Omega-3 Fatty Acids (eBook)

Mahabaleshwar V. Hegde, M.Sc., Ph.D.ProfessorCenter for Innovation in Nutrition Health Disease, IRSHA     Medical College Campus, Bharati Vidyapeeth Deemed University Dhankawadi    Pune, MaharashtraIndia Anand Arvind Zanwar,  M.Pharma., Ph.D.ScientistCenter for Innovation in Nutrition Health Disease, IRSHA     Medical College Campus, Bharati Vidyapeeth Deemed University Dhankawadi    Pune, Maharashtra    India Sharad P Adekar, M.D., Ph.DMedical Vice ChairWestern IRBDepartment of IRB AffairsPuyallup, WA USA

Preface 5
Acknowledgments 8
Contents 9
Editors and Contributors 12
1 Nutrition, Life, Disease, and Death 19
Introduction 19
We Are What We Eat 19
Human Body Knows no Pathies but Understands Nutrition 20
Entropy and Nutrition 20
Origin of Life, Chemical and Early Biological Evolution 21
Vegetarianism Is Healthier 22
Man Is Crippled in Evolution 23
Essential Micronutrients in Human Nutrition 23
Digestion Absorption, Critical in Nutrition 23
Survival of the Sickest 24
Omega-3 Fatty Acid Crucial Nutrient 24
Omega-3 Index 24
Free Radicals 25
Oxidative Stress 25
Autophagy 25
Integrating Homeostasis Allostasis and Stress 25
Life, Disease, Cancer, and Death: Simple Play of Redox 26
Telomers and the Lifespan 26
Role of DHA in Human Brain, Adaptability to the Diverse and Adverse Environment for Survival 26
Concluding Remarks 27
References 27
2 Flax Bio-village Concept 29
Introduction 29
Functional Foods and Public Health 29
Crucial Role of Omega-3 Fatty Acids in Public Health Today 30
Flax Bio-village Concept 33
Flaxseed (Linseed) 33
Linseed Is a Neglected Crop 34
Omega-3 Fatty Acids Are Very Unstable 34
Linseed Is not Readily Edible and Has Anti-nutrients 34
Awareness of Importance of Omega-3 for Public Health 34
Convergence of Linseed Agriculture to Health and Wealth 35
Flax Lignan for Pharmaceutical Application 35
Summary 36
References 36
3 Status Paper on Linseed/Flax Agriculture 39
Crop Description 39
Origin 39
Importance 39
Scientific Name and Species Relationship 40
Floral Biology 41
Nutritional Values 41
Comparative Analysis 43
Gap of Yield with Other Countries 43
Export–Import Status of the Crop Produce 43
Varietal Development 43
Climatic Requirement 43
Genetic Potentiality Advancement 43
Seed Scenario 49
Good Crop Production Practices 50
Cropping Systems 51
Integrated Nutrient Management 51
Crop Products 58
Special Initiatives for Encouraging the Cultivation of the Crop 59
Important Websites 59
Researchable Issues 59
References 60
4 Omega-3 Milk 63
Introduction and Background 63
Biofortification Not Economically Feasible in Ruminants 64
Role of Omega-3 Milk in Human Health 65
References 66
5 Omega-3 Egg 69
Introduction 70
Egg Nutritional Content 70
Health Benefits of Eggs 70
Global Egg Production 70
Omega-3 Fatty Acids and Health Benefits 72
Omega-3 Eggs 72
Advantages of Omega-3 Eggs Over Ordinary Table Eggs 73
Health Benefits of Omega-3 Eggs 73
Fish Oil Versus Omega-3 Eggs 73
Feed for Omega-3 Enrichment 74
Resources for Omega-3 Enrichment 74
Production Parameters and Egg Quality Characteristics 75
Benefits of Omega-3 Enrichment to Birds 76
Means to Improve Oxidative Stability and Quality of Omega-3 Eggs 77
Commercial Poultry Feed for Omega-3 Eggs 77
Commercial Aspects of Omega-3 Eggs 77
Major Findings and Conclusions of Consumer Surveys [47, 49, 135–141]: 78
Global Omega-3 Eggs Market 79
Major Market Players 79
Designer Egg—Value Addition Concept 79
Lutein-enriched Eggs 79
CLA-enriched Eggs 79
Low Cholesterol and Cholesterol Lowering Eggs 80
Herbal-enriched Egg 80
Immunoglobulin-enriched Eggs 80
Conclusion 80
References 80
6 Omega-3 Polyunsaturated Fatty Acids and Hyperlipidaemias 85
Hyperlipidaemia 85
Omega-3 Polyunsaturated Fatty Acids (n-3PUFA) 86
Structure 86
Dietary Sources and Metabolism 86
Omega-3PUFA and Blood Lipids 86
Triglycerides 86
Mechanisms by Which n-3PUFA Modulate Triglycerides 87
Very Low-Density Lipoprotein Production and NEFAs 87
TG Clearance and Lipoprotein Lipase (LPL) Activity 87
Transcription Factors 87
Trafficking of Fatty Acids Between Tissues 88
Total Cholesterol 88
LDL Cholesterol 88
LDL Concentration 88
Particle Size 89
HDL Cholesterol 90
N-3PUFA and Combination Therapies 90
Combined n-3PUFA and Lipid-lowering Drug Therapy 90
Combined n-3PUFA and Other Natural Therapies 91
Factors Affecting n-3PUFA Efficacy in Hyperlipidaemia 91
Apolipoprotein E Polymorphisms 91
Gender Differences 92
Conclusion 92
Summary 93
References 93
7 World Market of Omega-3 Fatty Acids 97
Introduction 97
Types and Sources of Omega-3 Fatty Acids 98
Krill 99
The Omega-3 Market 99
The Omega-3 World Market for Ingredients 100
