Sphingolipid Metabolism and Metabolic Disease (Advances in Experimental Medicine and Biology, 1372)

This book provides an up-to-date review of the fundamentals of sphingolipid metabolism and its role in metabolic diseases. Focusing on the sphingolipid de novo synthesis pathway, the effect of sphingomyelin, ceramide, and sphingosine-1-phosphate, and linkage between sphingolipids and other lipids, such as cholesterol, it covers serine palmitoyltransferase, ceramide synthases, ceramidases, sphingosine kinases, and sphingomyelin synthases, and more. While highlighting how rare diseases related to abnormal glycosphingolipid metabolism, this publication introduces sphingolipid metabolism-related diseases, such as lung diseases and cancers, as well as sphingolipid circadian regulation. The book demonstrates advances and limitations of research on sphingolipid metabolism and its roles in metabolic diseases and other diseases. It offers graduate students and researchers a coherent overview of sphingolipids, as well as the limitations of current research in the field, and promotes further studies on metabolic diseases, as well as pharmaceutical research on drug discovery based on sphingolipid de novo synthase. Preface 6 Contents 7 1: Sphingolipids and Cholesterol 9 1.1 Sphingolipids and Cholesterol on Cell Membrane 9 1.2 Sphingomyelin and Cholesterol in the Circulation 12 1.2.1 Apolipoprotein B (apoB)-Containing Lipoprotein Production 12 1.2.2 Cholesterol Absorption 13 1.2.3 Effect of SM on Cholesterol Efflux 13 1.2.4 SM and Atherosclerosis 14 1.3 Conclusion 14 References 15 2: Sphingolipids in Adipose: Kin or Foe? 23 2.1 Introduction 23 2.2 Sphingolipid Biosynthesis 24 2.3 Sphingolipids in Adipocyte Differentiation 24 2.4 Sphingolipid Roles in Obesity 26 2.5 Sphingolipids and Lipolysis 29 2.6 Sphingolipid Roles in Adipose Tissue Inflammation 30 2.7 Brown Adipose Tissue Function 31 2.8 Sphingolipids in Humans 34 2.9 Conclusion 35 References 36 3: De Novo Sphingolipid Biosynthesis in Atherosclerosis 38 3.1 Introduction 38 3.2 Sphingolipid Biosynthesis 39 3.3 Regulation of SPT 40 3.4 Role of Ceramide in Lipoprotein Metabolism and Vascular Regulation 42 3.5 Role of SM in Atherosclerosis 43 3.6 SMS and Atherosclerosis 44 3.7 SMS2 in Macrophages and Endothelial Cells 46 3.8 Pharmacological Modulation of SPT and SMS2 in Atherogenesis 47 3.8.1 SPT 47 3.8.2 SMS2 48 3.9 Conclusion 48 References 49 4: Serine Palmitoyltransferase Subunit 3 and Metabolic Diseases 54 4.1 The Serine Palmitoyltransferase and Long Chain Base Synthesis 54 4.2 Evolution of SPT and Structure 55 4.3 Role of SPTLC3 in Sphingolipid Metabolism 57 4.4 SPTLC3 in Metabolic Diseases 59 4.5 SPTLC3 in Other Diseases 60 References 61 5: Molecular Mechanisms of Sphingolipid Transport on Plasma Lipoproteins 64 5.1 Introduction 65 5.2 Biosynthesis of Sphingolipids 65 5.3 Lipoproteins as Lipid Transporters 65 5.4 Secretion and Transport of Sphingolipids 66 5.4.1 Transport of Ceramides 