Lipid Signaling and Metabolism

Lipid Signaling and Metabolism provides foundational knowledge and methods to examine lipid metabolism and bioactive lipid signaling mediators that regulate a broad spectrum of biological processes and disease states. Here, world-renowned investigators offer a basic examination of general lipid, metabolism, intracellular lipid storage and utilization that is followed by an in-depth discussion of lipid signaling and metabolism across disease areas, including obesity, diabetes, fatty liver disease, inflammation, cancer, cardiovascular disease and mood-related disorders. Throughout, authors demonstrate how expanding our understanding of lipid mediators in metabolism and signaling enables opportunities for novel therapeutics. Emphasis is placed on bioactive lipid metabolism and research that has been impacted by new technologies and their new potential to transform precision medicine. Provides a clear, up-to-date understanding of lipid signaling and metabolism and the impact of recent technologies critical to advancing new studies Empowers researchers to examine bioactive lipid signaling and metabolism, supporting translation to clinical care and precision medicine Discusses the role of lipid signaling and metabolism in obesity, diabetes, fatty liver disease, inflammation, cancer, cardiovascular disease and mood-related disorders, among others Cover Front matter Copyright Contents Contributors Preface Chapter-1 Chapter 1 - Homeostatic control of membrane lipid biosynthesis in bacteria Introduction General principles of fatty acid biosynthesis Biochemistry of bacterial fatty acid synthesis Acetyl-CoA carboxylase Initiation steps and elongation cycle Biochemistry of phospholipid biosynthesis Phosphatidic acid biosynthesis Acyltransferases The PlsB/PlsC system The PlsX/PlsY/PlsC system Control of lipid biosynthesis in bacteria Biochemical regulation of fatty acid and phospholipid biosynthesis Regulation at the Initiation steps Regulation at the elongation steps Transcriptional regulation of lipid metabolism Coordination of fatty acid metabolism in E. coli Control of unsaturated fatty acid synthesis in P. aeruginosa Global regulation of lipid synthesis in B. subtilis Control of unsaturated fatty acid synthesis in B. subtilis: The plasma membrane as a signaling structure Control of lipid metabolism in actinomycetes Perspectives References Chapter-2 Chapter 2 - Lipid trafficking and signaling in plants Outline Introduction General comparison between animal and plant lipids Synthesis of membrane lipids Lipid trafficking Phosphatidic acid as a biosynthetic intermediate Key signaling lipids in plants Development Plant growth and seedling development Root development Cytoskeleton Circadian clock Flowering Abiotic stress Ethylene and stress response Auxin and salt stress response Cold stress Abscisic acid and drought Biotic stress Systemic phospholipid signaling: a new area of lipid research in plants Conclusion Acknowledgments References Chapter-3 Chapter 3 - Sex as a modulator of lipid metabolism and metabolic disease Rationale for the study of sex differences in lipid metabolism Biological sex versus gender Components of biological sex—gonadal hormones and sex chromosomes Sex differences in lipoprotein metabolism Sex differences in fat storage and adipose tissue function Characteristics of male versus female fat Hormonal and genetic mechanisms that contribute to sex differences in adiposity Sex differences in adipose tissue energetics Sex differences in atherosclerosis Sex differences in the gut microbiota influence metabolism Future perspectives References Chapter-4 Chapter 4 - Local interactions in the bone marrow microenvironment and their contributions to systemic metabolic processes Outline Bone marrow adipose: a brief history BMAT is distinct from peripheral adipose depots Bone marrow niche cells arise from multipotent progenitor cells Factors from