Stearoyl-CoA Desaturase Genes in Lipid Metabolism

Obesity and diabetes develop as a complex result of genetic, metabolic and environmental factors and are characterized by increased lipogenesis and lipid accumulation in many tissues. Stearoyl-CoA desaturase (SCD) genes are a critical regulator of lipogenesis and catalyzes the synthesis of monounsaturated fatty acids (MUFA), mainly oleoyl- (18:1n9) and palmitoleoyl-CoA (16:1n7). These MUFAs are the major fatty acid substrates for the synthesis of triglycerides, cholesterol esters, wax esters and membrane phospholipids. There are 4 SCD isoforms (SCD1-4) in mice and two (hSCD1 and hSCD5) expressed in humans. At first glance, stearoyl-CoA desaturase enzyme would be considered a housekeeping enzyme because it synthesizes oleate a well-known fatty acid that is abundant in many dietary sources. However numerous studies have shown that SCD is a very highly regulated enzyme that features in so many physiological processes ranging from fat differentiation, carbohydrate and fat metabolism, inflammation and cancer. The editor’s studies using stearoyl-CoA desaturase knockout (SCD1-/-) mice and studies of other investigators using pharmacological approaches to reduce SCD1 expression in mouse tissues have all established that the expression of SCD1 gene isoform represents a key step in partitioning of lipids between storage and oxidation. High SCD expression favors fat storage leading to obesity while reduced SCD expression favors fat burning and leanness. Although these studies clearly illustrated that SCD1 expression is involved in the development of obesity and insulin resistance, questions remain in the elucidation of the mechanisms involved and role of SCD1. This book includes chapters by leading researchers on SCD Genes in the brain, heart, muscle, liver metabolism, Colitis, and more. ​ Preface 6 Contributors 10 Chapter 1: Early Studies on Role of Stearoyl-CoA Desaturase During Preadipocyte Differentiation 13 Background 13 Gene Expression During Adipocyte Differentiation 14 Identification of mRNAs Whose Expression Is Induced During Differentiation of 3T3-L1 Preadipocytes into Adipocytes 15 Identification of Stearoyl-CoA Desaturase as a Differentiation- 16 Isolation and Structure of the SCD1 Gene 17 Identification and Cloning of a Second Stearoyl-CoA Desaturase, SCD2 17 C/EBPα as Transcriptional Inducer of Gene Expression During Preadipocyte Differentiation 19 Conclusions 21 References 21 Chapter 2: Skin Stearoyl-CoA Desaturase Genes 24 Introduction 24 Identification of Scd1 Gene Defect in the Asebia Mouse by Positional Cloning 25 Impact of Scd1 Gene Defect in Mouse 28 Cloning of Scd3, a Gene with Restricted Expression in Skin 29 Expression of Mouse Scd Gene Family in Sebaceous Glands and During Hair Cycle 29 Human Skin Desaturases 32 Concluding Remarks 33 References 34 Chapter 3: Stearoyl-CoA Desaturase-1 Is a Biological Regulator of Energy Homeostasis 37 Role of Hepatic SCD1 in Regulation of Lipogenesis and Fatty Acid Oxidation 37 Conclusion 42 References 43 Chapter 4: Role for Stearoyl-CoA Desaturase-1 in the Metabolic Effects of Leptin 46 Obesity and Metabolic Disease 46 Leptin and the Regulation of Body Weight 47 Metabolic Effects of Leptin 48 Identification of SCD-1 as a Leptin-Repressed Gene in Liver 48 SCD-1 Repression Mediates the Metabolic Effects of Leptin 49 SCD-1 and Fatty Liver Disease 50 Mechanism for the Metabolic Effects of SCD-1 Deficiency 51 SCD-1 and Other Components of the Metabolic Syndrome 53 SCD-1 as a Potential Therapeutic Target 53 References 54 Chapter 5: Regulation and Metabolic Functions of White Adipose Tissue Stearoyl-CoA Desaturase 57 Introduction 57 Structure and Functions of WAT 58 Adipokines, Obesity, and Adipose Tissue Inflammation 59 Regulation of Adipose Tissue SCD Expression 60 Hormonal Control 60 Nutritional Control 62 Functions of WAT SCD 63 Regulation of Adipogenesis and Lipogenesis 63 SCD and Obesity 64 Effects of SCD on Adipose Tissue Inflammation 64 Conclusion 65 References 65 Chapter 6: Function and Regulation of Macrophage Stearoyl-CoA Desaturase in Metabolic Disorders 69 Introduction 