66 5.4.2 Transport of Sphingomyelin 67 5.4.3 Transport of Glycosphingolipids 68 5.4.4 Transport of Sphingosine 1-Phosphate 69 5.5 Conclusion 69 References 71 6: Sphingosine 1-Phosphate Metabolism and Signaling 73 6.1 Synthesis of S1P 73 6.2 S1P Kinases 73 6.3 S1P Degradation 74 6.4 S1P Phosphatases 74 6.5 S1P Lyase 75 6.6 Transportation of S1P and Transporters 76 6.7 S1P Carriers 77 6.8 S1P Signaling Receptors 77 References 78 7: Sphingomyelin Synthase Family and Phospholipase Cs 83 7.1 Sphingomyelin Synthase 1 83 7.2 Sphingomyelin Synthase 2 85 7.3 Sphingomyelin Synthase-Related Protein 86 7.4 SMS Family Is a Group of Phospholipase Cs 87 References 89 8: Sphingolipid Metabolism and Signaling in Endothelial Cell Functions 93 8.1 Endothelium: Structure and Functions 93 8.2 Sphingolipid Pathway 97 8.3 S1P Biosynthesis, Secretion, Carriers 99 8.4 S1P and Ceramides in Endothelial Barrier Functions 99 8.5 S1P Signaling in Endothelial Control of Vascular Tone 101 8.6 Endothelial Ceramide in Vascular Tone Regulation 102 8.7 Endothelial-Derived S1P: A Mechanotransduction Signaling in Blood Flow Regulation 104 8.8 S1P and Ceramide Rheostat in Blood Pressure Homeostasis 105 8.9 Endothelial Fine-Tuning of Sphingolipid De Novo Biosynthesis: Role of Nogo-B and ORMDLs 108 8.9.1 NOGO-B Regulates BP and Vascular Tone Via SPT 109 8.9.2 NOGO-B and Barrier Function 112 8.9.3 Endothelial NOGO-B and Pathological Cardiac Hypertrophy 113 8.10 Plasma Ceramide as Biomarker for Major Cardiovascular Events and Other Conditions 113 8.11 Gene Variants of Sphingolipid Pathway and Cardiovascular Diseases 114 References 115 9: Cholesterol Metabolism in Chronic Kidney Disease: Physiology, Pathologic Mechanisms, and Treatment 124 9.1 Introduction 125 9.2 Cholesterol Metabolism in Kidney 127 9.2.1 Lipoprotein Influx 128 9.2.2 Cholesterol Synthesis 128 9.2.3 Cholesterol Transport 129 9.2.4 Cholesterol Efflux 130 9.2.5 Cholesterol Catabolism 130 9.3 Pathological Pathways Associated with Obesity, Diabetes, Atherosclerosis, and NAFLD That Contribute to the Development of ... 131 9.3.1 Obesity 132 9.3.2 Diabetes 132 9.3.3 Atherosclerosis 132 9.3.4 NAFLD 132 9.4 Clinical Factors Contributing to Cholesterol-Related CKD 133 9.4.1 Sex 133 9.4.2 Aging 133 9.4.3 Hormones 134 9.4.4 Circadian Rhythm 134 9.4.5 Feeding 134 9.5 Therapeutic Targets and Interventions 134 9.5.1 Fasting and Time-Restricted Feeding (TRF) 135 9.5.2 Exercise 135 9.5.3 Statins and Ezetimibe 135 9.5.4 Apolipoproteins 136 9.5.5 Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors 136 9.5.6 miRNAs and lncRNAs 137 9.6 Cross-Talk Between Cholesterol and Sphingolipid Metabolism 138 9.7 Conclusions and Future Directions 138 References 139 10: Sphingolipids and Asthma 149 10.1 Asthma Is a Common Disease 149 10.2 17q12-21 Is a High-Risk Asthma Locus 150 10.2.1 ORMDL Proteins Are Evolutionary Conserved Endoplasmic Reticulum Proteins 150 10.2.2 ORMDLs Mediate Sphingolipid Homeostasis by Regulating