adipose and bone influence the fate of MSCs Marrow adiposity and bone formation are not always inversely related PPAR-γ directs MSC fate toward adipogenesis Bone cells regulate MSC fate Osteocalcin promotes peripheral insulin sensitization CXCL12-expressing stromal cells serve as an osteo-adipogenic progenitor and are required to support hematopoiesis Bone marrow vascular endothelial cells regulate MSC development and peripheral endothelial dysfunction Bone marrow vascular endothelial cells mobilize to repair dysfunctional peripheral endothelium Sympathetic nervous system activation fails to induce “browning” of BMAT but induces caloric restriction-induced BMAT expansion Sympathetic activation promotes MSC mobilization and adipogenesis Sympathetic activation alters adipocyte function BMAs and their progenitors support bone marrow malignancies References Chapter-5 Chapter 5 - Lipids in the transcriptional regulation of adipocyte differentiation and metabolism Outline Introduction Transcriptional regulation of adipocyte differentiation Lipids in adipocyte differentiation Lipids as PPARγ ligands COXs and their derivatives related to adipocyte differentiation LOXs and their derivatives related to adipocyte differentiation CYPs and their derivatives related to adipocyte differentiation Nitrolinoleic acid Endocannabinoids Lipids in brown and beige adipocyte development Regulation of brown/beige adipocyte development Lipidomics related to brown or beige adipocyte Lipids promoting biogenesis of brown/beige adipocyte PUFAs Plasmalogens Cardiolipin Lipid as dietary supplementation that can activate brown activity Oleic acid PUFAs Concluding remarks References Chapter-6 Chapter 6 - Lipid receptors and signaling in adipose tissue Introduction Receptor signaling systems in adipocytes CD36/SR-B2 Leukotriene receptors LTB4 and BLT receptors LTC4, LTD4, LTE4 and the CysLT, GPR17, GPR99 receptors Prostanoid receptors PGD2 and DP receptors PGE2 and EP receptors PGF2α and FP receptor PGI2 (prostacyclin) and IP receptors TXA2 (thromboxane) and TP receptor Free fatty acid receptors (Ffar) in fat cells Ffar2 and Ffar3 in adipose Ffar4 in adipose Concluding remarks Acknowledgments References Chapter-7 Chapter 7 - Adipocyte lipolysis and lipid-derived metabolite signaling Outline Dysfunction of adipocyte lipolysis is central to metabolic disease Regulation of lipolysis Increased lipolysis in disease Lipid mobilization during lipolysis Extracellular vesicles in disease Free fatty acid signaling to peripheral tissues Free fatty acids activate transcriptional regulation Free fatty acids reduce insulin sensitivity Perspectives on lipolysis-mediated lipid signals References Chapter-8 Chapter 8 - Regulation of intracellular lipid storage and utilization Outline Abbreviations Introduction Cytoplasmic lipid droplet composition and formation CLD composition Source of lipid for CLD formation Exogenous sources Endogenous sources TAG and CE synthesis pathways CLD formation CLD formation and budding from the ER membrane CLD expansion CLD protein association, removal, and role of Perilipins CLD protein association CLD protein removal Perilipin proteins regulate CLD dynamics CLD breakdown and fates of released lipids CLD breakdown Cytoplasmic TAG lipolysis Lysosomal TAG lipolysis Cholesteryl ester lipolysis Fates of FA released from CLD breakdown Fatty acid oxidation Lipoprotein synthesis Lipoprotein synthesis in enterocytes Lipoprotein synthesis in hepatocytes Signaling molecules Other functions of CLD proteins CLD proteins mediate connections to organelles CLDs as a protein storage reservoir Functions of other CLD proteins Conclusions and future perspectives References Chapter-9 Chapter 9 - The lipid droplet as a signaling node Outline Lipid droplet composition Lipids Proteins Lipid droplet signaling Lipid droplets as lipophilic storage units Lipotoxicity Ceramides Toxins Drugs Lipid droplets as a source of lipid