Handbook of Lipids in Human Function: Fatty Acids

Handbook of Lipids in Human Function

Fatty Acids

Editors

Ronald Ross Watson

Health Promotion Sciences Department, Mel and Enid Zuckerman College of Public Health, and School of Medicine, University of Arizona, Tucson, AZ, USA

Fabien De Meester

DMF Ltd Co, Marche, Belgium, TsimTsoum Institute, Krakow, Poland

Table of Contents

Cover image

Title page

Copyright

List of Contributors

Preface

Acknowledgments

Chapter 1. Personalized Diet and Lifestyle Interventions on Lipids and Lipoproteins

Abstract

Introduction

Diet Habits, Lifestyles, and Circulating Lipids and Lipoproteins

Genetic Determinants of Circulating Lipids and Lipoproteins

Gene–Diet/Lifestyle Interactions and Circulating Lipids and Lipoproteins

Lipidomics

Summary

References

Chapter 2. Trans Fats and Risks of Cardiovascular Diseases: Facts or Artifacts?

Abstract

Introduction

From Cis to TFAs: Natural Perfection to Industrial Imperfection

Physicochemical Characteristics of TFAs: Valuable Reasons for Industrial Production

Analytical TFA Characterization: Not Always Easy, But Often Present

TFAs on Health and Cardiovascular Diseases: Are They Really Hurting the Heart?

TFA-Mediated Molecular Mechanisms Leading to Higher CVD Risks

Contrasting Panorama of Worldwide TFA Consumption Is Relying on Technological Alternatives and Preventive Policies

Key Points

References

Chapter 3. Fatty Acids and Cardiac Ischemia Reperfusion Injury

Abstract

Introduction

Membrane Organization

Ischemia Reperfusion Injury

Cardioprotection

Myocardial Energetics

The n-3 Polyunsaturated Fatty Acids

The n-3 PUFAs in Cardiovascular Disease

The n-3 PUFA Antiarrythmetic Effects

The n-3 PUFA Alterations to Membrane Microdomain

The n-3 PUFA Effects on Cardiac Function

The n-3 PUFA Index

The n-3 PUFA Effects on Mitochondrial Function

The n-3 PUFA Metabolites

The n-6 Polyunsaturated Fatty Acids

n-6 PUFAs in Cardiovascular Disease

n-6 PUFAs: CYP-Derived Metabolites of AA

n-6 PUFAs: CYP-Derived Metabolites of LA

n-6 PUFAs: Cyclooxygenase-Derived Metabolites

n-6 PUFAs: Lipooxygenase-Derived Metabolites

The n-6/n-3 FA Ratio in Cardiovascular Disease

Trans Fatty Acids

Saturated Fatty Acids

References

Chapter 4. Lipids Nutrition and Epigenetic Modification in Obesity-Related Co-Morbitities

Abstract

List Abbreviations

Introduction

Obesity and Epigenetic

Atherosclerosis and Epigenetic

NAFLD and Epigenetic

Cancer and Epigenetics

Polyunsaturated Fatty Acids and Epigenetic

Conclusion

References

Chapter 5. Dairy Products: Their Role in the Diet and Effects on Cardiovascular Disease

Abstract

Introduction

Trends in the Consumption of Milk and Dairy Foods

Nutrients Provided by Dairy Foods

Contribution of Dairy Foods to Fat and Fatty Acid Intake

Epidemiological Evidence of the Association Between Dairy Consumption and Cardiovascular Disease

Saturated and Monounsaturated Fatty Acids from Milk and Cardiovascular Disease: Evidence from Intervention Studies

Dairy, Blood Pressure, and Arterial Stiffness

Trans Fatty Acids from Milk and Cardiovascular Disease

Conclusions

Acknowledgments

References

Chapter 6. Fatty Acids in Corn Oil: Role in Heart Disease Prevention

Abstract

Introduction

Effects of Corn Oil/Linoleic Acid on Plasma Lipid Profile

Effects of Corn Oil on Inflammation

Effects of Linoleic Acid on Inflammation

Conclusions

References

Chapter 7. Dietary Approaches to Reduce Aortic Stiffness

Abstract

Background on Aortic Stiffness

Measurement of Aortic Stiffness

Consequences of High Aortic Stiffness and Aortic BP

The Importance of Keeping Aortic Stiffness Low

Dietary Factors Associated with Arterial Stiffness: A Review of the Epidemiological Evidence

Dietary Factors Associated with Arterial Stiffness: A Review of Randomized Controlled Trials

Lifestyle Factors

Future Directions

Summary

References

Chapter 8. Inflammation and Atherogenic Effects Due to Saturated Fatty Acids

Abstract

Introduction

Epidemiology of Saturated Fatty Acid Intake and CHD Risk

Reasons Epidemiology Data Are So Inconsistent

Different Changes of Risk Factors over Time

Genetic Influence of Pro-Inflammation Status

Inflammation and Pathophysiology of Atherosclerosis

Molecular Mechanism of SFA Influence

Clinical Controlled Study of SFA Intake

Conclusion

Acknowledgments

References

Further Reading

Chapter 9. The Use of Omega-3 Polyunsaturated Fatty Acids (n-3 PUFAs) in Atrial Fibrillation

Abstract

Introduction

Overview of the Classification and Pathophysiology of AF

Potential Antifibrillatory Mechanisms of n-3 PUFA

Human Studies

Reasons for Inconsistent Results in Human Studies

Population Heterogeneity

AF Subtype and Duration

Differences in Fish Oil Supplementation and Duration

Are n-3 PUFAs Harmful?

Conclusion

References

Chapter 10. Individual Fatty Acids in Cardiometabolic Disease

Abstract

Introduction

Fatty Acids and Risk of CHD

Fatty Acids and Risk of T2D

References

Chapter 11. Omega-3 Polyunsaturated Fatty Acids in Patients with Coronary Disease Treated with Percutaneous Coronary Intervention

Abstract

Why Patients with Coronary Disease Undergoing Percutaneous Coronary Intervention Are Subjects at High Risk

Why Omega-3 Polyunsaturated Fatty Acids Might Offer Beneficial Effects in Patients Treated with PCI

OMEGA-PCI Study

Other Omega-3 PUFA Effects with Potential Benefit After PCI

Conclusions

Acknowledgments

References

Chapter 12. Effects of Omega-3 Fatty Acid Supplementation on Cognition in Children

Abstract

Introduction

The Role of n-3 Fatty Acids in the Brain

Consequences of n-3 Fatty Acid Deficiency

Relationship Between n-3 Fatty Acid Status and Cognition

Randomized Controlled Trials of n-3 Fatty Acid Supplementation in Children (2 Years and Older)

Summary and Future Directions

References

Chapter 13. The Effects of Glycerophospholipids and Fatty Acids on APP Processing: Implications for Alzheimer’s Disease

Abstract

Alzheimer’s Disease

Proteolytic Processing of APP

Link Between Lipids and AD

Glycerophospholipids and AD

Polyunsaturated FAs and AD

Trans Fatty Acids and AD

Nutritional FAs and AD

Conclusion

References

Chapter 14. Role of Dietary Fatty Acids in Mood Disorders

Abstract

Introduction

Monounsaturated Fatty Acids

Polyunsaturated Fatty Acids

LCn-3 Fatty Acids

Neurodevelopment

LCn-6 Fatty Acids

Summary and Conclusions

Acknowledgments

References

Chapter 15. Biochemical Aspects of n-6 and n-3 Fatty Acid-Derived Lipid Mediators in the Brain

Abstract

Introduction

n-6 Fatty Acid-Derived Lipid Mediators and Their Receptors in the Brain

n-3 Fatty Acid-Derived Lipid Mediators and Their Receptors in the Brain

Interplay Between n-6 Fatty Acid and n-3 Fatty Acid Metabolism

Levels of n-6 and n-3 Fatty Acid-derived Lipid Mediators in Neurological Disorders

Conclusion

References

Chapter 16. Neurocognitive Functions and Lipids

Abstract

Introduction

Cognitive Impairment, Dementia, and Alzheimer’s Disease

Conclusion

References

Chapter 17. What Are the Physiological Roles of Mead Acid (5,8,11-Eicosatrienoic Acid)?