The Omega-3 World Market for Application Segment 101
New Emerging Market for Novel Omega-3 Products 104
Other Omegas and Sources 105
Room for Everyone 105
References 105
8 Fortification of Food with Omega-3 Fatty Acids 107
Introduction 108
Advantages of Food Fortification as a Strategy to Combat MNM [3, 4] 108
Industry-Driven Fortification 109
Fortification Policy 109
National Food Law and Fortification 109
Guidelines on Food Fortification 109
Omega-3 Fortification 110
Safety 110
Market of Omega-3-Fortified Products 111
Omega-3-Fortified Food Products Available in Market 112
Market Drivers for Omega-3-Fortified Products 116
Market Restraints for Omega-3-Fortified Products 116
Who Will Benefit from Omega-3 Fortification of Food Products? 116
Conclusion 116
References 117
9 Importance of Polyunsaturated Fatty Acids from Marine Algae 119
Introduction 119
The Marine Environment and Algae 120
Terrestrial Plants and Fatty Acids 124
Codex Alimentarius and Human Nutrition 126
Fatty Acids from Marine Microalgae 127
Fatty Acids from Seaweeds 132
Biotechnology of Fatty Acids from Marine Algae 134
Concluding Remarks 138
Acknowledgments 139
References 139
10 Emulsions of Omega-3 Fatty Acids for Better Bioavailability and Beneficial Health Effects 145
Introduction 145
Oxidation of PUFAs 145
What Is Emulsion? 146
Phase Inversion Method 147
Phase Titration Method 147
High-pressure Homogenizer 147
Sonication Method 148
Emulsifiers 148
Low Molecular Weight Emulsifiers 148
High-Molecular Weight Emulsifiers 148
Microencapsulation of Emulsion 149
Spray Drying 149
Fluidized Bed Drying 150
Freeze-Drying (Lyophilization) 150
Coacervation 150
Extrusion 151
Factors Influencing Emulsion Formation 151
Salt Concentration 151
Alcohol Concentration 151
Hydrophobic Chain Length of Surfactant 151
pH 151
Oil Properties 151
Ionic Strength 151
Characterization of Emulsion 151
Physical Appearance by Visual Inspection 151
Size Determination 151
Limpidity Test 152
Microscopic Examination 152
Rheological Properties 152
Dilution Test 152
Staining Test 152
Tests for Assessment of Emulsion Stability 152
Stress Testing Using Centrifugation 152
Repeated Freezing and Thawing 152
Long-term Stability 152
Determination of Thermal Stability 152
Peroxides and Degradation Product Detection 152
Omega-3 Fatty Acid Emulsions and Microencapsulates: Bioavailability and Benefits 153
References 153
11 Omega-3 Fatty Acids in Inflammatory Diseases 158
Introduction 158
Immune System and Inflammation 158
Role of PUFAS in Inflammation 159
Mechanisms by Which Omega-3 Fatty Acids Influence Inflammation 160
Altering the Physical Properties of the Membrane 160
Exerting Effects on Cell Signaling Pathways 160
Altering the Pattern of Lipid Mediators Produced 160
Role of Omega-3 Fatty Acids in Rheumatoid Arthritis 162
Role of Omega-3 Fatty Acids in Inflammatory Bowel Diseases 164
Role of Omega-3 Fatty Acids in Asthma 164
Role of Omega-3 Fatty Acids in Multiple Sclerosis 166
Summary and Conclusion 167
References 169
12 Omega-3 Fatty Acids in Cancer: Insight into the Mechanism of Actions in Preclinical Cancer Models 173
Introduction 175
Role in Lipid Peroxidation 175
Role in Mitochondrial Membrane Lipid Peroxidation 176
Role in Inflammation 177
Role in Physicochemical Properties of Lipid Rafts and Signal Transduction 179
Role in Limitless Cell Proliferation 180
Role in Apoptosis 180
Role in Adhesion and Angiogenesis 180
Role in Metastasis 181
Role in Immunomodulation 181
Role in Combination with Chemotherapeutic Agents and Drug Resistance 181
Experimental Evidence from Animal Studies 183
Conclusion 183
Acknowledgments 184
References 184
13 Linseed as a Functional Food for the Management of Obesity 188
Obesity and Functional Foods 188
History of Linseed 188
Linseed Composition 189
Isolation of Linseed Oil 189
Pharmacology and Therapeutic Benefits of ALA 189
Obese Patients 192
Obese Rodents 193
Possible Mechanisms of Action of ALA 193
Isolation and Pharmacology of SDG from Linseed 194
Therapeutic Benefits in Humans 195
Actions in Rodents and Rabbits 195
Isolation and Therapeutic Effects of Dietary Fibre from Linseed Mucilage 196
Human Studies 197
Rodent Studies 198
Conclusion 198
References 198
14 Role of Omega-3 Fatty Acids in Metabolic Syndrome 203
Obesity and Metabolic Syndrome 204
n-3 PUFAs in Obesity and Metabolic Syndrome 205
Effects of n-3 PUFAs on Weight Loss and Body Composition 205
n-3 PUFAs Trials with Isocaloric Diets 205
n-3 PUFAs Trials with Hypocaloric Diets 207
n-3 PUFAs and Carbohydrate Metabolism in Metabolic Syndrome 207
N-3 PUFAs and Lipid Metabolism in Metabolic Syndrome 211
