseases with plant polyphenols, 423 food polyphenols, role of, 421–423 antioxidant capability, 422 apoptosis, 423 grape polyphenols, 422 mechanism of action of grape seed polyphenols on atherosclerosis, 422f natural products, 421 protease inhibition, 423 Olea europaea L. (Olive), 426–428 See also Olives (Olea europaea L.) optimal nutrition and “nutraceuticals,” 420–421 evolution from traditional principle, 420 “phytochemical products,” 420 tradition and popular wisdom, 421 response to stress and “nutrigenomics,” 418–420 genetic screening, 419 “metabolic adaptation,” 418 methylenetetrahydrofolate reductase (MTHFR), 420 optimal nutrition, 419 percentage of adults with obesity in industrialized and developing countries, 419f “stress reaction,” 420 standardization, 428 dietary antioxidant treatment, 423 GAPs, 428 Vitis vinifera L., 423–426 See also Grapes (Vitis vinifera L.) Dietary recommendations, 62, 306, 419 United States and international dietary recommendations, 91–92 Dietary supplements, cholesterol, and cardiovascular disorders, 227–239 atherosclerosis, 229–230 cholesterol, cardiovascular disease, and its management, 228–229 cholesterol-lowering nutraceuticals, 230–231 CD36 and α-Tocopherol, 238–239 organosulfur compounds, 234–235 other dietary products, 239 phytoestrogens, 233 phytosterols, 233 plant proteins, 235–237 polyphenols, 231–233 tocopherols, 237–238 Dietary supply of fat, trends in, 61t Dietary trials, saturated fat, 116

459

Diet failure, 435 Dioxin-like PCBs (DL-PCB), 306 Dioxins, 325 Disease prevention, 382–383, 420, 422 Disruptive Behavior Disorders (DBD) Rating Scale for Attention, 355 Docosahexaenoic acid (DHA), 264 chemical structure of, 9f presence in human diet, 307–308 DON, 279–280 Do not diet, adverse effects of the weight centered health paradigm concerns about weight-centered health paradigm, 432–433 determinants of weight gain, 435 dietary restraint and radical weight-control behaviours, 435 diet failure, 435 dieting, 435 “frequent dieters”/“infrequent dieters”/“nondieters,” 435 Growing Up Today Study (GUTS), 435 ineffective at controlling body weight, 434 physical activity, 434 evidence of weight-centered health paradigm, 433–434 “anti-obesity” voices, 434 “fat-phobia,” 434 “globesity,” 433 “obesity epidemic,” 434 weight-centered health policies and programmes for selected countries, 434t harmful effects of the weight-centered health paradigm, 436 death, 437 disordered eating, 437 dieting, 436 discrimination, 437 dissatisfaction, 436 weight cycling, 436 “yo-yo syndrome,” 437 ideal “healthy” body, 432–433 number of articles that include the term “obesity,” 432f “obesity,” 432 “weight-centered health paradigm,” 432 tenets of the weight-centered health paradigm, 433 DON (ribotoxic trichothecene deoxynivalenol) ribosome, role of, 293 ribotoxin DON, 292 treatment with, 292–293 Drug trials, cholesterol-lowering, 185–189 Dyslexia, 352

460

E Economic development, western diet, and obesity, 74–77 Ectopic fat, 446 “Effect of docosahexaenoic acid containing food administration on symptoms of ADHD, placebo-controlled double-blind study” (case study), 354 Eicosapentaenoic acid (EPA), 8, 307 chemical structure of, 9f presence in human diet, 307–308 Emotional and mood disorders, 352 Endothelium, 159 Enniatins, 275 ENOS, see Nitric oxide synthase (eNOS) Environmental change effect of school environment on diet, 35 environmental factors contribute to diet, 373 See also School-based foods to lower obesity and disease risk EPA, see Eicosapentaenoic acid (EPA) Ergot alkaloids, 275, 281 Essential fatty acid content of beef compared to three wild species, 106t European Concerted Action Project, 409 Exercise adiposity, effect of, 444–445 counter effect on caloric restriction, 445 versus diet with and without weight loss, 448–449 meals ingested after exercise, 449 obese women/men, studies on, 449 post-exercise energy deficit, 449 visceral fat, 445–446 weight training and endurance exercise, 448 endurance, 447 optimal “dose,” 444 resistance, 445–446 single bout and multiple bouts, 448 weight maintenance after weight loss, 445 See also Physical activity in diet-induced disease causation and prevention in women and men F Fast foods, 74–75 high fat content of, 75 industry, 78–79 reasons for popularity, 79 Fat distribution, 445–447 development of obesity, 446 ectopic fat storage, 446 importance of, 446

Subject Index

intramuscular triglycerides (IMTG), 446 “metabolic paradox,” 446–447 STRRIDE study, 446 visceral fat depot, 445–446 visceral fat reduction with excercise, 446 See also Physical activity in diet-induced disease causation and prevention in women and men Fat-modified dairy products and blood lipids in humans, 205–206 blood lipids, 207–208 dairy products, 206–207 modification of blood lipid composition via dairy products, 208–210 application, 210 Fat-modified milk, 209 “Fat-phobia,” 434 Fat–protein calories in chicken, 101t Fats and oil consumption, 58–59 Fatty acid ratios in free-living and domestic animals, 96–98 discussion, 103–107 methods, 98–99 results, 99–103 Fatty acids, 206 distribution, in cow’s milk, 207t metabolism of essential, 9f ω-3 fatty acids, see Omega-3 fatty acids ω-6 fatty acids, see Omega-6 fatty acids Fatty liver induced by CLA, see Insulin resistance and nonalcoholic fatty liver disease induced by CLA in humans FB1, 280 transcript profiling using oligonucleotide arrays, 295 FFA, see Free fatty acid (FFA) Field mycotoxins, see Fusarium mycotoxins Fish consumption, 305–306 beneficial aspects of fish consumption, 307 EPA and DHA, 307–309 iodine, 310 vitamin D, 309–310 sustainability aquaculture, 314 depletion of natural fish stocks, 314 wild versus farmed seafood, 314–315 toxicological aspects of fish consumption, 310 mercury, 310–311 PCDFs, PCDDs, PCBs, 311–312 right balance, 313 Fish oil dietary supplements, 322 PBDEs, HBCD, and total mercury (Hg + MeHg) in, 330t toxic contaminants from