signaling molecules Lipolytically derived fatty acids Steroids Eicosanoids Ceramides Proteins that link lipid droplets to cell signaling Histones CIDE Protein turnover Summary References Chapter-10 Chapter 10 - Lipid droplets in the immune response and beyond Outline Structure and topology of lipid droplets Signaling intermediates and lipid droplets Fatty acids in ER stress and lipotoxicity: lipid droplets to the rescue Free and esterified eicosanoids Diacylglycerol Monoacylglycerol Glyceryl prostaglandins Ether lipids Lipid metabolism in polarization of the immune response Adipogenic response to exogenous lipids LDs and inflammation Lipid droplet proteome in immune cells Lipid droplets in host–pathogen interaction Viruses and lipid droplets Intracellular bacteria hijacking lipid droplets Lipid droplets in immune defense of a newborn Concluding statement References Chapter-11 Chapter 11 - Fatty acid mediators and the inflammasome Outline Introduction The global obesity crisis Role of inflammation in the genesis and progression of comorbidities Contribution of the western diet to obesity and inflammation Regulation of inflammation in obesity The NLRP3 inflammasome NLRP3 priming (signal 1) NLRP3 activation (signal 2) The eicosanoid classes The prostanoids PGE2 TXA2 PGF2α PGI2 PGD2 15d-PGJ2 PGA2 Leukotrienes Lipoxins The docosanoids The specialized proresolving mediators Maresins and MCTR Protectins and PCTR Resolvins and RCTR Role of lipid inflammatory mediators in metabolic diseases Lipid mediators in atherosclerosis Lipid mediators in nonalcoholic steatohepatitis Lipid mediators in type 2 diabetes Lipid mediators in nonhealing diabetic wounds Lipids mediators in diabetic nephropathy Conclusion References Chapter-12 Chapter 12 - Identification and pathophysiological roles of LTB4 receptors BLT1 and BLT2 Outline Abbreviations Introduction Biosynthesis and metabolism of LTB4 Sex differences in the LTB4 pathway Identification and characterization of BLT1, a high-affinity receptor of LTB4 BLT1 in allergic diseases BLT1 in autoimmune diseases BLT1 in inflammatory diseases BLT1 in virus infection BLT1 in lung disease BLT1 in cancer BLT1 in other diseases BLT2, a low-affinity receptor of LTB4, and its ligand 12-HHT BLT2 in wound healing BLT2 in asthma BLT2 in cancer BLT2 in other diseases Conclusion Acknowledgments References Chapter-13 Chapter 13 - The forkhead box O family in insulin action and lipid metabolism Outline The forkhead box O family FoxO1 mediates the inhibitory action of insulin or IGF-1 in cells FoxO1 mediates the stimulatory action of glucagon in cells Hepatic FoxO1 expression is regulated by a feedback mechanism FoxO1 trans-activation versus trans-repression mechanism FoxO1 in gluconeogenesis and its contribution to hyperglycemia in diabetes FoxO1 in insulin regulation of hepatic MTP expression and VLDL production FoxO1 in hepatic ApoC3 production and its contribution to hyperlipidemia FoxO1 in hepatic lipogenesis and steatosis FoxO1 in fatty acid oxidation and its contribution to steatosis FoxO1 in macrophage activation and its contribution to hepatic inflammation and NAFLD Association of FoxO polymorphism with metabolic disease and aging Targeted FoxO1 inhibition for treating metabolic diseases Conclusions and perspectives Acknowledgments References Chapter-14 Chapter 14 - Interplays between nutritional and inflammatory signaling and fat metabolism in pathophysiology of NAFLD Outline Nutritional signaling Nutrient sensing and fat accumulation AMPK AKT-mTOR-SREBP signaling Fat metabolism: FFAs as signaling molecules Glucose and fat metabolism in acetylation Lipotoxicity: Oxidative stress, apoptosis and inflammation Inflammatory signaling pathways TLR4 A2AR signaling pathway NFkβ and Jnk signaling pathway cGAS-cGAMP-STING pathway Timed nutrition and inflammatory signaling Perspective on management of NAFLD and NASH Conclusion and future directions Conflict of interest