Effects on Triglycerides and Triglyceride-Rich Lipoproteins 211
Effects on LDL-ch and Non-HDL-ch Fractions 212
Effects on HDL-ch 212
N-3 PUFAs and Blood Pressure and Endothelial Health 212
n-3 PUFAs and Inflammatory Markers 212
Conclusions and Future Perspectives 213
References 214
15 Balancing Omega-6: Omega-3 Ratios in Oilseeds 217
Introduction 217
Fatty Acid Composition of Oilseeds 218
Importance of the Balance of ?-6 and ?-3 Fatty Acids in Human Diet 218
Fatty Acid Biosynthesis in Plants 219
Synthesis of Acetyl-CoA Inside Plastid 219
Energy Requirement for Fatty Acid Synthesis 220
Fatty Acid Biosynthesis Pathway in Plants 220
Formation of Malonyl-CoA and Malonyl Acyl Carrier Protein (ACP) 220
Condensation with Malonyl-ACP 221
Reduction of Keto Group 222
Dehydration of Hydroxyl Group 222
Reduction of Enoyl Group 222
Termination of Fatty Acyl Chain Elongation 222
Desaturation 222
The Role of Rubisco in Developing (Green) Oilseeds 222
Formation of TAGs 223
Cytoplasmic Fatty Acid (FA) Pool 223
De Novo Synthesis of DAG 223
Synthesis of PC-Derived DAG 223
TAG Synthesis from DAG 223
Metabolic Flux of TAG Synthesis 224
TAG Synthesis and Oil Accumulation During Seed Development 224
Biotechnological Approaches to Achieve Balanced Omega-6: Omega-3 Ratio 225
Engineering the Long-chain Polyunsaturated Fatty Acid (LC-PUFA) Pathway in Plants 226
Enzymes for LC-PUFA Biosynthesis 226
LC-PUFA Biosynthesis Pathway 227
Choice of Oilseeds for Balancing the Omega-6: Omega-3 Ratio 228
Heterologous Expression of LC-PUFA Biosynthesis Enzymes in Plant Seeds 228
Promoters for Ectopic Gene Expression 228
Potential Hurdles in Achieving Balanced ?-6/?-3 Ratio 229
Substrate Dichotomy Bottleneck 229
Reduced Metabolic Flux for PC-Independent Acyl Modifications 230
Conclusions and Future Prospects 230
Acknowledgments 230
References 230
16 Omega-3 Fatty Acids and Diabetic Complications 235
Introduction 235
Omega-3 and Diabetic Nephropathy 236
Omega-3 and Diabetic Retinopathy 236
Omega-3 and Diabetic Cardiomyopathy 237
Omega-3 and Diabetic Neuropathy 239
Omega-3 and Red Blood Cell Deformability 239
Conclusion 239
References 240
17 Omega-3 Fatty Acids and Mitochondrial Functions 242
Introduction 242
Neurodegenerative Diseases 243
Cardiovascular Diseases 244
Diabetes 244
References 245
18 Omega-3 Fatty Acids and Alzheimer’s Disease 247
Introduction 247
Role of Omega-3 in Brain 247
Neurodegenerative Diseases 247
Alzheimer’s Disease 247
Omega-3 and AD 248
Conclusion 249
References 249
19 Prevention of Oxidative Stress by Omega-3 Fatty Acids in the Brain 251
Introduction 251
Enzymic and Nonenzymic Lipid Mediators of ARA-Derived Metabolism and Their Antioxidant and Anti-inflammatory Effects 254
Enzymic and Nonenzymic Lipid Mediators of Omega-3 Fatty Acids 255
Enzymic and Nonenzymic Lipid Mediators of EPA Metabolism and Their Antioxidant and Anti-inflammatory Effects 255
Enzymic, Nonenzymic Lipid Mediators of DHA Metabolism and Their Antioxidant and Anti-inflammatory Effects 256
Prevention of Oxidative Stress and Neuroinflammation by EPA and DHA 258
Conclusion 259
References 259
20 Role of Omega-3 Fatty Acids for Eye Health 262
Introduction 262
Polyunsaturated Fatty Acids 262
Age-Related Macular Degeneration 262
Pathogenesis of Age-Related Macular Degeneration 262
Para-Inflammation in Age-Related Macular Degeneration 263
Treatment Options for Age-Related Macular Degeneration 263
Current Research in Age-Related Macular Degeneration 264
Dry Age-Related Macular Degeneration 264
Observational Studies in Age-Related Macular Degeneration 264
Wet Age-Related Macular Degeneration 265
Retinitis Pigmentosa 265
Current Research in Retinitis Pigmentosa 266
Stargardt Disease 266
Current Research in Stargardt Disease 266
Cone Dystrophies 267
Observational Studies in Macular Dystrophies 267
Severe Dry Eyes 267
Observational Studies in Severe Dry Eyes 268
Conclusions 269
References 269
21 DHA-Rich Algae Oil Is a Safe and Effective Vegetarian Source of Omega-3 273
Introduction 273
Supplementation 274
DHA in Pregnancy and Development 274
Is Algae DHA an Effective Co-therapy? 275
Conclusion 275
References 276
22 Role of n-3 (Omega-3) Polyunsaturated Fatty Acids in Postpartum Depression: Mechanisms and Implications for Prevention and Treatment 277
Introduction 277
Role and Regulation of n-3 PUFAs and the Brain 277
Modulation of Maternal n-3 PUFA Status by Pregnancy and Lactation 278
n-3 PUFA Status in Depression 278
Clinical Trials with n-3 PUFAs in Depression 279
Effects of n-3 PUFAs on Depression-Related Neurobiology and Behavior 283
Conclusion 286
References 287
23 Influence of Omega-3 Fatty Acids on Bone Turnover 294
Introduction 294