69 Role of Macrophages in Metabolic Disorders 70 Macrophages and Obesity-Associated Insulin Resistance 70 Macrophages and Atherosclerosis 71 Regulation of Macrophage SCD Expression 72 SCD and Macrophage Biology in Metabolic Disorders 73 Role of Macrophage SCD in the Pathogenesis of Obesity- 73 Macrophage SCD as a Mediator of Atherosclerosis 73 Conclusion 76 References 76 Chapter 7: Stearoyl-CoA Desaturase-1 in the Regulation of Toll-Like Receptor Signaling and Endoplasmic Reticulum Stress Signaling 80 SCD1 and Lipid Biosynthesis 80 SCD1 and Inflammation 81 SCD and ER Stress 84 Conclusion 88 References 89 Chapter 8: Stearoyl-CoA Desaturase in the Control of Heart Metabolism 92 Introduction 92 Role of SCD in the Regulation of Cardiac Substrate Utilization 94 SCD1 and Cardiac Function 97 SCD1 and Cardiomyocyte Apoptosis 99 The Role of Oleate in Regulation of Cardiac Metabolism 101 Plasma Desaturation Index as Predictor of Cardiac Health 103 Conclusion 103 References 104 Chapter 9: Stearoyl-CoA Desaturase-1 Activity in Skeletal Muscle: Is It Good or Bad? 109 Introduction 109 A Causative Role for SCD1 in Dysregulated Metabolism 110 The Role of SCD1 in the Modulation of Substrate Metabolism and Insulin Sensitivity 110 SCD1 and Inflammation 114 A Protective Role for SCD1 116 Dysregulated Lipid Metabolism and Insulin Resistance 116 Conclusions/Future Directions 118 References 119 Chapter 10: The Cellular Function of Stearoyl-CoA Desaturase-2 in Development and Differentiation 125 Introduction 125 Discovery of SCD2 127 SCD2 Regulation 128 SCD2 Function in the Skin 129 SCD2 Function in the Liver 130 SCD2 Function in the Adipose Tissue 130 SCD2 Expression in Immune Cells 132 SCD2 Function in Reproduction 133 Human Relevance 134 Conclusions 134 References 135 Chapter 11: Stearoyl-CoA Desaturase Isoforms 3 and 4: Avenues for Tissue-Specific ∆9 Desaturase Activity 137 Introduction 137 SCD3 138 Tissue Expression 138 Protein Structure and Substrate Specificity 139 Gene Structure and Regulation 140 SCD4 142 Protein Structure and Function 142 Gene Structure and Regulation 142 Summary 144 References 144 Chapter 12: Functional Development of Stearoyl-CoA Desaturase Gene Expression in Livestock Species 147 Introduction 147 SCD Tissue Distributions in Livestock Species 148 SCD Genetic Variation Across Livestock Species 149 SCD Chromosomal Locations in Livestock Species 149 SCD and Fatty Acid Quantitative Trait Loci 150 SCD Gene Polymorphisms in Asian Cattle 150 SCD Gene Polymorphisms in Pigs 151 Adipose Tissue Differentiation and SCD Gene Expression and Activity 151 Bovine Preadipocyte Culture Studies 151 Animal Studies 153 Regulation of SCD Activity by Fatty Acids 156 Regulation of SCD Gene Expression by Oleic Acid 159 Gene Expression in Co-cultured Preadipocytes and Myoblasts 160 Summary 161 References 161 Chapter 13: Expression and Nutritional Regulation of Stearoyl-CoA Desaturase Genes in the Ruminant Mammary Gland: Relationship with Milk Fatty Acid Composition 166 Introduction 166 Functions of SCD in the Mammary Gland of Ruminant 167 Characterization of SCD Genes 169 Regulation of Mammary SCD Genes Expression by Dietary Factors 173 Effect of Dietary Factors 173 Ruminant Species Specificities 179 Mechanisms of the Nutritional Regulation of Mammary SCD 181 In Vivo Studies with Specific Fatty Acid Infusion or Injection 181 In Vitro Studies on the Effect of Fatty Acids on Mammary SCD 184 Knowledge on the Signalling Pathways Mediating Nutritional Regulation of SCD Gene Expression in Ruminants 189 Conclusions 191 References 192 Chapter 14: Physiological Functions and Regulation of C. elegans Stearoyl-CoA Desaturases 199 The Caenorhabditis elegans Model for Studies of Lipid Synthesis and Function 199 C. elegans Encodes Three SCD Orthologs 200 Loss of One SCD Isoform Is Compensated for by Up-regulation of the Remaining SCDs 201 Double Mutant Strains Reveal Additional Requirements for SCDs 202 The fat-6;fat-7 Double Mutants Have Reduced Fat Stores and Increased Fat Oxidation, Similar to Mouse SCD1 Mutants 203 Nuclear Hormone Receptors Regulate Transcription of SCDs 203 Regulation of C. elegans