Acknowledgments References Chapter-15 Chapter 15 - Endocannabinoids: the lipid effectors of metabolic regulation in health and disease Outline Introduction to the endocannabinoid system Regulating energy balance by endocannabinoids Endocannabinoids and adipose tissue metabolism Regulation of insulin homeostasis by endocannabinoids Endocannabinoids and hepatic lipogenesis Conclusions Acknowledgments References Chapter-16 Chapter 16 - Gut microbiota interaction in host lipid metabolism Outline Introduction The liver comprises of several moonlighting duties Gut microbiota: an organ within an organ Gut metabolites regulate hepatic lipid metabolism Background Short-chain fatty acids: gut-derived lipogenic and gluconeogenic molecules Bile acids and FXR modulation of lipid homeostasis Choline metabolism and trimethylamine impacts fatty acid biosynthesis The gut microbiota-beiging axis Akkermansia muciniphila, intestinal integrity and adipose tissue metabolism Metabolic endotoxemia, inflammation, and hepatic lipogenesis Circadian disruption on gut microbiota alters lipid metabolism Lipidomics: a new tool to study gut microbiota management of lipid profiles Summary and future perspectives Acknowledgments Statement of ethics Disclosure statement References Chapter-17 Chapter 17 - Insights into the metabolism of lipids in obesity and diabetes Outline Introduction Obesity and diabetes Global status of obesity and diabetes Obesity and diabetes on the rise in sub-Saharan Africa Obesity and lipid metabolism Diabetes and lipid metabolism Role of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in obesity and diabetes Stearoyl-CoA desaturase in obesity and diabetes Plant-derived compounds in alleviation of obesity and diabetes Curcumin in obesity and diabetes Oleanolic acid in fructose-induced neonatal metabolic derangements Conclusion and future perspectives References Chapter-18 Chapter 18 - Lipid metabolic features of skeletal muscle in pathological and physiological conditions outline Lipid metabolic pathway in skeletal muscle Transport of FAs FAT/CD36 FATP FABPpm Regulation of FFA transport Signal transduction mediator Transcriptional regulation of lipid metabolism SREBPs Nuclear factor kB Liver X receptors Retinoid X receptors Peroxisome proliferator activated receptors Intracellular fatty acyl-CoA synthesis Triglyceride synthesis Fatty acid β-oxidation Skeletal muscle fiber type-dependent lipid metabolism Angiopoietin-like proteins as mediators of integrative metabolism of lipids Significance of ANGPTL3/4/8 in skeletal muscle Summary and future directions References Chapter-19 Chapter 19 - Sphingolipid mediators of cell signaling and metabolism Outline Introduction Sphingolipid metabolism and turnover Divergence of bioactive sphingolipid molecules in islets of Langerhans Ceramide as a principal contributor to lipotoxicity in pancreatic β-cells: evidence and mechanisms Role of ceramide in the control of insulin biosynthesis and secretion Mechanisms of ceramide-mediated β-cell apoptosis Regulation of islet dysfunction by deoxy-sphingolipids Effect of glycosphingolipid-dependent lipotoxicity in pancreatic islets Regulatory role of sphingomyelin in β-cell failure Sphingosine-1-phosphate improves pancreatic islet function and survival Sphingolipids and skeletal muscle metabolism Sphingolipids, oxidative stress, and skeletal muscle contractile function and fatigue Sphingolipids, skeletal muscle differentiation, and regeneration Metabolic substrate uptake Sphingolipids and insulin resistance Role of sphingolipids in adipose tissue metabolism Adipogenesis Insulin signaling and inflammation Sphingolipids as regulators of adipocyte lipid metabolism Sphingolipids in the cardiovascular system Ceramides in cardiac pathology Sphingolipids in cardioprotection Ceramides and vascular function Vascular reactivity Vascular remodeling Sphingolipids and vascular disorders Conclusion Acknowledgments