Bone Turnover 294
Oxidative Stress, Inflammation, and Bone Remodeling 295
Influence of Omega-3 Fatty Acids on Bone Turnover 296
Beneficial Effects of Omega-3 Fatty Acids on Bone Turnover 296
Omega-3 Fatty Acids and Bone Density 297
Omega-3 Fatty Acids, Breast Cancer and Bone Turnover 297
Negative Effect of Omega-3 Fatty Acids on Bone Turnover 298
References 298
24 Interactions Between Omega-3 Fatty Acids and Iron 301
Introduction 301
Iron Metabolism 301
Omega-3 Fatty Acid Metabolism 302
Omega-3 Fatty Acid and Iron Interactions 303
Interactions Between DHA and Iron During Gestation 304
Iron and Eicosanoid Metabolism 304
References 306
25 Role of Omega-3 Fatty Acid in Major Cardiovascular Events—A Current View 308
Introduction 308
Mechanistic Insights on omega-3 PUFAs in Cardiovascular Protection 308
Different Roles of Omega-3 PUFAs in Major Cardiovascular Events According to the Diverse Patient Populations 309
References 310
26 Modulation of Immune Response by Omega-3 in Health and Disease 313
Introduction 313
The Immune System 313
Long-Chain Fatty Acids and Immune Response 313
Effect of Omega-3 PUFAs on Components of Immune System 314
Inflammation 314
Extravasation 314
Effect on Phagocytosis 314
Production of Cytokines and Other Soluble Mediators 315
Antigen-Presenting Cells (APCs) 315
Expression of Adhesion Molecules 315
Lymphocytes 315
Lymphocyte Proliferation 315
Antibody Production 316
NK and LAK cell Activity 316
Regulatory T Cells 316
Effect of Omega-3 PUFAs in Health 316
Effect of Omega-3 Fatty Acid Supplementation on Healthy Donors: In Vivo Data 317
Effect of Omega-3 Diet Supplementation on Pregnancy and Lactation in Relation to Infant Allergies 317
Diet Supplementation with Fatty Acids in Older Population: Adverse Effects? 317
Omega-3 in Inflammatory Diseases 318
Rheumatoid Arthritis 318
Asthma 318
Inflammatory Bowel Disease (IBD) 318
Psoriasis 318
Cardiovascular Diseases 318
Diabetes 319
Effect of Polyunsaturated Fatty Acids on Complications Associated with Diabetes 319
Deficiency of Polyunsaturated Fatty Acids as a Causative Factor for Diabetes 319
Multiple Sclerosis 320
Systemic Lupus Erythematosus (SLE) 320
Summary and Research Leads 321
Acknowledgments 321
References 321
27 The Linoleic-to-Linolenic Dietary Intake Ratio: The Fundamental Implications of Imbalance and Excess Looked at from Both a Functional and an Evolutionary Perspective: An Overview 327
Evolutionary Importance of LA and ALA 327
Introduction 327
Conditions of Existence 328
Womb and Cradle of Life 328
Light and Energy 330
Light-Protective Evolutionary Niches 332
Anoxic Environment 333
Organised Structure—Chirality and Non-bifurcated Chains 337
Vesicles—Evolutionary Structural Importance of LA and ALA 338
Summary—Evolutionary Role of LA and ALA 345
Role of LA and ALA in Plants 345
Conservation of Gene Pathways in Eukaryotes—Evolutionary Importance 345
Plant—Photosynthesis and UV Protection 346
Plants—Galactolipids and Phosphatidylcholine 346
Plants—Peroxisomes 346
Plants—Energy Production and Storage 347
Plants—Enzymes LOX and COX 347
Plants—Oxidised Derivatives and Signalling Systems 348
Plants—Immune System and Predator Defence 348
Plants—Reproduction and Fat Storage 348
Plants—Cardiolipin 348
Plants—Light Sensing a Precursor to Vision 349
Chiral Lipid Forms, Enzymes, and Oxidation: Relevance to Messengering 350
Relevance to Mammals and Humans 350
References 350
28 Bioactive Oxidised Products of Omega-6 and Omega-3, Excess Oxidative Stress, Oxidised Dietary Intake and Antioxidant Nutrient Deficiencies, in the Context of a Modern Diet 355
LA and ALA: The Most Common Terrestrial Fats 357
LA: Enabler and Controller of Reproductive Capacity and Related Processes 357
LA and ALA: ‘Essential Nutrients’ 357
The Crucial Point 357
Roles of ALA, LA and Their Oxidised Products in Humans 357
The Centrality of LA to the Control of Reproductive Capacity and Function 358
The Physiological Consequences of LA/ALA Imbalances, Excesses and Increased Oxidative Stress 358
LA: Age of Menarche, Puberty and Consequent Effects on Brain Maturation 360
Desaturase Function: Dietary and Genetic Differences 360
Oxidative Overload: The Importance of Nutrients 361
LA/ALA Imbalance Overprocessed Food
Rising Oxidation of LA and ALA in Foods Combined with the Loss of Antioxidants 362
Overconsumption of LA and Its Oxidised Products Combined with Heavily Processed Foods—Relevance to ‘Western’ Disease 362
Limited Capacity of Plant-Based Antioxidants to Negate Effects of Omega-6 Oxylipins 362
Physiological Relevance of Oxidised Products of LA and ALA 364