Subject Index

anthropogenic contaminants, 324–331 naturally produced halogenated compounds, 331–333 Fluvastatin, 163–164 antioxidative effect of, 167f Food, 72 antioxidants and, 265–267 intakes (g/day) in relation to social class, 53t lipid peroxidation in, 261–265 Food consumption global and regional per capita, 61t patterns and body mass index of women, 59t and trends, 57–58 in western societies, changing, 4–7 Food contamination with mycotoxins, 283–285 detection of DON in food products, 285 incidence and mean values of OTA content of wheat bread from different countries, 284t International comparisons of AFM1 levels in urine, 27t maximum limits for mycotoxins in foods in various European countries and US, 286–287t milk and dairy products/breast milk, testing of, 283 national estimates of intake of fumonisin B1 in Europe and in world, 286t ochratoxin in tissue and fluids of humans from various countries, 284t Food in schools, 372–373 NSLP, 373 school lunches, 30 calories, 373 See also School-based foods to lower obesity and disease risk Food intakes social class and coronary disease in Indian women, 55t Food lipids and antioxidants, 251–253 antioxidants and food quality, 265–267 free radicals and reactive oxygen and nitrogen species, 253–255 lipid peroxidation in food and its consequences, 261–265 meat consumption and cancer, 260–261 three levels of antioxidant defense, 255–260 trends in food industry, 267–269 Food Research and Action Center, 373 Food Service Directors/Management, 373–374 Fractionation technologies, 218–223 combining melt crystallization with short-path distillation, 220–223

461

complexation processes, 219–220 fractionation with solvents, 219 melt crystallization fractionation, 220 short-path distillation, 220 supercritical CO2 extraction, 219 Free fatty acid (FFA), 447 “Frequent dieters,” 435 Full Scale Attention Control Quotient, 355 Fumonisins, 280, 285, 289 Fungal genera are Aspergillus, Fusarium, and Penicillium, 275 Fusaproliferin, 275 Fusarium mycotoxins, 275 G GAPs, see Good agricultural practices (GAPs) GDM, see Gestational diabetes mellitus (GDM) Gene expression, 290 Genes, 200–201 Genetic obesity, 199 Genetic risk factors, 51t Genetic screening, 419 Gestational diabetes mellitus (GDM), 392 “Globesity,” 433 Glucosinolates, 234 Glutathione peroxidase (GSH-Px) and Se in type 2 diabetes, 393 Good agricultural practices (GAPs), 428 Grape seed proanthocyanidins (GSPs), 423 Grapes (Vitis vinifera L.), 423–426 “antioxidant effects,” 423 antithrombotic effect, 424 atherosclerosis, reduction of, 423 biological effect in vivo, 425–426 estimated GSP dietary intake, 425 levels of plasma cholesterol, reduction by GSP, 425 oxidative stress, 423–424 platelet-derived growth factor (PDGF) receptor signaling, 424 structure of procyanidins, the main component of proanthocyanidins, 424f TNF-á-induced expression of vascular adhesion molecule-1 (VCAM-1), 425 Growing Up Today Study (GUTS), 435 GSPs, see Grape seed proanthocyanidins (GSPs) GUTS, see Growing Up Today Study (GUTS) H Haber–Weiss reaction, 253 Halogenated compounds, naturally produced, 331–333 Halogenated dimethyl bipyrroles, 332–333

462

Health at every size, 438 guidelines to physician, nurses, and adverse events of statin therapy, 171–174 remaining safe, 171 safe use of statins, 170 partially hydrogenated fats in cancer, 91 cognitive health, 890–91 maternal health, 90 metabolic and cardiovascular health, 89–90 obesity, 91 Health-promoting effects of optimal Se status aging, 389–390 low plasma Se, 390 plasma Se, decrease in, 389 quality of life, 391 cancer, 383–386 mechanisms, chemopreventive effects of Se, 385 protective effects, 385 purified SeMet, 385 cardiovascular diseases, 386–387 atherosclerosis, 387 myocardial energy metabolism and contractile proteins, 386 preventive intervention for diabetesaccelerated atherosclerosis, 387 Selenoprotein W, 386 other diseases, 391 epileptic patients, role of Se, 391 Se deficiency in goitre, 391 reproductive disorders, 388–389 GSH-Px, 388 oxidative stress, 388 Se supplement on pregnancy, 389 in vitro motility and oxygen uptake of human sperm, 388 Healthy meals via antioxidant enrichment and decreased lipid peroxidation, 267t Heart, 43, 199 disease, 45 expression of leptin and its receptors in, 194–195 Hexabromocyclododecane (HBCD) in fish oil dietary supplements, 330t High-fat diets, 360, 362 relationship between availability and intake of, 76f HMG-CoA reductase inhibitors, 157 Homocysteine, role in cardiovascular disease determinants of homocysteine, 408–409 factors that influence plasma homocysteine levels, 408t