Abstract

Part 1: Effects of Mead Acid on Osteoblasts and Osteoclasts

Part 2: The Effects of MA on Angiogenesis

General Conclusion

References

Chapter 18. Fat Metabolism During Exercise and Dietary Interventions for Enhancing Fat Metabolism and Athletic Performance

Abstract

Introduction

Fatty Acid Metabolism During Exercise

Conclusions and Implications

References

Chapter 19. Ruminal Metabolism of Fatty Acids: Modulation of Polyunsaturated, Conjugated, and Trans Fatty Acids in Meat and Milk

Abstract

Introduction

Rumen, the Site of Fatty Acid Metabolism in Ruminants

Postruminal Absorption of Fatty Acids

Fatty Acid Transfer to Mammary Gland and Muscle and FA Effect on Tissue Metabolism

How to Increase PUFA Flows

Modulation of Trans and Conjugated Fatty Acids

Conclusion and Perspectives

References

Chapter 20. Lipids and Metabolic Syndrome

Abstract

The Origin of Metabolic Syndrome

Criteria for Clinical Diagnosis of MetS

Prevention and Treatment of MetS

Lipids and MetS

Summary

References

Chapter 21. Fatty Acids and Hypothalamic Dysfunction in Obesity

Abstract

Hypothalamic Networks Regulating Energy Balance

Insulin and Leptin in Hypothalamic Control of Energy Metabolism

Gastrointestinal Hormones in Hypothalamic Control of Energy Balance

Hypothalamic Lipid Metabolism Modulating Energy Balance

Inflammation in Obesity and Molecular Mechanisms

Fatty Acids and Hypothalamic Inflammation

ER Stress and Lipotoxicity

Summary and Conclusions

Acknowledgments

References

Chapter 22. Dietary Lipid Determines the Health of Airway Epithelia and the Lungs

Abstract

Introduction

Role of Balanced Diet in Maintenance of Lung Health

Dietary Lipids and Pulmonary Diseases

12/15-LOX Metabolism in Airway Injury

References

Chapter 23. Oleic Acid and Lung Injury

Abstract

Introduction

Oleic Acid

The Lungs

Lung Injury

Origin of Pulmonary Insult

Oleic Acid-Induced Lung Injury

Experimental Animal Models in the Induction of Acute Lung Injury

Putative Targets to the Lung Injury Treatment

References

Chapter 24. Dietary Fats and Inflammation

Abstract

Introduction

Metabolism of Essential Fatty Acids

Lipid Mediators of Immunity and Inflammation

Obesity and Systemic Inflammation

Dietary Saturated Fats and Inflammation

Arthritis and Related Inflammatory Diseases

Asthma and Atopic Disease

Conclusions

References

Chapter 25. Intensive Lipid-Lowering Treatment in Patients with Inflammatory Joint Diseases

Abstract

Introduction

Underestimation of CV Risk in IJD

Lipid-Lowering Treatment in IJD

Experiences from a Preventive Cardio-Rheuma Clinic

Systemic Inflammation and Lipid-Lowering Therapy

Effect on Atherosclerosis After Intensive Lipid-Lowering Therapy in IJD

References

Chapter 26. Arachidonic Acid and Cancer Risk

Abstract

Nutritional Importance of Arachidonic Acid in Humans

ARA-Enriched Oils: Manufacturing Processes and Industrial Applications

Safety Assessment of ARA-Enriched Oils: Basic Toxicological Tests and Carcinogenic Potential

ARA and Cancer Risk: A Systematic Review of Observational Studies

Conclusions

References

Appendix 26.1 PubMed Search Terms and Strategies

Chapter 27. Blood Cell Membrane Omega-3 (n-3) Fatty Acid Abnormality and Supplementation in Patients with Sickle Cell Anemia

Abstract

Sickle Cell Disease

Cell Membrane Defect in SCD

Omega-3 Fatty Acid Supplementation of Sickle Cell Patients

Conclusions

References

Further Reading

Chapter 28. Lipids, Low-Grade Chronic Inflammation and NAFLD: A Ménage À Trois?

Abstract

Introduction

Effect of Individual Dietary and Lipids

Hormonal and Nonhormonal Regulators of Lipid, Glucose and Energy Metabolism in NAFLD

JNK Pathways

Low-Grade Chronic Inflammation: The Main Role of IL-6

Future Directions and Conclusive Remarks

References

Further Reading

Chapter 29. Disturbances of Lipid Metabolism in a Cancer Cell and How This Knowledge Increases Its Role in Clinical Oncology

Abstract

Cancer Development and Lipid Metabolism

Cancer Management and Lipid Metabolism

Conclusion

References

Index

Copyright

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List of Contributors

Sri Nagarjun Batchu,     Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada

Jeannine Baumgartner,     Centre of Excellence for Nutrition, North-West University, Potchefstroom Campus, Potchefstroom, South Africa

Patrícia Burth,     Departamento de Biologia Celular e Molecular, Instituto de Biologia, Universidade Federal Fluminense, Niterói, RJ, Brazil

Fernanda Michielin Busnello,     Department of Nutrition, Federal University of Health Sciences of Porto Alegre – UFCSPA, Porto Alegre, RS, Brazil

Mauro V. Castro-Faria,     Laboratório Integrado de Nefrologia, Departamento de Medicina Interna, Faculdade de Ciências Médicas, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil

Hugo C. Castro-Faria-Neto,     Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, RJ, Brazil

Ketul Chaudhary,     Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada

Philip D. Chilibeck,     College of Kinesiology, University of Saskatchewan, Saskatoon, SK, Canada

Rajiv Chowdhury,     University of Cambridge, Cambridge, UK

Cristina Contreras

Department of Physiology, Research Center of Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain

Fisiopatología de la Obesidad y Nutrición (CIBERobn), Madrid, Spain

Stephen M. Cornish,     Faculty of Kinesiology & Recreation Management, University of Manitoba, Winnipeg, MB, Canada

Ahmed A. Daak

Lipidomics and Nutrition Research Centre, Faculty of Life Sciences and Computing, London Metropolitan University, London, UK

Faculty of Medicine, University of Khartoum, Sudan

Michel Doreau,     INRA, UMR Herbivores, Saint-Genès-Champanelle, France

Akhlaq A. Farooqui,     Department of Molecular Cellular Biochemistry, The Ohio State University, Columbus, OH, USA

Tahira Farooqui,     Department of Molecular Cellular Biochemistry, The Ohio State University, Columbus, OH, USA