Sensitivity of ALA and LA to Oxidation, the Variety and Different Physiological Properties of Their Oxidised Products 364
Multiple Pathways for Oxidation 364
9 and 13HODE 365
LA Oxylipins in Food Actively Cross the Gut Membrane 366
ALA and Wider Oxylipins Including Conjugated Lipids—Current Knowledge 366
Photo-Oxidation Products 366
Cox and Lox 12/15 Enzymes—Functional Differences and Relevance to LA and ALA 366
CYP450 Enzymes 368
Oxylipins Generally 368
4HNE 369
MDA 370
Omega-3 Oxylipins 370
TRVP1 Pain Pathways 370
Oestrogen Desaturase and Cardiovascular Disease 371
Oxidised Lipids: PPAR Gamma and Alpha Activators 371
Chiral Oxylipin Products 371
Nitrogen-Related (Nitrous) Oxidation Products 371
Metabolic Sensing and Pathway Preferences for Oxidised Product 372
Wider Implications of Excess Oxidative Stress 372
Deficiency of ALA in the Diet—Oxidative Stress Implications 372
Phosphatidylcholine and Cardiolipin: Their Particular Relevance 372
Lysophosphatidylcholine 373
Cardiolipin—LA a Primary Component and Likely Metabolic Regulator 373
LA Species in Cardiolipin Are Very Susceptible to Oxidation Impacting Cytochrome C Function and so Energy Production 374
Oxidation of Foods Crosslinking
General Processing 375
Protein–Sugar–Lipid Crosslinks Including DNA Damage 375
Damage to Lipids and Use of Lysophosphatidylcholine in Food Processing 375
Oxidative DNA Damage 375
Internal Antioxidants for Hydroxyl Radicals and Oxylipins Are Limited 376
Glutathione 376
Catalase PPAR Alpha, Delta and Gamma
Oxidative Stress and DNA Damage 377
Cancer 377
Role of Epithelial Tissues in Cancer 378
Relationship of Oxidised Products of LA with Cancer 378
Oxidised Lipoprotein Receptor OLR1 378
Cancer Is Complex, but LA May Increase and ALA May Reduce the Risk of Cancer Initiation 379
Diet and Western Disease—Conclusion 380
References 381
29 In a Western Dietary Context Excess Oxidised Linoleic Acid of Dietary and Endogenous Origin by Over-Activation of PPAR Gamma so Immune and Inflammatory Pathways, and through Cardiolipin Damage, Increases Cardiovascular Risk 390
Importance of Lipids to Cardiac Function and Cardiovascular Health 391
Is excess Oxidised LA within a ‘Western’ Dietary Context a Key to Cardiovascular Disease? 391
Delivery of LA and ALA to Tissue: Phospholipids Chylomicrons and LDL 392
The Digestion, Delivery, Absorption and Uptake Pathways of LA and ALA 392
Absorption, Chylomicrons and Portal Vein 392
Phosphatidylcholine Composition Is Affected by Diet thereby Altering Lipoprotein Shell Composition and Delivery from Lipids to Tissue 393
Phosphatidylcholine an Important Mechanism for Delivery of Lipids and Choline 393
Importance of Phosphatidylcholine to Lipoprotein Membranes 394
Galactolipids 394
Albumin as a Transport Mechanism 395
Export of LA from the Liver and Implications for Non-alcoholic Fatty Liver Disease 395
LA Promotes Increased Liver LDL Output yet LA Reduces Plasma LDL: A Paradox? 396
LDL a Major Transporter of LA to Vascular Epithelial Cells Hence Cardiac Tissue 396
MUFA PUFA and Saturated Fat Content of LDL 396
LDL: An Evolutionary Lipid Supply Mechanism, to Support Reproductive Tissue Needs, Adipose Tissue Lipid Supply, and Sequester Blood Borne Oxidised Material and Pathogens into Tissue for Reprocessing? 396
Importance of Peroxisomes 399
Potential Recycling of Oxygen 399
Short Saturated MCTs and Cardiovascular Function 399
Peroxisomal Dysfunction-Related Cardiac Impairment 399
Impact of Failure to Activate PPAR Alpha Through Energy Restriction, Exercise and/or ALA Availability, and Over Activation of PPAR Gamma 400
Benefits of Short-Term Fasting 400
Delivery of Lipids and Oxidised Substrate to the Heart 400
Receptors for Oxidised LDL Including CD36 and ORL1 400
Fed State 401
Intermediate State Between Fed and Fasted 401
Non-fed Fasted State 401
Relevance of LDL LA-Related Oxidative Stress to Cardiovascular Disease 401
Oxidised Cholesterol Phosphatidylcholine and LA Significantly Influence of Gene Expression 402
Relevance of Oxidative ‘Western’ Dietary Factors to Cardiovascular Disease 402
Oxidised Lipids and Other Products Including AGE Actively Cross the Gut Membrane 402
The Relative Importance of LOX12/15 and COX to Oxidative Stress Induction 402
LA Oxylipin Including HODE-Related Oxidised Stress and Damage to Vascular Membranes 402
Dietary Oxidised LA: A Significant Factor in Cardiac Disease 403
LA-Not-Saturated Fat Is the Primary Constituent of Vascular Plaque 404
LDL via Receptors Sweep and Regulate Levels of Oxidised Product in the Blood 405
Omega 3 Fats and Vascular Plaque 405
Cardiolipin Damage 405
HDL: Antioxidant Transport for Oxidised Phospholipids and Cholesterol 406