Subject Index

homozygous CβS deficiency, 409 Hcy and vitamins, 411–412 folate and vitamins B6 and B12 , 411 regular fruit and vegetable intake, 411 HHcy, 406 homocysteine metabolism, 407f methionine, essential amino acid/ remethylation of Hcy to methionine, 407 pathogenic mechanisms of HHcy, 410–411 ADMA, 410 DNA methylation impairment, 410 endothelial cell desquamation, production of, 411 homocysteine-induced oxidative stress, 410 reactive oxygen species (ROS), 389 thiol generation, suppression, 410 risk of coronary heart disease European Concerted Action Project, 409 Hcy correlations, 409 hyperhomocysteinemia, 409 increased risk of vascular disease, associated with, 409 traditional risk factors, 405–406 Human health and mycotoxins, 276–277 adverse human health effects, 288–289 developmental defects, 289 exposure through several routes, 288 selected mycotoxin-producing fungi of relevance to children’s health, 288t some human diseases in which analytic and/or epidemiologic data, 288t Se deficiency in, 380–381 pharmacological/nutritional, approaches, 395 Se content in plant-based food, 395 Se-enriched yeast, 396 Se fertilization, results of workshop, 396 Se supplements in tablet or capsular, 395 Soil Se availability, 395 supplementation of staple foods, 396 Hydrogenated fats, 87 Hydrogenation reaction, 85f Hyperhomocysteinemia, 406 Hyperlipidemia, 171 Hypertension, 45, 48–50, 90, 205 inverse relationship between monounsaturated FA and cardiovascular mortality, 365 prevalence in rural and urban population of India, 49 See also Dietary fat in insulin resistance and type 2 diabetes

Subject Index

I Ideal “healthy” body, 432–433 number of articles that include the term “obesity,” 432f “obesity,” 433–434 “weight-centered health paradigm,” 432 IMTG, see Intramuscular triglycerides (IMTG) “Infrequent dieters,” 435 Insulin resistance, 363 and CLA, 134–140 hyperglycemic conditions, 135 lack of an effect of CLA, 139 men with abdominal obesity, 139 noninsulin-dependent diabetes (NIDD), 135 oral glucose tolerance test (OGTT), 135 quantitative insulin-sensitivity check index (QUIKI), 135 See also Insulin resistance and nonalcoholic fatty liver disease induced by CLA in humans omega-3 (n-3) FAs, 155 See also Dietary fat in insulin resistance and type 2 diabetes Insulin resistance and nonalcoholic fatty liver disease induced by CLA in humans CLA and insulin resistance, 134–140, 136t–138t hyperglycemic conditions, 135 lack of an effect of CLA, 139 men with abdominal obesity, 139 noninsulin-dependent diabetes (NIDD), 135 oral glucose tolerance test (OGTT), 138 quantitative insulin-sensitivity check index (QUIKI), 135 CLA and nonalcoholic fatty liver disease, 140–141 CLA supplementation on markers of NAFLD, 140 NAFLD, 140 CLA and weight loss, 134 normal weight human subjects, 134 overweight and obese subjects, 134 potential mechanisms for CLA action adipokines like leptin and adiponectin, 143 decrease in the concentration of MUFA, 142 fish oils, 142 pancreatic β-cell hyperplasia, 143 PPAR-γ, 143 spleen, exceptional, 142 reasons for discrepancies exercise, 435 fat content of the diets and its fatty acid composition, 141 insulin and glucose clamp methods, 142

463

Insulin resistance syndrome, see Metabolic syndrome Insulin sensitivity and lipid metabolism, 447–448 endurance exercise, 447 free fatty acid (FFA), 447 lipid metabolites, 447 resistance exercise, 447 single bout and multiple bouts of exercise, 448 whole-body glucose disposal capacity, 447 Interesterification, 217–218 Intermediate Visual and Auditory/Continuous Performance Test (IVA/CPT) Full Scale Response Control Quotient, 355 Intramuscular triglycerides (IMTG), 446 Iodine, beneficial aspects of fish consumption, 310 J “Junk” food, 353 K Keshan’s disease (KD), 381 dwarfism and joint deformation, 382 histopathological features, 381 Se-responsive bone and joint disease, 381 symptoms, 381 L L-Carnitine, 174–175 LDL receptor activators, 228 Leptin, 195–196 and obesity, 193–194 expression of leptin and its receptors in heart, 194–195 link between obesity and cardiovascular diseases, 194 effect on cardiac remodeling, 195–196 obesity-induced cardiac remodeling, 194 Linoleic acid (LA), 64, 207, 353 chemical structure of, 9f See also Conjugated linoleic acid (CLA) α-linolenic acid (ALA), 8 chemical structure, 9f Lipid peroxidation, 129, 254–255, 388, 447 in food and its consequences, 261–265 healthy meals via antioxidant enrichment and decreased, 267t Lipids, 11, 170, 208, 252–253 lowering and dietary fat intake, 155–157 versus side effects of statins, see Dietary fat intake versus statin therapy in carotid artery disease, 175 metabolism, disorders of, 364–365 diet-heart hypothesis, 364