Anne Ferlay,     INRA, UMR Herbivores, Saint-Genès-Champanelle, France

Veerle Fievez,     Gent University, LANUPRO, Melle, Belgium

Carmine Finelli,     Independent Researcher, MD, PhD, Naples, Italy

Oscar H. Franco,     Erasmus University, Rotterdam, Netherlands

Grzegorz Gajos,     Department of Coronary Disease and Heart Failure, Jagiellonian University Medical College, Krakow, Poland

Kebreab Ghebremeskel,     Lipidomics and Nutrition Research Centre, Faculty of Life Sciences and Computing, London Metropolitan University, London, UK

Ian D. Givens,     Department of Food Production and Quality, School of Agriculture, Policy and Development, Institute for Cardiovascular and Metabolic Research, University of Reading, Reading, UK

Cassiano F. Gonçalves-de-Albuquerque,     Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, RJ, Brazil

Marcus O.W. Grimm

Experimental Neurology, Saarland University, Homburg/Saar, Germany

Neurodegeneration and Neurobiology, Saarland University, Homburg/Saar, Germany

Deutsches Institut für DemenzPrävention (DIDP), Saarland University, Homburg/Saar, Germany

Kei Hamazaki,     Department of Public Health, Faculty of Medicine, University of Toyama, Toyama City, Toyama, Japan

Tomohito Hamazaki,     Department of Internal Medicine, Toyama Jonan Onsen Daini Hospital, Toyama City, Toyama, Japan

Tobias Hartmann

Experimental Neurology, Saarland University, Homburg/Saar, Germany

Neurodegeneration and Neurobiology, Saarland University, Homburg/Saar, Germany

Deutsches Institut für DemenzPrävention (DIDP), Saarland University, Homburg/Saar, Germany

Ditte A. Hobbs,     Hugh Sinclair Unit of Human Nutrition, Department of Food and Nutritional Sciences, Institute for Cardiovascular and Metabolic Research, University of Reading, Reading, UK

Barkat Ali Kahn

School of Pharmacy, Kampala International University-Western Campus, Kampala, Uganda

Faculty of Pharmacy, Gomal University, Dera Ismail Khan, Pakistan

Peter R. Kowey,     The Lankenau Institute for Medical Research, Philadelphia, PA, USA

Glen D. Lawrence,     Department of Chemistry and Biochemistry, Long Island University, Brooklyn, NY, USA

Miguel López

Department of Physiology, Research Center of Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain

Fisiopatología de la Obesidad y Nutrición (CIBERobn), Madrid, Spain

Julie A. Lovegrove,     Hugh Sinclair Unit of Human Nutrition, Department of Food and Nutritional Sciences, Institute for Cardiovascular and Metabolic Research, University of Reading, Reading, UK

Ulaganathan Mabalirajan,     Molecular Pathobiology Laboratory, CSIR-Institute of Genomics and Integrative Biology, Delhi, India

Laura McBreairty,     College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, Canada

Robert K. McNamara,     University of Cincinnati College of Medicine, Cincinnati, OH, USA

Abder Menaa,     Department of Clinical Nutrition and Anti-Aging Medicine, Centre Médical des Guittières, Loire-Atlantique, France

Bouzid Menaa,     Infection Unit Control, Hymetec, SA, Isnes, Belgium

Farid Menaa,     Department of Pharmaceutical Sciences and Nanomedicine, Fluorotronics USA, Inc., San Diego, CA, USA

Janine Mett,     Experimental Neurology, Saarland University, Homburg/Saar, Germany

Annabelle Meynadier,     Université de Toulouse, INPT-ENVT, INPT-ENSAT, INRA, UMR GenPhySE, Toulouse, France

Lipsa Panda,     Molecular Pathobiology Laboratory, CSIR-Institute of Genomics and Integrative Biology, Delhi, India

Matthew P. Pase

Centre for Human Psychopharmacology, Swinburne University of Technology, Hawthorn, VIC, Australia

Department of Neurology and Framingham Heart Study, Boston University School of Medicine, Boston, MA, USA

Pinal S. Patel,     University of Cambridge, Cambridge, UK

Jasmine Pawa,     Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada

Gustavo D Pimentel,     Department of Internal Medicine, State University of Campinas (UNICAMP), Campinas, Brazil

Rudolf Poledne,     Laboratory for Atherosclerosis Research, Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic

Bruna Pontin

Department of Nutrition, Universidade do Vale do Rio dos Sinos – UNISINOS, São Leopoldo, RS, Brazil

Institute of Food, Innovation and Health – ITT NUTRIFOR, UNISINOS, São Leopoldo, RS, Brazil

Lu Qi

Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA

Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA

Victoria M. Robinson

The Manchester Royal Infirmary, Manchester, UK

The Lankenau Institute for Medical Research, Philadelphia, PA, USA

S. Rollefstad,     Preventive Cardio-Rheuma Clinic, Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway

Mai Sakai

Quality Assurance Department, Suntory Wellness Limited, Tokyo, Japan

Department of Social and Preventive Epidemiology, School of Public Health, The University of Tokyo, Tokyo, Japan

Zilda Elisabeth de Albuquerque Santos,     Department of Nutrition, Federal University of Rio Grande do Sul – UFRGS, Porto Alegre, RS, Brazil

Satoshi Sasaki,     Department of Social and Preventive Epidemiology, School of Public Health, The University of Tokyo, Tokyo, Japan

A.G. Semb,     Preventive Cardio-Rheuma Clinic, Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway

John M. Seubert,     Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada

Hossein Sharafkhaneh,     Kingwood Research Institute, Kingwood, TX, USA

Adriana R. Silva,     Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, RJ, Brazil

Marinka Steur,     University of Cambridge, Cambridge, UK

Marie-Pierre St-Onge,     Department of Medicine, College of Physicians and Surgeons, Institute of Human Nutrition, Columbia University, New York, NY, USA

Katarzyna Szarlej-Wcislo,     Department of Oncology, Military Institute of Medicine, Warsaw, Poland

Giovanni Tarantino

Department of Clinical Medicine and Surgery, Federico II University Medical School of Naples, Naples, Italy

National Cancer Institute Foundation G. Pascale, IRCS, Mercogliano, Italy

Alexane Travers,     Institut AgroParisTech, Paris, France

Gabriel Wcislo,     Department of Oncology, Military Institute of Medicine, Warsaw, Poland

Gordon A. Zello,     College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, Canada

Yan Zheng,     Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA

Igor Zlobine,     Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada

Preface

Fabien De Meester and Ronald Ross Watson

A Handbook of Lipids in Human Function. Why? The editors felt that the time had come to stop, think, and apply a fresh perspective to the historical concept that nonessential nutrients, such as cholesterol, saturated fats, glucose, and the like—which represent 90% of our daily energy intake—are primary risk factors of chronic degenerative diseases. This concept is outdated and has been proven wrong. The time has come to admit the obvious, to recognize this error as the first step towards progress. Today we know that caloric intake is the trigger for these diseases; obesity is a communicable disease of the mind, not a non-communicable disease of the body. Changing this paradigm will go a long way toward addressing the obesity epidemic. In its current form, Handbook of Lipids in Human Function is a review of the approach that has prevailed over the past century, with medical practice lagging behind scientific understanding. This handbook will hopefully serve as a springboard to the next level, and help usher in a culture of individual care in prevention and therapy.