HDL Unlike LDL Contains Antioxidant Enzymes Including Glutathione and Paraoxonase 407
HDL in Extreme Oxidative Scenarios May Lose Its Antioxidant Capacity and Become Proatherogenic 407
Populations with High-Saturated Fat Intake 408
Coconut Fat—A Dietary Staple, Highly Saturated and Significant Source of MCTs 408
Saturated Fat and Cardiovascular Disease? 408
Monosaturated Fats and Cardiovascular Disease 409
Cardiac Protective Effects of Unrefined Cold Pressed Oils 410
The Importance of Plant-Based Fat-Soluble Antioxidants 410
Low-Fat Diets, Low in Antioxidants, Containing Oils with Pre-oxidised LA Content 411
ALA and Vascular Disease 411
Population Studies: LA Intake, LDL Plasma Levels, Oxidative Stress and Vascular Disease 411
‘High-Fat’ Preindustrialised Diets Are not Comparable to Modern ‘High-Fat’ Diets 412
Hypertension and Cardiovascular Disease Were Unknown to Those on Traditional Pre-industrialised Diets 412
Primary Causes of Cardiovascular Disease—Summary 412
References 412
30 Linoleic Acid and Alpha-Linolenic Acid Have Central Roles in Brain Energy Substrate Provision, Endogenous Lipid Production, Immune and Repair Function, via Peroxisomal Beta-Oxidation-Related Pathways? 418
Linoleic Acid (LA) and Alpha-Linolenic Acid (ALA) Multiple Roles in the Brain Including as Potential Energy Substrates 419
Current Metabolic View as to Brain Energy Sources 419
ALA and LA Presence in Structural Brain Lipids 419
LA, ALA, PA, OA and POA Uptake and Usage by the Brain 419
Astrocytes Are Numerous, Populate the Blood–Brain Barrier and Contain Peroxisomes 420
Importance and Presence of Peroxisomes in the Brain 421
Brain Mitochondria Have Limited/Very Limited Ability to Beta-Oxidise Long-Chain Fats 421
Astrocytes But Not Neurons Can Metabolise Medium-Chain Fats MCFs 422
Protection of Long-Chain Fats in the Brain Structural Membrane from Beta-Oxidation 422
Are Ketones or MCFs and ACoA the Primary Alternative Brain Fuel to Glucose? 422
Do Peroxisomal Pathway Substrates Fuel the Brain of Inuit with a CPT1A Variant? 422
Potential Use of Peroxisomal Pathways to Fuel Neonate Brains 423
Polyunsaturated Percentage Content of Breast Milk Is Significant and Has a Wide Range 424
PPAR Alpha Null Rodent Pups Exhibit Increased Mortality 424
MCAD Deficiency Disorder 424
Role of Palmitate and Other Fats as Peroxisomal Substrates 424
Alternate Potential Fuel Products of ACoA 425
Wider Importance of Brain Peroxisomes 425
Roles of PPAR Gamma 425
Impact of PPAR Gamma Peroxisomal Activation on Oxidative Stress and Its Relationship with iNOS 425
PPAR Gamma Induced Glial Death: PPAR Alpha Activation in Contrast Did Not 425
PPAR Alpha-Related Peroxisomes: Activation by Energy Deficit Stress Including Through Fasting and Exercise 426
PPAR Alpha Activation Increases Antioxidant Production Potentially Protecting the Brain from Inflammation 426
Role of PPAR Delta in Brain Antioxidant Protection 426
Dietary Balance of ALA and LA: Relevance to Brain Function 426
Sensitivity of the Brain to Oxidative Stress 426
Cardiolipin: Mitochondrial Function Including Energy Production and Apoptosis 426
Potential Role of LOX12/15 and LA Oxylipin HODEs During Brain Damage or Injury 427
Effect of Dietary ALA on Brain Function 427
DHA in the Brain 427
Alzheimer’s PPAR Gamma, PPAR Alpha, OA, POA, Mead Acid, SCD1
Wider Functional and Behavioural Implications of Lipid and Wider Redox Imbalances 429
References 430
31 The Roles of Linoleic and Alpha-linolenic Acid, Their Oxylipins and the PPAR Alpha-, Delta- and Gamma-Related Peroxisomal Pathways on Obesity in the Context of a “Western” Diet 434
Western processed nutrient depleted preoxidised LA rich diets are obesogenic 435
Adipose Tissue—Evolutionary Rules 435
LA and ALA Cannot Be Made by Mammals so Are Essential Nutrients 435
Intake of LA and ALA in “Native” and “Westernised” Diets 435
LA Ultimate Controller of Reproduction and Fat Deposition? 436
Adipose Tissue—a Seasonal Storage Depot Primarily Directed to Support Reproduction and/or Hibernation 436
Iodine and Other Fat-Soluble Antioxidants Are Delivered by LDL to Fat Tissue 437
Oxidised Product Reprocessing and Related Immune Function Centre 438
Obesity Is Signalled by Oxidative Stress 438
Delivery Mechanisms 438
Delivery of Lipids to Fat Cells by Chylomicrons 438
Delivery of Lipids Oxidised Material and Cellular Detritus  to Fat Cells by LDL 438
Rates of Mobilisation of Fats Out of Adipose Tissue and Subsequent Beta-Oxidation 439
LA Roles in Adipose Tissue Accretion 439
Hibernators Store Very High Levels of LA Prior to Hibernation, Which May Have a Role in Lowering Metabolism 439
Effect of LA on Metabolism Including in Metabolic Syndrome Through Induction of Mitochondrial Inhibition 440