464

Lipids (cont.) recommendations, by American Dietetic Association, 364 oversupply to skeletal muscles, 361–362 altered lipid metabolism, 361 dietary fats on development of insulin resistance on rats, 361 diet rich in n-6 polyunsaturated fat, 362 See also Dietary fat in insulin resistance and type 2 diabetes Lipoproteins, 89–90, 156, 165 Livestock products, 59–62 per capita consumption of, 62t Low-fat foods, 373 M Malondialdehyde (MDA), 166 Maternal health, partially hydrogenated fats in, 90 Meats sold for human consumption, storage and structural fats in, 102t Mechanisms for CLA action adipokines like leptin and adiponectin, 143 decrease in the concentration of MUFA, 142 fish oils, 142 pancreatic β-cell hyperplasia, 143 PPAR-γ, 143 spleen, exceptional, 142 See also Insulin resistance and nonalcoholic fatty liver disease induced by CLA in humans Mechanistic evidence in the role of dietary fat, 360–361 commonly ingested saturated FAs, 360 intracellular insulin signaling, 360 intracellular receptor pathways for FA signaling, 360 PPAR family, 360 quality of dietary fat, 360 See also Dietary fat in insulin resistance and type 2 diabetes Mediterranean diet, 230–231 Melt crystallization fractionation, 220 Melt crystallization, with short-path distillation, combining, 220 Mental health, 4, 20, 107 health—rising cost of mental ill health in UK, 96f Mercury (Hg + MeHg) in fish oil dietary supplements, 330t toxocological aspects of fish consumption, 310–312 Metabolic disorders, 88, 205 Metabolic health, partially hydrogenated fats in, 91 Metabolic syndrome, 205, 364

Subject Index

5,10-methylenetetrahydrofolate reductase, 406 Methylenetetrahydrofolate reductase deficiency, 406 Methylenetetrahydrofolate reductase (MTHFR), 420 Methyl mercury, 330–331 Milk and milk products, intake of, 206 Milk fat/modified milk fat/nonhydrogenated margarine, consuming postprandial changes in plasma triacylglycerols, 221f postprandial changes in plasma TRL-apo B-48/TRL-apo B-100, 222f Mitochondrial dysfunction, 362–363 diet rich in n-3 FA from flaxseed, 363 impaired flux of FAs into mitochondria, 362 See also Dietary fat in insulin resistance and type 2 diabetes Modified milk fat, 209, 216, 221 Moniliformin, 275 Monounsaturated fatty acids (MUFA), 11, 66, 77, 142, 206, 216 MTHFR, see Methylenetetrahydrofolate reductase (MTHFR) MUFA, see Monounsaturated fatty acids (MUFA) Myalgic encephalomyelitis role of modern western diets in antiviral actions of interferon, 347 biological illness, evidences, 346 dietary deficiency, 347 Oxford Criteria for chronic fatigue syndrome/Canadian Criteria, 346 placebo, use of, 347 revised CDC criteria, 345–346 Mycotoxin of concern, 276–281 Aflatoxin (AF), 277–278 Ergot, 281 Fumonisin B1, 280 mould growth and mycotoxin, related factors, 276 Ochratoxin A, 278–279 Patulin, 281 “storage mycotoxins,” 277 T-2 toxin, 279 Vomitoxin (deoxynivalenol, DON), 279–280 Zearalenone (ZEA), 280–281 Mycotoxins in human diet AFB1 on polymorphonuclear leukocyte (PMN) chemotaxis and chemiluminescence (CL), 295 and apoptosis, 290 distinguishable from necrosis, 290 “programmed cell death” or, 290

Subject Index

biological effects, 276 of concern, 276–281 mould growth and mycotoxin, related factors, 276 “storage mycotoxins,” 277 DON (ribotoxic trichothecene deoxynivalenol) ribosome, role of, 279 ribotoxin DON, 292 treatment with, 292 FB1, 295–296 transcript profiling using oligonucleotide arrays, 295 food contamination with mycotoxins, 283–285 detection of DON in food products, 285 incidence and mean values of OTA content of wheat bread from different countries, 284t International comparisons of AFM1 levels in urine, 283t maximum limits for mycotoxins in foods in various European countries and US, 286t–287t milk and dairy products/breast milk, testing of, 283 ochratoxin in tissue and fluids of humans from various countries, 284t some national estimates of intake of fumonisin B1 in Europe and in world, 286t fungal genera are Aspergillus, Fusarium, and Penicillium, 275 human health, 285–289 molecular mechanisms of mycotoxin action, major points, 289–290 mycotoxins and gene expression, 290 OA, 293–294 changes in gene expression, 294 in cultured kidney tubulus cells, 294 modulation of lipopolysaccharide (LPS), 294 RGN (regucalcin), 293 study using cDNA microarray technology, 294 oxidative stress as a consequence of mycotoxicoses, 289–290 primary classes, 275 problems that complicate mycotoxin prevention issues, 298 protection against mycotoxins, 296–297 animal self-defense against, 296 effects of esterified glucomannans (E-GM, Mycosorb), 297 E-GM can reduce AFM1, 297

465

lipid peroxidation, role of, 296 prevention of formation by special management programs, 296 synergistic interactions among, 282–283 Citrinin (CTN) and penicillic acid, 282 combinative toxicity of AFB1 and T-2, 282 Combined treatment with FB [1], BEA, and OTA, 282 DON and T-2 toxin, 282 T-2 toxin, 290–292 Bcl-2 homodimers, 291 expression of apoptosis-related genes, 291 expression of pro-inflammatory cytokines, 292 mitogen-activated protein kinase (MAPK)-related genes, 292 P450 1A-related activities, 292 ratio of Bax to Bcl-2 protein, 291 zearalenone, 296 N National School Lunch Program (NSLP), 373 Naturally produced brominated compounds, Median and concentration range, 332t n–3 Fatty Acids, 262, 308 Nitric oxide synthase (eNOS), 158 Nonalcoholic fatty liver disease and CLA, 140–141 CLA supplementation on markers of NAFLD, 140 NAFLD, 140 “Nondieters,” 435 NSLP, see National School Lunch Program (NSLP) Nutraceuticals, 239 cholesterol-lowering, 239 Nutrients, 25, 251–252 and affective function, 11–23 and brain function, 10–11, 11t and cognitive function, 23–24 effects on brain and psychological function, 11t percentage of intake, 54t psychological disorders related to, 12 “Nutrigenomics” and stress, 418–420 genetic screening, 419 “metabolic adaptation,” 418 MTHFR, 420 optimal nutrition, 419 percentage of adults with obesity in industrialized and developing countries, 419f “stress reaction,” 420 See also Dietary plant extracts to modify effects of high-fat modern diets