Tackling obesity by treating the mind has resulted in medical practice heading ahead of scientific understanding; prevention and intervention with vibrational medicine is accumulating success. Although this strategy is in its infancy, its applications in clinical medicine are many and ever increasing (vibrational or sound wave therapy, http://www.energymedc.com/sound_wave_therapy.htm). It is still perceived as alternative because of—justifiably—a lack of understanding and knowledge of physical and biological interactions at all levels of human physiology. The editors attended the 2014 World Congress of Music Therapy in Austria, which was entirely devoted to Mozart music therapy (http://www.musictherapy2014.org/final-programme-and-more/); it would be unreasonable to ignore such innovative developments.

An overview of public health aspects leads to a hypothesis of opposing effects of omega-3 and trans fatty acids at cell membrane (functional influence), cytoplasm (inflammatory processes), and nucleus (PPAR system) levels and suggests plausible explanations as to why the eradication of omega-3 fatty acids in the human diet—through substitution for omega-6 and hydrogenation—has had such a dramatic cumulative effect on human long-term health. It may also explain why current omega-3 interventions report lower than expected benefits in the absence of the confounding factor, that is, trans fatty acids. The Menaa group elaborates on industrial trans fats as secondary rather than primary risk factors of cardiovascular disease and emphasizes the potential benefits of naturally occurring trans fatty acids, and expresses a need for promotion of further research in the field. Zheng and Qi offer a diet and lifestyle/gene expression perspective—lipidomics. As historically coined public health research evolves into personalized medicine research, circulating lipids reveal more of their secrets, such as environmental and gene-related markers of cardiovascular disease.

Batchu et al. review current knowledge of the roles of each subclass of fatty acids (saturated, including trans, omega-6, and omega-3) in triggering and controlling intra- and extracellular functions with an emphasis on cardiac ischemia-reperfusion (I/R) injury; they conclude it is important to maintain an omega-6 and omega-3 intake balance. Tarantino and Finelli initiate a debate on diet-, lifestyle-, and environment-induced epigenetic modifications and inheritance of proinflammatory gene expression. Understanding these contributors will obviously help address public health concerns if only in regard to how modern dietary fats depart from evolutionary standards. They review obesity, atherosclerosis, nonalcoholic fatty liver disease (NAFLD), and cancer from that perspective. Hobbs et al. confirm that dairy fats are beneficial to cardiovascular health in Caucasians and encourage further evaluation in suitably powered dietary intervention studies. Just as cholesterol in eggs was re-evaluated, saturated fats in dairies deserve another investigation of their respective risk-benefit attributes, especially because their carriers (i.e., eggs and milk) are unique sources of essential nutrients. St-Onge and Travers address the debate among those in favor of trans for linolenic acid substitution and those instead in support of a return of saturated fats in association with a more balanced omega-6/omega-3 ratio of polyunsaturates. (The first approach has economical, historical, and practical advantages to the latter.)

Pase reports on the use of Pulse Wave Velocity (PWV), which is an ideal marker for assessing changes in aortic stiffness upon aging and thereby identifying the development of cardio- and cerebrovascular risks. In turn, he explains how omega-3 fatty acids (and other nutrients) can favorably influence PWV—and also pulse pressure as a direct consequence—through their contribution to aortic elasticity versus stiffness. Within the same framework of competition among schools of thoughts and interests, Poledne reminds us that saturated fats are proinflammatory in the current generalized omega-6 spectrum of dietary fatty acids and warns of the potential risk taken by generalizing conclusions of recent epidemiological data that show no evidence between saturates and CHD mortality. Robinson and Kowey remind us that the dose-risk/benefit response to omega-3 supplementation most probably is an individual U-curve; that is, the minimum risk/maximum benefit is expected to lie at a subject-specific level rather than at population level, and may even become counterproductive at higher than optimal individual doses. They discuss the example of subjects suffering lone atrial fibrillation—where omega-3 was shown proarrhythmic—with wisdom within this context. Chowdhury et al. point out to the currently well-established fact that individual fatty acids—not only individual subjects—are specific in the way they influence fat/disease relationships; not all saturated and omega-6 fats are necessarily bad, not all monounsaturated and omega-3 fats are necessarily good, and perhaps classic markers such as serum glucose and lipid profiles also need requalification from metabolic ward controlled studies. Finally, Gajos reports on his OMEGA-PCI study. In this method, omega-3 fatty acids were used as adjunct to classical pharmacotherapy and shown to potentiate antithrombotic, antiplatelet, antiinflammatory, and antioxidative therapies, thereby contributing a substantial decrease in risk of atherothrombotic events in patients after percutaneous coronary intervention.

Connecting fats with brain health and neurological diseases, Baumgartner offers an extensive review of observational and random clinical trials aimed at confirming the benefits of omega-3 supplementation to cognition and behavior in children, although concludes there is need for more evidence, if only to circumvent the a posteriori identification of weaknesses in protocol designs, such as the absence of an omega-6/omega-3 marker, or oversight of socioeconomic status, gender, age, which have proven be confounding factors. Mett et al. strengthen the message on the opposing effects of dietary omega-3 and trans fatty acids on the inception and progression of Alzheimer’s disease. Cell membrane phospholipids and fatty acids do have an impact on the activity of the transmembrane amyloid precursor protein complex and on the accumulation of amyloid-beta peptides, thereby affecting the cascade of events leading to the onset and development of the disease; although omega-3 are able to significantly reduce the production of amyloid-beta peptides, trans fats stimulate the generation of these peptides. Efforts are invested at addressing the lipidomics of the disease as well as establishing prophylactic and interventional dosages of omega-3. McNamara takes us to mood disorders, including depressive and bipolar events, and pinpoints oleic acid—taken as olive oil within a Mediterranean-type diet and in partial substitution to omega-6—in addition to omega-3 as a potential remedy to the recurrent chronic inflammatory sets of brain diseases. Farooqui and Farooqui entertain us with a review of current knowledge of the biochemical aspects of omega-6/omega-3-derived lipid mediators in the brain, eicosanoids and docosanoids respectively, whose synergistic anti- and proinflammatory properties once again signal the importance of maintaining balanced dietary amounts of those preformed long chain or of their plant-derived precursors. Sharafkhaneh focuses on cognitive dysfunctions—from mild benign impairments to serious ill-health conditions—in an effort to identify lipid biomarkers that can reveal early stages of neurodegenerative decline. Not only do omega-3 fatty acids appear promising from a prophylactic perspective, but sphyngolipids and other cell membrane phospholipids metabolites as marker of cell apoptosis may reveal great promise in terms of distinguishing—and perhaps supplementing and treating—subjects at risk of progressing from minor cognitive impairments to dementia and Alzheimer’s disease.

In the chapter on metabolism and bioactivation, Hamazaki and Hamazaki study the physiological role of mead acid (C20:3w9), a monounsaturated fatty acid normally present only in bone- and vessel-free tissues (cartilage, cornea, lens) but otherwise detected in blood serum only in case of severe dietary deficiencies in essential omega-6/omega-3 fatty acids. They show that mead acid has the unique property of inhibiting calcification and angiogenesis, which in turn leads to its own synthesis and accumulation because of a local deficiency in essential fatty acids. Fat metabolism into energy during exercise is reviewed by Cornish et al., who interestingly demonstrate that not only that fat is the fuel of choice for low to two-thirds VO2 moderate training, but also that fasting promotes fat combustion, that conjugated linoleic acid (CLA) enhances kinetics and in turn performance, that there is an independent beneficial influence on body fat distribution, and that omega-3 may help the elderly combat sarcopenia. Doreau et al. elaborate on fat metabolism in ruminants to show that acetate—a ketone body—is a major energy transporter and thereby substrate for meat and milk production post-rumen fermentation and that CLAs are fatty acids derived from trans monounsaturated fatty acids leaving the rumen. Feeding practices may refine as the understanding of the potential benefits for human health of naturally conjugated and trans fats improves. Michielin-Busnello et al. close with a review statement on obesity-derived cascades to metabolic syndrome and warn about the danger of trying to single out any specific nutrient as a potential causal factor, including saturated fats, for the disease. A wise message, indeed.