Activation of Oxidised LDL Receptors in Adipose Tissue 441
Adipose Tissue—A Store of and Regulator of Blood Cholesterol? 441
PPAR Gamma Master Adipogenic Controller 441
LA in Fat Tissue Relevance of PPAR Gamma, LA, HODEs 441
ALA and Relevance of PPAR Alpha 443
PPAR Alpha Is Activated Primarily by Energy Deficit Stress Including Exercise and Fasting 443
Roles of PPAR Alpha and Differences with PPAR Gamma 443
ALA in Human Fat Tissue 444
ALA in Monogastrics and Other Animals 444
Potential Use of Peroxisomal Beta-Oxidation of ALA to Provide Substrate to Mitochondria 444
ALA, LA and NAFLD 445
ALA Uprated Metabolism, Thermogenesis and Reduced “Feed Efficiency” in Livestock 445
Dietary Absence of ALA 445
Oxidative Stress and Obesity 445
ALA as a Competitive Substrate for LOX 12/15 446
LA Oxylipins the HODEs Primary Endogenous Activators of PPAR Gamma Are Associated with Obesity and Diabetes 446
Adipose Tissue, Macrophage Content and Related Immune Including Cytokine Signalling Capacity 446
Correlation Between Obesity and Oxidative Stress 447
Fructose Synergy with LA and Fat Deposition 447
LA and Glucose in Nature Are Found in the Same Foods, but Available Independently in Refined Food the Metabolic Consequences
Both Glucose and LA Raise Insulin 448
Beta-Cell-Related Insulin Resistance, INOS, NO, PPAR Alpha, Delta and Gamma, and LA Excess 448
Role of Malonyl-CoA, and ACoA in Regulation of Insulin, and Partition of Fats to Peroxisomal Beta-oxidation 449
“Mitochondrial” Wider Tissue Insulin Resistance: Restricted Long-Chain Lipid Access to Mitochondria by CPTIA Malonyl-CoA Randle Cycle-Related Blocking 449
Half-Life of Adipose Tissue and Implications for Long-Term Oxidative Stress 449
Competition for Plasma Nutrients by Adipose Tissue—An Under-recognised Issue in Obesity 450
LA and Weight Loss in the Obese 450
References 450
32 The Crucial Relevance of ALA and LA as Primary Peroxisomal Beta-Oxidation Substrates, of Oxidised LA as the Primary Endogenous Activator of PPAR Gamma, and Energy Deficit as the Primary Activator of PPAR Alpha 455
The Crucial Relevance of LA and ALA to Peroxisomes 456
Peroxisomes 456
Some Basic Features and Roles of Peroxisomes 456
Different Roles of PPAR Alpha Gamma and Delta Related Peroxisomes 457
Overall Oxidation Rates of Fats 457
Preferred Substrates and Rates of Beta-Oxidation of ALA GLA LA and Other Fats by Peroxisomes 458
Wider Functional Roles of Peroxisomes 458
Potential Mitochondrial Damage from Reliance on LA for Fuel During Conditions of Oxidative Stress 458
Peroxisomes Produce Short Chain Fats and ACoA 458
Potential Restrictions on Peroxisomal DHA Beta-Oxidation 459
Potential Energetic Advantages Including Altered Respiratory Quotient of Metabolism of Lipids via the Peroxisomal in Combination with Mitochondrial Pathways 459
Peroxisomal Oxidative Combined with Blood Brain Barrier Lipid Preferences Largely Determines Structural Lipid Composition of the Brain? 459
Peroxisome Proliferation and/or Increased Size and Activity in Humans 459
LA and ALA—Their Different Metabolic Roles and Activation Pathways 460
PPAR Gamma Different Roles Normal Physiological Activation V ‘Excess’ Activation
PPAR Alpha Activation by Energy Deficit and to a Lesser Extent by Omega-3S 460
Peroxisomes Peroxide Production, the Hydroxyl Radical and Oxidative Stress
Peroxisome Antioxidant Production Capacity Including of Catalase 461
Role of Peroxisomal Peroxide Production in Conjunction with INOS Produced NO in Phagocytosis? 462
Mammals—Peroxisomes PPAR Gamma and Cellular Creation Maintenance and Repair
Capacity of Peroxisomal Beta-Oxidation Products to Support Mitochondrial ATP Production as Alternative Fuel Substrates to Glucose and/or Ketosis 462
Peroxisomes, PPAR Alpha, Energy Production, Malonyl-CoA 463
Peroxisomes and Calories 463
Thermogenesis Temperature Adaption and Hibernation 464
PPAR Delta Antioxidant Promotion
Stored LA, Impact of Peroxisomal Pathways, Dieting and Oxidised Stress 465
References 465
33 Effects of Omega-3 Fatty Acids in Myocardial Infarction 468
Introduction 468
Intervention Studies 471
The DART Study 471
Singh et al. 471
The GISSI-Prevenzione Study 471
Svensson et al. 471
The JELIS Study 471
The GISSI-HF Trial 472
JELIS Trial Subgroup Analysis 472
The Omega Trial 472
Alpha Omega Trial 472
The SU.FOL.OM3 Trial 473
The ORIGIN Trial 473
The Risk and Prevention Study 474
Meta-analysis 474
Rizos et al. 474
Kwak et al. 474
Wen et al. 474
Conclusions 474
References 475
34 Alternative Origins for Omega-3 Fatty Acids in the Diet 477
Introduction 477
Why Do We Need Alternative Sources of EPA and DHA PUFA? 478