SCDs by SREBP 205 MDT-15 Interacts with SBP-1 and NHRs to Regulate C. elegans SCDs 206 FOXO Regulates SCDs to Confer Long Lifespan and Cold Tolerance 206 Fatty Acid Desaturation and Other Lipid Modifications in Germ Cells Regulate Lifespan 207 Conclusions 208 References 208 Chapter 15: Remodeling of Membrane Phospholipids by Bacterial Desaturases 212 Unsaturated Fatty Acids 213 Unsaturated Fatty Acids Synthesis in Bacteria 213 Biochemical Characteristics of Desaturation Systems 216 Bacterial Desaturases 218 Desaturases from the Genus Bacillus 218 Cyanobacterial Desaturases 220 Pseudomonas aeruginosa Desaturases 221 Mycobacterial Desaturases 221 Modulation of Membrane Fluidity 222 The Des Pathway of Bacillus subtilis 223 Two Inducible Aerobics Pathways of UFAs Synthesis in Pseudomonas aeruginosa 226 A Multi-Stress Sensor in Cyanobacteria 227 Concluding Remarks and Future Perspectives 228 References 229 Index 235 James Ntambi has gathered top authors to write about the remarkable growth of research on the role of the stearoyl-CoA desaturase (SCD) genes in metabolism in different species including human. The book shows that beginning with simple cellular models of differentiation a broad and comprehensive analysis of the SCD gene family in a number of species and biological systems has been carried out over the course of the last twenty five years. SCD is a central enzyme in lipid metabolism that synthesizes monounsaturated fatty acids (MUFA) from saturated fatty acid precursors. At first glance, SCD would be considered a housekeeping enzyme because its product oleate is a well-known MUFA that is abundant in many dietary sources and tissue lipids. A particular highlight in the chapters of the book is that MUFAs may have signaling properties that regulate metabolism. For example, a proper ratio of saturated to MUFA contributes to membrane fluidity, and oleate has also been implicated as a mediator of signal transduction, cellular differentiation and metabolic homeostasis. It is also highlighted that SCD-1 repression mediates the metabolic effects of the hormone leptin. Conditional alleles and corresponding tissue-specific knockout mouse models for many of the SCD gene isorfms have provided a wealth of information on not only tissue-specific fatty acid metabolism but also the key transcription factors that regulate SCD expression under a variety of metabolic and genetic backgrounds. The studies described indicate that control of SCD expression occurs via a series of complex signal transduction schemes making SCD one of the most highly studied lipogenic gene families to date Front Matter....Pages i-xi Early Studies on Role of Stearoyl-CoA Desaturase During Preadipocyte Differentiation....Pages 1-11 Skin Stearoyl-CoA Desaturase Genes....Pages 13-25 Stearoyl-CoA Desaturase-1 Is a Biological Regulator of Energy Homeostasis....Pages 27-35 Role for Stearoyl-CoA Desaturase-1 in the Metabolic Effects of Leptin....Pages 37-47 Regulation and Metabolic Functions of White Adipose Tissue Stearoyl-CoA Desaturase....Pages 49-60 Function and Regulation of Macrophage Stearoyl-CoA Desaturase in Metabolic Disorders....Pages 61-71 Stearoyl-CoA Desaturase-1 in the Regulation of Toll-Like Receptor Signaling and Endoplasmic Reticulum Stress Signaling....Pages 73-84 Stearoyl-CoA Desaturase in the Control of Heart Metabolism....Pages 85-101 Stearoyl-CoA Desaturase-1 Activity in Skeletal Muscle: Is It Good or Bad?....Pages 103-118 The Cellular Function of Stearoyl-CoA Desaturase-2 in Development and Differentiation....Pages 119-130 Stearoyl-CoA Desaturase Isoforms 3 and 4: Avenues for Tissue-Specific ∆9 Desaturase Activity....Pages 131-140 Functional Development of Stearoyl-CoA Desaturase Gene Expression in Livestock Species....Pages 141-159 Expression and Nutritional Regulation of Stearoyl-CoA Desaturase Genes in the Ruminant Mammary Gland: Relationship with Milk Fatty Acid Composition....Pages 161-193 Physiological Functions and Regulation of C. elegans Stearoyl-CoA Desaturases....Pages 195-207 Remodeling of Membrane Phospholipids by Bacterial Desaturases....Pages 209-231 Back Matter....Pages 233-239