Pimentel et al. review studies revealing that the hypothalamus acts as an organ modulator of chronic inflammation associated with impaired insulin/leptin (energy metabolism) and ghrelin/glucagon-like peptide 1 (energy balance) sensitivity, whereas excess saturated, trans, and omega-6 fatty acids play an important role in the hypothalamus impairing the adequate function of these hormones. Panda and Mabalirajan pinpoint linoleic acid (LA; C18:2w6) as a major dietary concern across India where asthma and obesity have soared in parallel to pollution over the recent years. They show how enzymatically peroxidized inflammatory LA metabolites can—and in fact do—induce and sustain mitochondrial dysfunction, airway epithelial injury, constriction, and apoptosis. Gonçalves-de-Albuquerque et al. make an interesting contribution by demonstrating that nonesterified fatty acids (NEFA)—sometimes referred to as free fatty acids (FFA)—are basically cytotoxic and are transported in the bloodstream bound to albumin in a way to mask their cytotoxicity. Taking oleic acid as a model, they report on how NEFA may cause lung functional and structural damage, eventually leading to the inception and development of acute respiratory distress syndrome, when present as FFA either in the air and/or in blood serum. Lawrence re-emphasizes the wise statement that naturally occurring saturated and balanced omega-6/omega-3 fats are good rather than bad for optimum immune and inflammatory response, irrespective of their influence on blood lipid profiles. Finally, Rollefstad and Semb indicate that clinical patients with inflammatory joint diseases have an increased risk of cardiovascular disease, a condition which should warrant statin-type intensive lipid lowering treatments in such groups, with the double benefit of improving blood lipid profile and containing systemic inflammation in primary prevention.

The last section on lipids and cancers is introduced by Sakai and Sasaki, who searched the PubMed database (http://www.ncbi.nlm.nih.gov/pubmed/) for observational studies on the relationship between dietary or blood arachidonic acid (ARA; C20:4w6) levels and cancer risk published up to May 17, 2010. In total, 52 articles were selected and scored for quality according to standard methodology for observational studies. No relationships between ARA exposure and cancer risk could conclusively be demonstrated, which leads the authors to conclude that further evidence from well-designed observational studies is required to confirm or refute the association between ARA exposure and cancer risk. Daak and Ghebremeskel report on the omega-6/omega-3 imbalance characteristic of a disease medically referred to as sickle cell disease—affecting red blood cell, mononuclear cell, and platelet—and characterized by anomalies of membrane phospholipid composition and organization and related rheology (fluidity, deformability, permeability, and propensity to stick and aggregate). Along an intervention, they demonstrate that re-adjusting the omega-6/omega-3 balance at cell membrane level has the potential to be an effective, safe, and affordable therapy for people with the disease. Tarantino and Fineli extend the analysis of fatty acids structure–function relationships to obesity-related comorbidities, with an emphasis on NAFLD, and end up broadening the analysis and conclusions to the constellation of metabolic disorders that affect ever more individuals, thereby recognizing and re-enforcing the call for more individualized preventive and interventional approaches. Wcislo reviews lipid metabolism in cancer cells and shows how cholesterol metabolism and serine/threonine kinase—involved in regulation of cell growth, aging, and metabolism—are closely related, evolutionary and functionally, from yeast to human, rendering blood serum cholesterol levels a marker of clinical value in oncology practice.

All in all, the wide multidisciplinary contributions to this handbook offer a wealth of information about where to start reflecting on new knowledge about lipids in human function. The time when cell membranes will be seen and studied as biotransistors carrying memes in addition to regulating genes is just around the corner.

Acknowledgments

The work of Dr Watson’s editorial assistant, Bethany L. Stevens, in communicating with authors and working on the manuscripts was critical to the successful completion of the book. It is very much appreciated. The encouragement, advice, and support of Janet Brown at AOCS in producing the books was very helpful. Support for Ms Stevens’ and Dr Watson’s editing was graciously provided by DMF Ltd Co. (www.dmfrontiers.com), the TsimTsoum Institute (www.tsimtsoum.net), the Natural Health Research Institute (www.naturalhealthresearch.org), and Southwest Scientific Editing & Consulting, LLC. The encouragement and support of Elwood Richard and Dr Richard Sharpee was vital. Finally, the work of the librarian at the Arizona Health Science Library, Mari Stoddard, was vital and very helpful in identifying key researchers who participated in the book.

Chapter 1

Personalized Diet and Lifestyle Interventions on Lipids and Lipoproteins

Yan Zheng¹ and Lu Qi¹,²,    ¹Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA,    ²Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA

Abstract

Disturbed metabolism of lipid and lipoprotein is a major risk factor for cardiovascular diseases and other metabolic disorders. Circulating lipid profiles are heritable and meanwhile modifiable, mainly by diet habit and lifestyle. Genetic research has identified more than 150 common variants associated with lipid traits; and compelling evidence has shown that diet/lifestyle interventions might affect circulating lipid profiles in humans. Emerging data from observational studies and randomized clinical trials have further shown that dietary and lifestyle factors might modify the genetic factors in determining lipid levels. In addition, the emerging -omics research, especially lipidomics, provides potentials to reveal novel and systematic insights into the molecular mechanisms underlying genetic effects, diet/lifestyle influence, and gene–diet/lifestyle interactions. Studies in these research areas hold promise to inform future personalized diet and lifestyle interventions based on genetic background, and eventually to improve lipid profiles and mitigate related disorders.

Keywords

Genetics; dietary intervention; lifestyle intervention; gene–environment interaction; lipidomics; personalized medicine

Introduction

The risk of various chronic diseases, such as cardiovascular diseases, diabetes, and certain cancers, has been related to abnormal metabolism of lipids and lipoproteins (Danesh et al., 2000; Greenhill, 2011; Lamarche et al., 1997; Mora et al., 2010; van Duijnhoven et al., 2011) and improvement of lipid profiles has been the therapeutic target of such diseases. The combined effects of habitual diet (Wolk et al., 2001; Zheng et al., 2014), lifestyle (Chorell et al., 2012), genetics (Global Lipids Genetics et al., 2013; Teslovich et al., 2010), metabolism (Cao et al., 2008), and their interactions (Smilowitz et al., 2013) influence the overall composition of circulating lipids. From the environmental aspect, the obesogenic factors, such as energy-dense foods and sedentary lifestyle, exacerbate the abnormal metabolism of circulating lipids; from the genomic aspect, the wide application of genome-wide association studies (GWASs) has led to identification of a large number of novel genomic loci related to circulating lipids, though for many of them the functions have yet to be clarified. The interplays of various genetic variants and environmental factors result in gene–environmental interactions, which in turn shape an individual’s phenotype (Corella and Ordovas, 2009). The levels of circulating lipids are primarily determined by dietary intake and lifestyle in each individual, and the interindividual heterogeneity in lipid profiles is mainly determined by the genomic variations. Therefore, the circulating lipid profiles are the functional signatures of the interactions between the genetic and environmental factors such as diet and lifestyle. Studies of gene–diet/lifestyle interactions offer substantial potential to understand the wide interindividual variation and hold great promise to mitigate abnormalities in lipid metabolisms through individual-centric diet and lifestyle modifications, also known as personalized intervention. In addition, recent development in metabolomic methods of measuring global lipid profiles, namely lipidomics, has opened a new avenue to explore more complex gene–environment interactions that will further improve personalized intervention in the near future.