466

Nutritional–toxicological dilemma of fish consumption, 313 beneficial aspects of fish consumption, 307 EPA and DHA, 307–309 iodine, 310 vitamin D, 309–310 sustainability aquaculture, 314 depletion of natural fish stocks, 314 farmed seafood, 314 wild versus farmed seafood, 314–315 toxicological aspects of fish consumption, 310 mercury, 310–311 PCDFs, PCDDs, PCBs, 311–312 right balance, 313 Nutrition transition, characteristics of five patterns of, 5t–6t O OA, 293–294 changes in gene expression, 294 in cultured kidney tubulus cells, 294 modulation of lipopolysaccharide (LPS), 294 RGN (regucalcin), 293 study using cDNA microarray technology, 294 Obesity, 91, 193–196, 199 controversies, dietary fat, 364 and disease risk, school-based foods to lower, 371–376 economic development, western diet, and, 74–77 genes involved in animal model, 200 leptin and, 193–194 expression of leptin and its receptors in heart, 194–195 leptin: link between obesity and cardiovascular diseases, 194 leptin’s effect on cardiac remodeling, 195–196 obesity-induced cardiac remodeling, 194 partially hydrogenated fats in, 91 See also Dietary fat in insulin resistance and type 2 diabetes “Obesity epidemic,” 31, 434 Ochratoxins, 278, 282 Olives (Olea europaea L.), 423 DNA mutation, 427 free radical-scavenging properties, 427 hydroxytyrosol, 427 oleuropein and hydroxytyrosol chemical structure, 427f polyphenols, 426 in vivo effects of polyphenols, 427–428

Subject Index

See also Dietary plant extracts to modify effects of high-fat modern diets Omega-3 fatty acids, 11, 23, 25, 307 role in human body, 308–309 Omega-6 fatty acids, 155, 169 Omega-3/Omega-6 Polyunsaturated Fatty Acids (PUFAs), 8–10 Omega-3 PUFA on depressed mood and other affective manifestations, 14t–16t Optimal exercise “dose,” 444 Optimal nutrition and “nutraceuticals,” 420–421 evolution from traditional principle, 420 “phytochemical products,” 420 tradition and popular wisdom, 421 See also Dietary plant extracts to modify effects of high-fat modern diets Organochlorine pesticides (OCPs) in fish oil dietary supplements median and concentration range (ng/g oil) of, 326t–327t Organohalogenated contaminants, 333 Organosulfur compounds, 234–235 Overweight in children, measurement of, 372 Body mass index (BMI) calculation, 372 “Oxidation theory,” 424 Oxidative stress, 362 “heart-healthy” meal, 362 lipoic acid-supplemented high-fat diet, 362 See also Dietary fat in insulin resistance and type 2 diabetes Oxidative stress as consequence of mycotoxicoses, 289–290 feed-born stress factors, 289 thiobarbituric acid reactive substances (TBARS) accumulation, 289 Oxidative stress markers, 165t P Partially hydrogenated fats in US diet and their role in disease, 85–92 health effects, 88–89 intake of partially hydrogenated fats, 89 partially hydrogenated fats in health and disease cancer, 91 cognitive health, 91 maternal health, 90 metabolic and cardiovascular health, 89–90 obesity, 91 process of hydrogenation, 86 sources of trans fats, 86–88 United States and international dietary recommendations, 91–92 Partially hydrogenated oils, 87t

Subject Index

Penicillium, 275 Physical activity in diet-induced disease causation and prevention in women and men adiposity, 444–445 exercise, effect of, 444–445 optimal exercise “dose,” 444 weight maintenance after weight loss, 445 benefits of exercise versus diet with/without weight loss, 448–449 meals ingested after exercise, 449 obese women/men, studies on, 449 post-exercise energy deficit, 449 visceral fat, 445–446 weight training and endurance exercise, 448 chronic perturbations in energy balance, 444 fat distribution, 445–447 development of obesity, 446 ectopic fat storage, 446 importance of, 446 IMTG, 446 “metabolic paradox,” 446 STRRIDE study, 446 visceral fat depot, 445 visceral fat reduction with excercise, 446 insulin sensitivity and lipid metabolism, 142 endurance exercise, 447 free fatty acid (FFA), 447 lipid metabolites, 447 resistance exercise, 447–448 single bout and multiple bouts of exercise, 448 whole-body glucose disposal capacity, 447 physical activity and fitness attenuate obesity and chronic disease risk, 448 Phytoestrogens, 233 Phytosterols, 234 Plant proteins, 235–237 Plasma lipids, 56, 216–219 modified milk fat and, 215–223 Plasma triacylglycerol concentrations, modified milk fat reduces, 215–223 cow feeding modification, 216–217 fractionation technologies, 218–219 combining melt crystallization with short-path distillation, 220–223 complexation processes, 219–220 fractionation with solvents, 219 melt crystallization fractionation, 220 short-path distillation, 220 supercritical CO2 extraction, 219 interesterification, 217–218 Polybrominated diphenyl ethers (PBDEs) in fish oil dietary supplements, 330t