De Novo Synthesis 150 10.2.3 ORMDLs Stabilize the Multi-Dimeric SPT Homocomplex 151 10.3 ORMDL3 and Asthma 151 10.4 Decreased Sphingolipid Synthesis and Asthma 152 10.5 Blood Sphingolipids Are Decreased in Children with Non-Allergic Asthma 153 10.5.1 Plasma Sphingolipids Are Higher Than Controls in Non-Allergic and Allergic Asthma 154 10.5.2 Risk Alleles Correlate with Whole Blood Sphingolipids 154 10.5.3 Sphingolipid De Novo Synthesis Is Decreased in Asthma and Associated with an Asthma-Risk Genotype 154 10.5.4 Increasing Sphingolipid De Novo Synthesis Decreases Airway Reactivity 154 10.6 Conclusion 155 References 155 11: Manifold Roles of Ceramide Metabolism in Non-Alcoholic Fatty Liver Disease and Liver Cancer 160 11.1 Overview of NAFLD and HCC 160 11.2 Metabolism of Ceramides in NAFLD 161 11.2.1 Dysregulation of Metabolism of Sphingolipids in the Liver of Patients with NAFLD 161 11.2.2 Role of Ceramide and Sphingosine in Hepatocyte Injury 163 11.2.3 Role of S1P in Steatosis and Inflammation in NAFLD 164 11.3 Sphingolipid Metabolism in HCC 164 11.3.1 Dysregulation of Ceramide Metabolism in HCC 164 11.3.2 Role of Ceramides in HCC 164 11.3.3 Role of S1P in HCC 166 11.3.4 Therapeutic Role of Exogenous Ceramide in HCC 166 11.4 Conclusions 167 References 167 12: Drug Development in the Field of Sphinogolipid Metabolism 172 12.1 Background 172 12.1.1 Serine Palmitoyl Transferase Inhibitors 175 12.1.2 Ceramide Synthase Inhibitors 176 12.1.3 Glucosylceramide Synthase Inhibitors 178 12.1.4 Sphingomyelinase Inhibitors 181 12.1.5 Sphingomyelin Synthase Inhibitors 183 12.2 Conclusion 185 References 186 13: Rare Diseases in Glycosphingolipid Metabolism 192 13.1 GM1 Gangliosidosis 193 13.1.1 Condition and Genetic Defects 193 13.1.2 Lab Findings 193 13.1.3 Clinical Features and Diagnosis 194 13.1.4 Treatment and Advances 195 13.2 GM2 Gangliosidosis 195 13.2.1 Condition 195 13.2.2 Genetic Defects 196 13.2.3 Clinical Features 196 13.2.4 Diagnosis 196 13.2.5 Treatment 196 13.3 Fabry Disease 197 13.3.1 Condition and Genetic Defects 197 13.3.2 Clinical Features 197 13.3.3 Diagnosis 197 13.3.4 Treatment 198 13.4 Gaucher ́s Disease 198 13.4.1 Condition 198 13.4.2 Genetic Defects 198 13.4.3 Lab Findings 198 13.4.4 Clinical Features and Diagnosis 199 13.4.5 Treatment 200 13.5 Metachromatic Leukodystrophy 200 13.5.1 Condition 200 13.5.2 Genetic Defects 201 13.5.3 Clinical Features and Diagnosis 201 13.5.4 Treatment and Advances 202 13.6 Krabbe Disease 203 13.6.1 Condition 203 13.6.2 Genetic Defects 203 13.6.3 Clinical Features 203 13.6.4 Diagnosis 203 13.6.5 Treatment and Advances 204 13.7 Niemann-Pick Disease A and B 204 13.7.1 Condition 204 13.7.2 Genetic Defects 205 13.7.3 Clinical Features and Diagnosis 205 13.7.4 Treatment and Advances 205 13.8 Farber Disease 205 13.8.1 Condition 205 13.8.2 Genetic Defects 206 13.8.3 Lab Findings 206 13.8.4 Clinical Features and Diagnosis 206 13.8.5 Treatment and Advances 206 13.9 Summary 207 References 209