This chapter aims to summarize recent advances in research of diet/lifestyle, genetics, and gene–diet/lifestyle interactions on lipids. We also review the findings in the emerging research area of lipidomics. In particular, we address the potential application of personalized diet and lifestyle intervention in improvement of lipid profiles and prevention and treatment of the related disorders.

Diet Habits, Lifestyles, and Circulating Lipids and Lipoproteins

Diet and lifestyle factors intimately modulate the dynamic levels of circulating lipids, which are closely related to obesity. The transition from traditional, nutrient-dense diets and active lifestyles to an obesogenic life pattern featuring energy-dense diets and sedentary lifestyles in the past several decades is believed to be a major driving force behind the epidemic of obesity and related metabolic disorders, including dyslipidemia (Qi, 2012). Since 1999, the percentage of adults with abnormally elevated total cholesterol levels has been decreasing (Carroll et al., 2012), partially as a consequence of a combination of diet/lifestyle improvement and the use of drugs such as statins.

Dietary intake is among the most important factors that influence circulating lipid profiles. For example, it has been well documented that high carbohydrate intake might lead to an increase in blood triglycerides (Parks, 2001). The effects of the amount and type of dietary fat on circulating lipid profiles have also been extensively investigated. Mensink et al. (2003) conducted a meta-analysis of 60 feeding controlled trials including 1700 volunteers who were fed with tested diets over 13–91 days. The results suggest that isoenergetic replacement of saturated fatty acids with carbohydrates does not improve the serum total cholesterol to high-density lipoprotein (HDL) cholesterol ratio, and replacement with unsaturated fatty acids may lower the ratio; the cis-monounsaturated fatty acids had a modest but significant low-density lipoprotein (LDL) cholesterol-lowering effect relative to carbohydrates; and the replacement of trans fatty acids with unsaturated fatty acids from unhydrogenated oils showed the strongest effects on improving blood lipid profiles (i.e., decreased the total cholesterol to HDL cholesterol ratio).

Recently, Aucott et al. (2011) performed a systematic review to evaluate the long-term effects of diet and lifestyle interventions on weight loss and changes in lipid profile in adults. This study included seven prospective cohorts involving advice on diet and exercise, as well as seven intervention trials that tested the impact of meal replacement/instruction and physical exercise plans for follow-up periods of 2–6 years. This study showed that the effects of diet and lifestyle modifications on the changes in body weight and lipids were significantly beneficial, though the mean effect size was moderate. Among the included studies, the significantly sustained mean weight loss was 1.2 kg, ranging from a loss of 10 kg (Ditschuneit et al., 1999) to a gain of 4.8 kg (Sedgwick et al., 1990). The mean weight loss accounted for 73% of the overall variation in the mean change of total cholesterol. In addition, it was found that persistent long-term (2–3 years) weight loss of 1 kg was associated with a 1.3%, 1.6%, and 0.34% reduction in total cholesterol, triglycerides, and LDL cholesterol, respectively, as well as a 4% increase in HDL cholesterol.

Similar results were also reported in children. Ho et al. (2012) performed a systemic review of 15 studies comparing the effectiveness of diet/lifestyle intervention programs incorporating a nutrition or dietary component with that of no treatment or usual care, or minimal advice or written diet and physical activity education materials, among overweight/obese children and adolescents aged 18 years and younger. It was found that diet/lifestyle interventions led to significant improvements in LDL cholesterol (–0.30 mmol/L, 95% CI –0.45 to –0.15) and triglycerides (–0.15 mmol/L, 95% CI –0.24 to –0.07) up to 1 year from baseline. No differences were found for HDL cholesterol. Taken together, these data indicate that long-term (≥1 year) diet/lifestyle interventions incorporating dietary components along with exercise and/or behavioral therapy components are effective in improving lipid profiles with sustained weight loss among both children and adults.

The mechanisms underlying effects of diet and lifestyle intervention on disease and health are more complex than simply modulating blood lipids, as suggested by many dietary interventional trials (Burr et al., 1989; de Lorgeril et al., 1997, 1999).

Genetic Determinants of Circulating Lipids and Lipoproteins

The search for the genetic determinants for plasma lipid and lipoprotein levels began more than 25 years ago, and the early efforts are dominated by studies using classic approaches such as twin studies, family studies, linkage analyses, and candidate-gene-based association studies (Breslow, 2000; Hegele, 2009; Pirruccello and Kathiresan, 2010). Even though several lipid genes such as CETP, APOE, and LIPC were successfully identified through these methods, the vast majority of the reports from the classic approaches have not been accompanied by compelling replication data, suggesting that many of the findings are likely to be fictitious. Mendelian mutations are usually rare and a single mutation has a huge phenotypic effect. Most of the well-characterized disorders of lipoprotein metabolism are monogenic, familial disorders with extreme phenotypes. Linkage studies in families are powerful to detect such mutations. For example, familial hypercholesterolemia is a genetic disorder characterized by high cholesterol levels, especially very high circulating levels of LDL cholesterol and early-onset cardiovascular disease. Many patients have mutations in the LDL receptor gene, and the homozygous familial hypercholesterolemia occurs in 1 of 1 million births (Rader et al., 2003). Although these patients harbor extreme traits, the population-wide impact of the known Mendelian disorders is attenuated by their rarity (Pirruccello and Kathiresan, 2010).

Discovery of the common variants associated with lipids has been substantially facilitated by the application of GWASs in the field (Diabetes Genetics Initiative of Broad Institute of Harvard and MIT et al., 2007; Hunter et al., 2008; Kathiresan et al., 2008, 2009; Krauss, 2008; Lusis and Pajukanta, 2008; Pharoah et al., 2008; Sandhu et al., 2008; Teslovich et al., 2010). The first large-scale GWAS of circulating lipids was published in 2007 and involved 1464 type 2 diabetes patients and 1467 matched controls. The study genotyped about 400,000 single nucleotide polymorphisms (SNPs) and identified an SNP in an intron of glucokinase regulatory protein (GCKR) associated with serum triglycerides (Diabetes Genetics Initiative of Broad Institute of Harvard and MIT et al., 2007). Recently, two large-scale GWAS meta-analyses revealed 157 loci (95 and 62 loci in >100,000 individuals and 188,000 individuals, respectively) significantly contributing to circulating HDL cholesterol, LDL cholesterol, or triglyceride levels (Figure 1.1) (Global Lipids Genetics et al., 2013; Teslovich et al., 2010). Of these loci, 46 demonstrated the strongest associations with HDL cholesterol, 16 with triglycerides, 18 with total cholesterol, and 9 with LDL cholesterol. Not surprisingly, many loci affected multiple lipid fractions. For example, 36 loci showed significant associations with both total cholesterol and LDL cholesterol and 4 loci (CETP, TRIB1, FADS1–2–3, and APOA1) showed associations with total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides (Figure 1.1). By identifying the large number of loci and the diverse proteins they encode, these findings have provided novel insights into lipid biology (Global Lipids Genetics et al., 2013).