The Growing Concern of Overfishing and Habitat Loss 478
Pollution and Metal Toxin Accumulation 479
Vegetarians and Vegans 479
Currently Explored Alternatives 480
Plant Sources of Omega-3 PUFA as an Alternative to Oily Fish 480
Aquaculture and Fish Feeds 482
Animal Sources of LC PUFA as an Alternative to Oily Fish 483
Macro and Microalgae Sources of LC PUFA as an Alternative to Oily Fish 484
Conclusion 484
Conflict of Interest 485
References 485
35 Maternal Long-chain Polyunsaturated Fatty Acids and Pregnancy Outcome 489
Maternal Nutrition and Pregnancy Outcome 489
Long-chain Polyunsaturated Fatty Acids (LCPUFA) 489
LCPUFA Biosynthesis 490
LCPUFA Metabolism During Pregnancy 490
LCPUFA Intake/Status during Pregnancy and Fetal LCPUFA Status 490
Role of LCPUFA in Pregnancy 490
Initiation of Labor 491
Length of Gestation 492
LCPUFA in Placental Growth and Development 492
Transport of Maternal LCPUFA to Fetus Through Placenta 493
Consequences of LCPUFA Inadequacy/Insufficiency 493
Preterm Labor 493
Intrauterine Growth Restriction 494
Gestational Diabetes Mellitus 494
Preeclampsia 495
Maternal LCPUFA and Fetal Development 495
Fetal Size and Weight 495
Maternal LCPUFA and Brain Development 495
Maternal LCPUFA and Fetal Health 496
LCPUFA Recommendations During Pregnancy 496
Conclusion 496
References 496
36 Role of Antioxidants in Human Health 502
Introduction 502
Natural Antioxidants and Sources 503
Cardiovascular Disease (CVD) 503
Diabetes Mellitus 505
Chronic Kidney Disease (CKD) 505
Cancer 506
Neurodegenerative Diseases 507
Aging 508
Obesity 508
Conclusion 508
References 509
37 Role of Omega-3 Fatty Acids in Cardiovascular Disorders 514
Introduction 514
Biochemistry 514
Proposed Mechanisms of Action 515
Effects on Diabetes 517
Omega-3-FA in the Primary Prevention of Ischemic Heart Disease (IHD) 518
Omega-3-FA in the Secondary Prevention of Cardiovascular Disease 519
Role in IHD 519
Role in Heart Failure 520
Role in Arrhythmia 520
Role in Prevention of Secondary Composite Cardiovascular Events 520
Omega-3-FA in Preventing Cardiac Events in Patients with Chronic Kidney Disease (CKD) 522
Omega-3-Index and CV Health 523
Pharmacological Preparations and Dosages 524
Adverse Effects 524
Conclusion 525
References 525
38 Beneficial Effect of Long-Chain Omega-3 Fatty Acids in Psoriasis 532
Introduction 532
Pathophysiology of Psoriasis 533
Omega-3 Fatty Acids and Their Potent Metabolites as Nutritional Value in Psoriasis Pharmacotherapy 533
DHA-Derived Resolvins and Protectins 534
EPA-Derived Resolvins 535
Omega-3 Fatty Acids: Immunosuppression in Psoriasis by Various Mechanisms 535
PKC Activation 535
MAPK Cascade 536
Nuclear Factor ? (NF-?) 537
Challenges Face Toward Effective Delivery of Omega-3 Fatty Acids in Psoriasis Pharmacotherapy 537
Scope of Nanomedicine in Effective Delivery of Omega-3-Fatty Acids 537
Conclusion 538
References 538
39 Pharmacokinetics and Safety Profile of Omega-3 Polyunsaturated Fatty Acids 542
Introduction 542
Synthesis Pathways of the n-3 PUFA 543
Pharmacokinetic Properties 545
Digestion of n-3 PUFA 545
Oral Bioavailability 547
Clinical Trials 547
Short Clinical (Postprandial) Trials 547
Long-Term Clinical Trials 552
Limitation of the Short and Long-Term Studies 554
Factors Regulating the Absorption 555
Age and Gender 555
Fat Content in Diet 555
Influence of Chemical Binding Form 556
Effect of the Galenic Formulation 556
Distribution 559
In Plasma Lipids and Red Blood Cells 559
Dietary Supplementation with Fish Oils 559
ALA Supplementation 560
EPA and DHA Supplementation 560
DHA Supplementation 561
Incorporation into the PL of Cell Membrane as a Major Structural Component 563
Storage in Adipose Tissue for Later Use 564
Effects of DHA and EPA Supplementation on Tissue Content 564
Metabolism 567
Beta-Oxidation of n-3 PUFA 567
Recycling of Carbon from ALA into SFA and MUFA 567
Formation of Ketonic Bodies 567
Metabolic Biotransformation 567
Excretion 570
Adverse Effects 570
Bleeding Complications 570
Carcinogenesis and Mutagenesis 572
Reproduction Studies 573
Pregnancy and Breast-feeding 573
Contraindications 574
Possible Drug Interactions 574
Antiplatelet Agents 574
HMG-CoA Reductase Inhibitors: Statins 576
Antihypertensive Drugs 576
Other Interactions 576
Conclusions 577
Acknowledgment 577
References 577
40 Fish Oil Fatty Acids for Aging Disorders 586
Introduction 586
Fish Oil Fatty Acids and Cardiovascular Health 587
Mechanism(s) of Action 587
Clinical Evidence 588
The Case with Arrhythmia 590
Aging, Bone Health, and n-3 Fatty Acids 591
Clinical Evidence 592
Fish Oil and Pain 592
Conclusion 595
References 595
Index 600