467

Polybrominated hexahydroxanthene derivatives, 332 Polybrominated methoxylated diphenyl ethers, 331–332 Polychlorinated biphenyls (PCB) chemical structures of, 312f in fish oil dietary supplements, 326t–327t Polychlorinated dibenzofurans (PCDF) chemical structures of, 312f in fish oil dietary supplements, 326t–327t Polychlorinated dibenzo-p-dioxins (PCDD) chemical structures of, 312f in fish oil dietary supplements, 326t–327t Polyphenols, 231–233, 421–423 antioxidant capability, 422 apoptosis, 423 grape polyphenols, 422 mechanism of action of grape seed polyphenols on atherosclerosis, 422f natural products, 421 protease inhibition, 423 See also Dietary plant extracts to modify effects of high-fat modern diets Polyunsaturated fatty acids (PUFA), 10–11, 156, 230, 322 acids in muscle tissue lipids of free-living and domestic bovids, 99t Poultry data, 101 PPAR agonists, 229 Prevalence of overweight in children, 372 National Health and Nutrition Examination Surveys (NHANES), 372 Protection against mycotoxins, 296–297 animal self-defense against, 296 effects of esterified glucomannans (E-GM, Mycosorb), 297 E-GM can reduce AFM1, 297 lipid peroxidation, role of, 296 prevention of formation by special management programs, 296 Proton neurospectroscopy, 346 Psychological disorders, 11 related to nutrients, 12f PUFA content of TG and PL in different meats, 104t means of, 105t R Reactive oxygen species (ROS), 165, 229–230 Refined foods, 73 Remodeling, 169 Resistance exercise, 447–448 Resveratrol, 233

468

S S-adenosylhomocysteine (SAH), 406 S-adenosylmethionine (SAM), 406 SAH, see S-adenosylhomocysteine (SAH) SAM, see S-adenosylmethionine (SAM) Saturated fat and bodyweight, 115 cohort and case–control studies of saturated fat intake, 113–114 cross-sectional studies, 112 dairy products, 115–116 dietary trials, 116 ecological studies, 111–112 influence of saturated fat on the blood lipids, 110–111 saturated fat intake and atherosclerosis, 114–115 and type 2 diabetes, 115 School-based foods to lower obesity and disease risk competitive food sales, 375–376 calorie-dense foods, 375–376 restriction on competitive foods, 376 food in schools, 372–373 NSLP, 373 school lunches, 30 calories, 373 implications for practice, 376 measurement of overweight in children, 372 Body mass index (BMI) calculation, 372 National School Lunch Program (NSLP), 373 prevalence of overweight in children, 372 National Health and Nutrition Examination Surveys (NHANES), 372 school-based nutrition interventions, 373–375 Bienestar Health Program, 374 CATCH Eat Smart Program, 374 CATCH-ON, 374 Child and Adolescent Trial for Cardiovascular Health (CATCH), 374 Children’s Activity and Nutrition (Texas I-CAN!), 375 Food Service Directors/Management, 374–375 low-fat foods, 373 School interventions related to nutrition, 373–375 Bienestar Health Program, 374 CATCH Eat Smart Program, 374 CATCH-ON, 374 Child and Adolescent Trial for Cardiovascular Health (CATCH), 374 Children’s Activity and Nutrition (Texas I-CAN!), 375 Food Service Directors/Management, 374–375 low-fat foods, 373

Subject Index

See also School-based foods to lower obesity and disease risk Seafood, 306–308 consumption, 306 nutritional-toxicological conflict related to increased, 306f wild versus farmed, 314–315 Selenium deficiency, 380–381 associated disease, 380 essentiality for human, 380 Kaschin-Beck disease, 380–382 Keshan’s disease (KD), 381 severe deficiency characteristics, 394 Selenium enigma, health implications of an inadequate supply controversy around Se roles in diabetes, 391–394 gestational diabetes mellitus (GDM), 392 Glutathione peroxidase (GSH-Px) and Se in type 2 diabetes, 393 insulin-mimic properties in vitro and in vivo, 393 oxidative stress, reduction of, 391 preventive intervention for diabetes-accelerated atherosclerosis, 394 Se-proteins, pancreatic cell function improvement, 394 Se treatment of diabetics, benefits, 393 STZ, treatment of, 392 different strategies to address Se deficiency in human, 395–396 pharmacological/nutritional, approaches, 395 Se content in plant-based food, 395 Se-enriched yeast, 396 Se fertilization, results of workshop, 396 Se supplements in tablet or capsular, 395 Soil Se availability, 395 supplementation of staple foods, 396 health-promoting effects of optimal Se status aging, 389–391 cancer, 383–386 cardiovascular diseases, 386–387 other diseases, 391 reproductive disorders, 388–389 meeting selenium requirement, 382–383 GSH-Px activity, 390 low daily selenium intakes in selected countries, 384t–385t RDI suggested by other countries, 383 selenium deficiency, 380–382 associated disease, 380 essentiality for human, 380