Figure 1.1 Overlap of loci associated with different lipid traits. The Venn diagram illustrates the number of loci that show association with multiple lipid traits. The number of loci primarily associated with only one trait is listed in parentheses after the trait name, and locus names are listed below. Loci that show association with two or more traits are shown in the appropriate segment. Besides the loci listed in the figure, two loci (GCKR and NAT2) are associated with both total cholesterol and triglycerides, and one locus (ACAD11) is associated with both HDL cholesterol and LDL cholesterol. Modified from Global Lipids Genetics et al. (2013).

Besides GWAS, the next generation of genetic sequencing of the entire exome or even whole genome would further improve identification of novel, low-frequency mutations affecting lipids. In some cases, sequencing may particularly identify smoking-gun variants, such as early truncations, that strongly indicate causation. For example, the genetic architecture of plasma LDL cholesterol levels is complex, with multiple common, low-frequency, and rare variants in the Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) gene contributing differentially in effect size to plasma LDL cholesterol levels in the population (Kotowski et al., 2006). If such a mixture pattern of common, low-frequency, and rare variants present at a lipid locus is typical, then sequencing near genome-wide association loci may identify additional novel and potentially causal variants (Pirruccello and Kathiresan, 2010). In a recent whole-genome sequencing analysis of about 1000 participants (Morrison et al., 2013), it was found that the common variants contributed more than the rare variants to heritability of HDL cholesterol levels. Besides, this study highlighted the value of regulatory and nonprotein-coding regions of the genome in addition to protein-coding regions, and illustrated three novel regulatory sites relating to HDL cholesterol levels as examples (Morrison et al., 2013).

Besides the above-mentioned informative genetic studies, functional studies are needed to provide convincing molecular mechanisms and inform causality. However, there are many challenges, especially when the loci of interest harbor unknown genes (Pirruccello and Kathiresan, 2010).

Gene–Diet/Lifestyle Interactions and Circulating Lipids and Lipoproteins

Recently emerging data have shown compelling evidence that genetic factors may interact with diet and lifestyle factors in determining metabolic traits such as obesity (Qi et al., 2012, 2014; Zhang et al., 2012). Investigating the gene–diet/lifestyle interactions holds great potential to improve our understanding of the integrated roles of diet/lifestyle and genomic makeup in lipid metabolism, and therefore to inform future personalized recommendation on diet and lifestyle modifications. Early research in the field of gene–diet/lifestyle interactions revealed that variants in the candidate genes (such as apolipoproteins APOE, APOA4, APOB, and lipoprotein lipase) determined a small but statistically significant fraction of the individual variability in response to dietary or lifestyle modifications (Ordovas, 2001). However, the majority of these findings were limited by lack of replications. The widespread use of GWASs in the past years has led to identification of numerous new loci related to circulating lipids and provided huge potentials to test gene–diet/lifestyle interactions on a genome-wide scale. In fact, several gene–diet/lifestyle interaction studies focusing on the GWAS-identified genetic variants have emerged (Tables 1.1 and 1.2).

Table 1.1

Selected population observational studies of gene–environment interaction on lipid profile.

Table 1.2

Selected population interventional studies of gene–environment interaction on lipid profile.

The Δ-5 and Δ-6 desaturases, encoded by the fatty acid desaturase (FADS)1 and FADS2 genes, are rate-limiting enzymes in polyunsaturated fatty acid (PUFA) biosynthesis. SNPs in the FADS gene cluster region have been associated with both PUFA concentrations in plasma or erythrocyte membrane phospholipids and cholesterol concentrations in recent GWASs. In a large study of 3575 European individuals from eastern Netherlands, Lu tested the interactions between dietary intake of n-3 and n-6 PUFAs measured by a food-frequency questionnaire and selected variants in the FADS gene cluster region on plasma lipid profile (Lu et al., 2010). The C allele carriers of rs174546 were reported to have significantly higher HDL cholesterol concentration than the noncarriers in the group with high n-6 PUFAs intake (≥5.26% of total energy) but not in the group with a low intake (P for interaction=0.02). Consistently, another cohort study of 4635 Swedish individuals showed similar results. Hellstrand et al. (2012) tested the interaction between another SNP in FADS region and the dietary PUFA intake measured by a diet history method on fasting lipid profile and detected significant interactions between rs174547 and long-chain omega-3 PUFA intakes on LDL cholesterol (P for interaction=0.01) and interactions between rs174547 and the ratio of α-linolenic acid and linoleic fatty acid intakes on HDL cholesterol concentrations (P for interaction=0.03). Both studies suggest that the dietary intakes of different PUFAs may modify the effect of the genetic variations in FADS on LDL cholesterol and HDL cholesterol concentrations, and they emphasize the importance of dietary fat composition in modifying the effect of genetic susceptibility on blood lipid and lipoprotein concentrations.

In a study of 1128 Seattle Caucasian veterans (772/356 in the discovery/replication cohorts, respectively), Kim et al. (2013) explored whether gut-expressed genetic variants associated with plasma cholesterol levels differentially affect the relationship between dietary and plasma cholesterol levels. Four SNPs within three genes (APOB, CETP, and NPC1L1) were significantly associated with plasma cholesterol in the discovery cohort. These SNPs were subsequently evaluated for gene–dietary cholesterol interactions on plasma cholesterol. Significant interactions were identified and replicated for two variants: rs1042034, an APOB Ser4338Asn missense SNP, and rs2072183 (in males only), a synonymous NPC1L1 SNP in linkage disequilibrium with SNPs 5′ of NPC1L1. This study provides support to the presence of novel gene–diet interactions and suggests that differential gut absorption is the potential basis, and such interactions may account for part of the missing heritability not accounted for by the main genetic effects.

The modification of alcohol consumption of the effects of different variants in genes LIPG, ApoC-III, and APOE (Corella et al., 2011; Liu et al., 2011; Ruixing et al., 2010; Yin et al., 2013) on circulating lipid profile were reported from different cohort studies of both Chinese and Spanish populations. Besides, Garcia-Rios et al. (2010) found a significant gene–smoking interaction among 500 Spanish patients with familial hypercholesterolemia, in which smokers carrying the minor alleles at ABCG5 SNPs displayed significantly lower HDL cholesterol, higher total cholesterol, and higher triglyceride, respectively, and nonsmoker carriers of the minor alleles had significantly lower triglyceride concentrations compared with homozygous for the major allele (P values for interaction=0.030–0.047).

Studies in observational settings are subject to various biases such as residual confounding and measurement errors. In contrast, randomized clinical trials tend to minimize the potential confounding and measurement errors in exposures. In addition, prospective analyses on dynamic changes in lipids may lower the risk of reverse causation. Because randomized clinical trials evaluate the response in lipids, the findings would directly inform personalized diet/lifestyle recommendations in health practice (Qi, 2012). Ideally, the randomization process should involve the genotypes of interest (Ordovas and Tai, 2008). However, most of the current gene–diet/lifestyle interaction studies have used post hoc analyses of existing dietary intervention trials designed for nongenetic research. Recently, several diet/lifestyle intervention studies have emerged to shed light on their potential to detect gene–diet/lifestyle interactions on lipids (Table 1.2).