References Chapter-20 Chapter 20 - Role of bile acid receptors in the regulation of cardiovascular diseases Outline Bile acid receptors in the regulation of cardiovascular diseases bile acids and bile acid receptors Atherosclerosis and vascular calcification Farnesoid X-activated receptor signaling and functions FXR functions and the development of cardiovascular diseases G-protein-coupled bile acid receptor (TGR5) signaling and functions Effects of TGR5-specific activation and dual activation of TGR5 and FXR in the development of atherosclerosis Pregnane X receptor (PXR) signaling, functions and cardiovascular diseases Constitutive androstane receptor signaling, functions and atherosclerosis Vitamin D receptor signaling, functions and cardiovascular diseases Conclusion Acknowledgments References Chapter-21 Chapter 21 - Molecular mechanisms underlying effects of n−3 and n−6 fatty acids in cardiovascular diseases outline Abbreviations Polyunsaturated fatty acids and cardiovascular diseases: an overview Cardiovascular regulatory mechanisms of n−3 and n−6 fatty acids Reduced lipid levels Molecular pathways Transcriptional regulation Upregulating LDL receptors Reducing ApoC-III Reducing remnant lipoprotein levels Vascular endothelial function and blood pressure Molecular pathways Cardiac arrhythmias Molecular pathways Atherosclerosis Inflammation and atherosclerosis Molecular pathways Inhibiting production of pro-inflammatory cytokines and adhesion molecules Effects of PUFA on additional contributors of atherogenesis Molecular pathways Inhibiting lipoprotein lipase activity Enhancing reverse cholesterol transport Improving plaque stability Pro-atherogenic effects of n−6 PUFA PUFA-derived lipid mediators Molecular pathways SPMs Anti-inflammatory eicosanoids from AA Pro-inflammatory eicosanoids from AA Reduced platelet aggregation Molecular pathways PUFA and CVD outcomes: updates Conclusions References Chapter-22 Chapter 22 - Lipid metabolism and signaling in cancer Outline LXR and cholesterol homeostasis LXR in cancer metabolism SCD1 and fatty acids homeostasis SCD1 in cancer metabolism Conclusion References Chapter-23 Chapter 23 - Altered lipid metabolic homeostasis in the pathogenesis of Alzheimer’s disease Outline Abbreviations Introduction Alzheimer’s disease Pathological hallmarks of AD AD therapeutics A note on studies of lipid alterations in AD Genetics implicates altered lipid metabolism in the etiology of AD APOE4 CLU ABCA7 PLD3 TREM2 PLCG2 Apolipoproteins and AD Effect of APOE genotype and lipidation on Aβ clearance Lipid delivery by ApoE is necessary for neuroprotection, synapse formation, and memory Phosphoinositide dysregulation by ApoE4 and presenilin-1 mutations Myelin lipids and peroxisomal deficits Ceramides and sphingosine 1-phosphate (S1P) Sphingolipids and cholesterol promote amyloidogenic processing of APP The polyunsaturated fatty acid DHA AD is associated with cerebrovascular disease The relationship between lysosomal storage diseases and dementias, including AD The example of GBA mutations in Parkinson’s disease How dysfunction of the endosomal and lysosomal systems leads to neurodegeneration Conclusions References Chapter-24 Chapter 24 - Role of Xenosterols in Health and Disease Outline Introduction Absorption of dietary sterols Plant sterols as double-edged swords in various cellular processes Phytosterols, ABCG5/G8 and sitosterolemia Xenosterols accumulation and cell membrane dysfunction Plant sterols and cardiovascular disorders Plant sterols and central nervous disorders disorders Conclusion References Chapter-25 Chapter 25 - Adipose tissue development and metabolic regulation Outline Function and importance of adipose tissues Developmental origin of WAT Regulation of WAT development Transcriptional regulation of the thermogenic adipose program Fat metabolism in WAT and BAT Fatty acid versus glucose metabolism for thermogenesis Conclusion References Index