Subject Index

Kashin-Beck disease, 380–382 Keshan’s disease (KD), 381 SeMet, 385 Short-path distillation, 219 with melt crystallization, combining, 219 Social and cultural factors, diet and, 71–72 Social class, food intakes and risk of coronary artery disease in developing world, 43–44, 55t burden of cardiovascular disease in Asia, 47–48 blood pressure variability, 51 coronary artery disease, 51–52 hypertension, 48–50 type 2 diabetes mellitus, 51 food consumption patterns and trends, 57–58 fats and oil consumption, 58–59 fruit and vegetable availability and consumption, 62–63 livestock products, 59–62 nutritional and epidemiological transition in Asia, 53–55 South Asian paradox, 55–57 population growth in southeast Asia, 45t recommendations for dietary consumption, 63–66 social class and mortality, 44–47 social class, coronary risk factors, and Asian paradox, 52–53 Social context of dietary behaviors, 31–32 childhood influences affecting eating behavior, 32–33 dietary fat intake and increasing consumption of meals at fast food restaurants, 33–34 increasing availability of fruits and vegetables, 33 need for a change in school policies, 35 parental influences, positive role modeling, and family meals, 34–35 social context of feeding behavior, 32 social influences on dietary practices of adults, 35–36 social support interventions, 36–38 Statins, 157–160 anti-inflammatory actions, 162–164 for cardiovascular incapability, 176 anti-inflammatory actions of statins, 162–164 antioxidative effects of statins, 166 effects of statins on myocardial protection, 169 effects of statins on neovascularization, 168

469

effects of statins on platelets activation and thrombogenesis, 166–168 inflammation in process of atherosclerosis, 161–162 oxidative stress in atherogenesis, 165–166 statins’ actions for carotid artery endothelial dysfunction, 157–159 vascular endothelial function evaluation and effect of statins, 159–160 vascular smooth muscle dysfunction and statin, 160–161 in clinical trials, 157 effects on vascular endothelial function, 160f safe use of, 170 Statin therapy adverse events of, 171–174 in carotid artery disease, lipid lowering versus, 175–176 “Stress reaction,” 420 Stroke, 48 association between intake of saturated fat and, 113t mortality, 47 Syndrome X, see Metabolic syndrome Synergistic interactions among mycotoxin, 282–283 Citrinin (CTN) and penicillic acid, 282 combinative toxicity of AFB1 and T-2, 282 Combined treatment with FB [1], BEA, and OTA, 282 DON and T-2 toxin, 282 T TEF, see Thermic effect of food (TEF) Tests of Variables of Attention (TOVA), 354 Texas Public School Nutrition Implementation Policy, 376 Thermic effect of food (TEF), 445 α-Tocopherol, 238–239 Tocopherols, 237–238 Tocotrienols, 234, 237 Trans-fatty acids, 86, 141 dietary sources of, 88t sources, 86–88 structure of, 86f Trichothecenes, 293 T-2 toxin, 279 Bcl-2 homodimers, 291 expression of apoptosis-related genes, 291–292 expression of pro-inflammatory cytokines, 292 mitogen-activated protein kinase (MAPK)-related genes, 291 P450 1A-related activities, 292 ratio of Bax to Bcl-2 protein, 291

470

V Vasoregulatory endothelial functions, 159t Vegetable, supply per capita, 63t Visceral fat, 445–446, 449 Visual Attention Quotient, 355 Visual Response Control Quotient, 355 Vitamin D, beneficial aspects of fish consumption, 307–310 Vitamin Intervention for Stroke Prevention Trial, 412 W Weight-centered health paradigm concerns about, 434–435 determinants of weight gain, 435 dietary restraint and radical weight-control behaviours, 435 diet failure, 435 dieting, 435 “frequent dieters”/ “infrequent dieters”/“nondieters,” 435 Growing Up Today Study (GUTS), 435 ineffective at controlling body weight, 434 physical activity, 434 evidence of, 433–434 “anti-obesity” voices, 434 “fat-phobia,” 434 “globesity,” 433 “obesity epidemic,” 433 weight-centered health policies and programmes for selected countries, 434t

Subject Index

harmful effects of, 436 death, 437 dieting, 436 discrimination, 437 dissatisfaction, 436 weight cycling, 436 “yo-yo syndrome,” 437 tenets of, 433 Weight loss and CLA, 134 normal weight human subjects, 134 overweight and obese subjects, 134 See also Insulin resistance and nonalcoholic fatty liver disease induced by CLA in humans Western diet and behavior, 3–4 changing patterns of food consumption, 4–7 Columbus concept, 8 healthful change in behavior, 7–8 nutrients and affective function, 11–23 nutrients and brain function, 10–11 nutrients and cognitive function, 23–24 Omega-3 and Omega-6 Polyunsaturated Fatty Acids (PUFAs), 8–10 WHO, see World Health Organization (WHO) World Health Organization (WHO), 433 Y “Yo-yo syndrome,” 437 Z Zearalenone, 277

About the Editors

Fabien De Meester was until recently the president and CEO of the Luxembourg-based family-owned group BNLfood (www.bnlfood.com), formerly Belgian-based Belovo SA, egg science and technology. The brand “Belovo” stands for “Belgian Egg” (Latin translation). The group has specialized itself in the fractionation of eggs into value-added ingredients for the food, infant food, cosmetic, and pharmaceutical industries. In addition, the company has developed the Columbus Concept (www. columbus-concept.com), a program that pioneers “wild-type lipid nutrition,” i.e., balanced essential dietary/plasma fatty acid ratio and healthy dietary/blood cholesterol. Dr. De Meester is a Ph.D. in protein chemistry from the University of Liège (ULg) in Belgium. He was a postdoctoral fellow at the Weizmann Institute of Science (WIS) of Israel where he specialized in molecular biology. Then, he returned to Belgium, studied for an executive master degree in general management (CEPAC) at the Solvay Business School (SBS) and finally joined the family company at the age of 30 where he initially led the research–development–production departments while reshuffling the management of the company onto modern ISO standards. In early 1999, upon retirement of his father, he became the president and CEO of the Belovo company and on January 1, 2006, the BNLfood group was established. On May 1, 2009, he decided to step down from d2d management at BNLfood and to create his own venture, DMF, to further develop and promote his ideas on the market. His goals and strategy are to catalyze sustainable changes in the egg/food industry toward the inception of a modern science and technology-led business in the global economy. Dr. De Meester has published over 50 research articles, patents, and communications on topics related to organic chemistry, enzymology, biochemistry, molecular biology, food science and business and has organized a series of international workshops on the Columbus Concept. He has recently launched a 2-D concept of holistic health (www.tsimtsoum.net) that studies body–mind interactions at the chronobiological level. Fabien De Meester, Managing Director, DMF Ltd Co, Luxembourg Str 46, 6900 Marche/Famenne, Belgium