The Preventing Overweight Using Novel Dietary Strategies (Pounds Lost) trial is a clinical dietary interventional trial of 811 overweight and obese adults who were randomly assigned to one of four weight-loss diets varying in macronutrient contents (dietary fat, protein, and carbohydrates) for 2 years (Sacks et al., 2009). In the Pounds Lost trial, we have tested hypothesis-driven gene–diet interactions on serum lipid profiles. For example, in a recent study, we found significant interactions between an APOA5 gene variant rs964184 and dietary fat intake (low-fat vs. high-fat) in relation to changes in plasma levels of lipids such as total cholesterol, LDL, and HDL cholesterol (Zhang et al., 2012). The results indicate that a low-calorie, low-fat diet intervention may improve the lipid profiles better in the individuals carrying APOA5 rs964184 risk allele than those not carrying the allele.

The Diabetes Prevention Program (DPP) is a large clinical trial to examine the effects of metformin or intensive lifestyle modification on the incidence of type 2 diabetes (The Diabetes Prevention Program, 1999; Knowler et al., 2002). Among 2993 DPP participants, Pollin et al. (2012) identified a genetic risk score (GRS) based on deleterious alleles at 32 lipid-associated SNPs modifies the effects of lifestyle and/or metformin interventions on LDL cholesterol levels. The GRS was associated with higher baseline-adjusted LDL cholesterol levels and a higher level of baseline-adjusted small LDL particles at 1 year in the lifestyle intervention group, but not in the placebo or metformin groups. This result suggests that a high genetic burden confers an adverse lipid profile and predicts attenuated response in LDL cholesterol levels and small LDL particle numbers to dietary and physical activity interventions.

The Diet Obesity and Genes (DiOGenes) study is a 6-month Pan-European randomized dietary intervention study exploring the effect of diets with different contents of protein and glycemic index on weight regain and metabolic health after weight loss among 841 baseline overweight or obese but otherwise healthy participants (Larsen et al., 2010). Brahe explored 240 SNPs in presumed nutrient-sensitive lipid metabolism genes and identified an interaction between an SNP in the lipin 1 (LPIN1) gene and dietary protein consumption on triglyceride concentration (Brahe et al., 2013). The finding suggests that, regarding the changes in blood triglyceride concentration, the low-protein weight maintenance diet may be more beneficial to the GG carriers of LPIN1 SNP rs4315495.

In addition, Ordovas and his team have identified significant interactions between polymorphisms in several genes, such as ABCG5/G8, PDZK1, LIPG, APOA5, TRIB1, and dietary intake/smoking on various plasma lipid components (Garcia-Rios et al., 2011; Junyent et al., 2009a, 2009b; Mattei et al., 2009; Smith et al., 2009). For example, among 7018 participants in a randomized trial (two Mediterranean diet intervention groups and a control group) of the PREvención con DIetaMEDiterránea study, the association between the transcription factor 7-like 2 (TCF7L2) rs7903146 TT genotype and fasting lipids was modulated by adherence to the Mediterranean diet (Corella et al., 2013). When adherence to Mediterranean diet was low, individuals with TT genotype presented higher concentrations of total cholesterol, LDL cholesterol, and triglycerides than those carrying CC+CT genotypes. However, when adherence was high, plasma concentrations of these parameters did not differ between genotypes (Corella et al., 2013).

Despite the promising findings, the research in gene–diet/lifestyle interaction faces many challenges. The majority of the findings have yet to be replicated, and large-scale collaboration appears to be essential to improve study power in detection of moderate gene–diet/lifestyle interactions (Armah et al., 2013; Lockyer et al., 2012; Walker et al., 2011).

Lipidomics

The term lipidome refers to comprehensive profiling of lipid components in biological samples such as cells, tissues, biofluids, and organisms; the term lipidomics refers to the systems-level scale analysis of lipids and their modulators (Wenk, 2005). Lipidomics is a branch of metabolomics, which has been recently developed to comprehensively measure small molecular chemical compounds, such as amino acids, lipids, carbohydrates, and so forth (Lewis et al., 2008). Similar to other metabolites serving as intermediate phenotypes that are beyond the genome and the clinically observed phenotypes, lipids mediate the effects of upstream genetic and environmental signals on downstream homeostatic and processes and disease states. Lipidomics can be expected to provide more details on potentially affected pathways and to be more directly related to the etiology of the disease (Gieger et al., 2008). Meanwhile, lipids stand out from other metabolites because of the structural diversity and the sheer number of discrete yet well-defined biomolecules, may be in the hundreds of thousands (Quehenberger and Dennis, 2011; Shevchenko and Simons, 2010). Unlike the proteins or amino acids, lipids are not composed of similar units. Instead, lipids are a large group of compounds diverse in structures and functions, and they are chemically distinct molecular species arising from the various combinations of fatty acids with backbone structures. Because of their chemical and structural diversity, lipidomics cannot be achieved in a single experimental approach and presents technological challenges (Murphy and Nicolaou, 2013).

There are a few commonly used complimentary approaches in lipidomic analysis (Meikle and Christopher, 2011; Shevchenko and Simons, 2010). Shotgun lipidomics begins with an off-line lipid extraction, and then subjects the extracts directly into mass spectrometry without lipid chromatography separation. This approach provides a broad coverage of the lipidome with high sample throughput. Targeted lipidomics combines liquid chromatography with multiple reaction monitoring and stable internal standards to provide accurate and precise quantification of hundreds of lipid species of particular interest. Global/untargeted lipidomics typically combines liquid chromatography (with or without internal standards) with high mass accuracy analysis to profile many hundreds of lipid species, and is suitable to detect novel lipids in broad spectrum. However, the lipids identified by this approach may have unknown chemical structure, and further identification may need the involvement of other techniques, such as nuclear magnetic resonance spectroscopy.

Lipidomics has emerged speedily since the last decade, as a consequence of development of novel technologies in quantitative and comprehensive molecular measurements (Quehenberger and Dennis 2011; Quehenberger et al., 2010). A comprehensive lipidomic approach is advocated to integrate multiple related samples such as blood and organ tissue to study lipid complexity (Shevchenko and Simons, 2010), and therefore provide a systems-level view of lipidomics to reveal the complex connections between lipid signaling pathways.

In 2010, the first comprehensive analysis of human plasma lipidomics identified and quantified over 500 different lipid molecular species covering six main categories: fatty acyls, glycerolipids, glycerophospholipids, sphingolipids, sterol lipids, and prenol lipids (Quehenberger et al., 2010). Application of targeted lipidomics in population studies has shown perturbed lipid profiles in hypertensive, obese, or diabetic patients, suggesting novel lipid molecules may be involved in development of these disorders (Barber et al., 2012; Graessler et al., 2009; Sorensen et al., 2010). In addition, lipidomics has been used to assess antihypertensive drug therapies (Hu et al., 2011), to identify novel biomarkers of hypertension (Kulkarni et al., 2013), to explore the influences of dietary fatty acids on insulin resistance (Kien et al., 2013), and to identify predictors for diabetes risk (Rhee et al., 2011). Therefore, comprehensive lipidomic profiles may act as intermediate markers in studying gene–diet/lifestyle interactions in relation to various metabolic disorders, and research in this novel area would considerably improve our understanding of personalized diet/lifestyle interventions on human health.

Nevertheless, lipidomics is withstanding challenges in several aspects. Lipids are products of diet and their metabolism, that is, the substrates and products of enzymes. Therefore, lipids are not directly from the inherited genome of organisms and exhibit a large variation