Dr. Sherma Zibadi received her M.D. degree from the Mashhad University of Medical School in 2001. Dr. Zibadi has recently completed her doctorate degree from the Department of Nutritional Sciences at the University of Arizona. Her main scholarly interest and experience involve the study of heart failure and its major risk factors such as hypertension, obesity, and metabolic syndrome, finding ways to prevent the undesirable cardiac alternations, and extend the healthy heart life span. Her current research focus lies in developing animal models of various forms of heart failure to study the potential mediators of cardiac remodeling process, which helps to identify new targets for the treatment of heart failure. Dr. Zibadi’s research also extends into alternative medicine, exploring the preventive and therapeutic effects of natural dietary supplements on heart failure and its major risk factors in both basic animal and clinical studies, translating lab research finding into clinical practice. Dr. Zibadi is the author of several full-length publications in prestigious journals and books and manuscripts submitted for publication or in preparation dealing with the underlying mechanisms of heart failure and complementary medicine as novel therapeutics against heart disease.

Ronald R. Watson attended the University of Idaho but graduated from Brigham Young University in Provo, Utah, with a degree in chemistry in 1966. He earned his Ph.D. in biochemistry from Michigan State University in 1971. His postdoctoral schooling in nutrition and microbiology was completed at the Harvard School of Public Health, where he gained 2 years of postdoctoral research experience in immunology and nutrition. From 1973 to 1974 Dr. Watson was assistant professor of immunology and performed research at the University of Mississippi Medical Center in Jackson. He was assistant professor of microbiology and immunology at the Indiana University Medical School from 1974 to 1978 and associate professor at Purdue University in the Department of Food and Nutrition from 1978 to 1982. In 1982 Dr. Watson joined the faculty at the University of Arizona Health Sciences Center in the Department of Family and Community Medicine of the School of Medicine. He is currently professor of health promotion sciences in the Mel and Enid Zuckerman Arizona College of Public Health. Dr. Watson is a member of several national and international nutrition, immunology, cancer, and alcoholism research societies. He is presently funded by the National Heart Blood and Lung Institute to study heart disease. In addition he has an NIH grant from NCCAM to study dietary supplements in modulating immune function and thus heart structure and function. For 30 years he was funded by Wallace Research Foundation to study dietary supplements in health promotion. Dr. Watson has edited more than 35 books on nutrition and other 53 scientific books. He has published more than 500 research and review articles.

About the Series Editor

Dr. Adrianne Bendich is clinical director, Medical Affairs, at GlaxoSmithKline (GSK) Consumer Healthcare where she is responsible for leading the innovation and medical programs in support of many well-known brands including TUMS and OsCal. Dr. Bendich had primary responsibility for GSK’s support for the Women’s Health Initiative (WHI) intervention study. Prior to joining GSK, Dr. Bendich was at Roche Vitamins Inc. and was involved with the groundbreaking clinical studies showing that folic acid-containing multivitamins significantly reduced major classes of birth defects. Dr. Bendich has coauthored over 100 major clinical research studies in the area of preventive nutrition. Dr. Bendich is recognized as a leading authority on antioxidants, nutrition and immunity and pregnancy outcomes, vitamin safety, and the cost-effectiveness of vitamin/mineral supplementation. Dr. Bendich is the editor of nine books including Preventive Nutrition: The Comprehensive Guide For Health Professionals coedited with Dr. Richard Deckelbaum and is the series editor of Nutrition and Health for Humana Press with 36 published volumes including Probiotics in Pediatric Medicine edited by Dr. Sonia Michail and Dr. Philip Sherman; Handbook of Nutrition and Pregnancy edited by Dr. Carol Lammi-Keefe, Dr. Sarah Couch, and Dr. Elliot Philipson; Nutrition and Rheumatic Disease edited by Dr. Laura Coleman; Nutrition and Kidney Disease edited by Dr. Laura Byham-Grey, Dr. Jerrilynn Burrowes, and Dr. Glenn Chertow; Nutrition and Health in Developing Countries edited by Dr. Richard Semba and Dr. Martin Bloem; Calcium in Human Health edited by Dr. Robert Heaney and Dr. Connie Weaver, and Nutrition and Bone Health edited by Dr. Michael Holick and Dr. Bess Dawson-Hughes. Dr. Bendich served as associate editor for Nutrition, the International Journal; served on the Editorial Board of the Journal of Women’s Health and Gender-Based Medicine; and was a member of the board of directors of the American College of Nutrition. Dr. Bendich was the recipient of the Roche Research Award, is a Tribute to Women and Industry awardee, and was a recipient of the Burroughs Wellcome Visiting Professorship in Basic Medical Sciences, 2000–2001. In 2008, Dr. Bendich was given the Council for Responsible Nutrition (CRN) Apple Award in recognition of her many contributions to the scientific understanding of dietary supplements. Dr. Bendich holds academic appointments as adjunct professor in the Department of Preventive Medicine and Community Health at UMDNJ, has an adjunct appointment at the Institute of Nutrition, Columbia University P&S, and is an adjunct research professor, Rutgers University, Newark Campus. She is listed in Who’s Who of American Women.