Cholesterol: From Chemistry and Biophysics to the Clinic

Description

With Cholesterol, Drs. Anna Bukiya and Alex Dopico have compiled a comprehensive resource on biological and clinical aspects of cholesterol, spanning biophysics and biochemistry, as well as the latest pharmacological discoveries employed to tackle disorders associated with abnormal cholesterol levels. Early chapters on basic biology offer guidance in cholesterol lab chemistry, cholesterol metabolism and synthesis, molecular evolution of cholesterol and sterols, cholesterol peptides, and cholesterol modulation. Chapters on cellular and organismal development discuss cholesterol transport in blood, lipoproteins, and cholesterol metabolism; cholesterol detection in the blood; cellular cholesterol levels; hypercholesterolemia; and the role of cholesterol in early human development. Pathophysical specialists consider familial hypobetalipoproteinemia, critical illness and cholesterol levels, coronary artery disease, CESD, cholesterol and viral pathology, cholesterol and neurodegenerative disorders, and cholesterol and substance use disorders. A final section examines pharmacology of drug delivery systems targeting cholesterol related disorders, cholesterol receptors, cholesterol reduction, statins, citrate lyase, cyclodextrins, and clinical management. Cholesterol: From Biophysics and Biochemistry to Pathology and Pharmacology empowers researchers, students, and clinicians across various disciplines to advance new cholesterol-based studies, improve clinical management, and drive drug discovery. Front Cover Cholesterol: From Chemistry and Biophysics to the Clinic Copyright Contents Contributors Preface Afterword Section 1 Cholesterol chemistry and cell function Chapter 1 Cholesterol chemistry and laboratory synthesis Introduction Cholesterol structural characterization Cholesterol laboratory synthesis Cholesterol total synthesis—Historical perspective Woodward’s cholesterol total synthesis Robinson’s cholesterol total synthesis Cholesterol hemisynthesis Synthesis of ent -cholesterol: The unnatural enantiomer Concluding remarks References Chapter 2 Molecular evolution of cholesterol and other higher sterols in relation to membrane structure Introduction: The overlooked lipids Key features of the cholesterol molecule Evolution and streamlining of a molecule Phase equilibria in lipid membranes Cholesterol and lipid membrane phase equilibria: The liquid-ordered phase Cholesterol, transverse membrane order, permeability, and mechanics Cholesterol and lateral membrane organization Other higher sterols: Universality in sterol function A case study: Cholesterol, lateral membrane structure, and the functioning of Na + /K + -ATPase Cholesterol and membrane evolution Acknowledgments References Chapter 3 Role of cholesterol in maintaining the physical properties of the plasma membrane Introduction Phase diagram for cholesterol/phospholipid mixtures Basic membrane physical properties and how cholesterol regulates them Membrane “fluidity” Order parameter Rotational diffusion Direct EPR spectroscopy (continuous-wave EPR) Saturation recovery EPR (pulse EPR) Vertical fluctuation Chol effect on unsaturated bilayers Small paramagnetic molecules as probes of bilayer properties Molecular oxygen (a nonpolar probe molecule) Fe(CN)63 − (a polar probe molecules) Hydrophobic barriers of lipid bilayer membranes formed by Chol Properties of polar headgroups Membrane physical properties at the saturating Chol content (three-dimensional dynamic structure of the lipid-bilayer memb ... Membrane physical properties at the saturating Chol content in intact PMs Lateral organization of membranes: Effect of cholesterol Raft domains CBDs New information from the saturation recovery electron paramagnetic resonance stretched exponential function approach Concluding remarks Influence of Chol-induced physical properties of lipid bilayers on chemical reactions occurring in the membrane environment Enhancement of antioxidant action of macular xanthophylls in retina membranes Maintaining membrane, cell, and organ homeostasis Summary Acknowledgments References Chapter 4 The fundamental interaction of cholesterol with lipid membranes: The umbrella model Introduction Maximum solubility of cholesterol in phosphatidylcholine (PC) and phosphatidylethanolamine (PE) bilayers The umbrella model Monte Carlo simulation of chemical potential of cholesterol using multibody interactions A family of small headgroup molecules: Sterols, ceramides, and diacylglycerols Molecular dynamics (MD) simulation of the umbrella effect Measurement of the chemical potential of cholesterol in PC bilayers Concluding remarks Acknowledgments References Chapter 5 Model peptides and cholesterol On the energy and entropy parameters of the free energy of the membrane Acknowledgment References Chapter 6 Cholesterol and ceramide: An unlikely pair Introduction: Membrane heterogeneity Sphingolipids and cholesterol: Biological impact Sphingolipids and cholesterol: Membrane biophysics Sphingolipid biophysics: Ceramides The context: A tale of displacements Unveiling the interaction of cholesterol and ceramide Cholesterol and ceramide in fluid membranes Lowering Cer and Chol ratios in gel phases Red blood cell lipid extracts: The simplest of the complex models? The case for N-acyl sphingolipid variability: Drifting away from canonical C16:0 lipids Conclusions and future perspectives Acknowledgments References Chapter 7 Cholesterol-recognizing amino acid consensus motifs in transmembrane proteins: Comparative analysis of in silico ... Introduction Cholesterol: Bifacial structure, multifaceted functions Cholesterol footprint on a membrane protein: Starting the investigation CARC and CRAC algorithms: Basic principles at work Cholesterol-binding motifs in 3D: What structural studies reveal Moving to the 3rd dimension Conclusion References Chapter 8 Effects of cholesterol on the GPCR AT1 receptor and its interplay with AT1 antagonists Introduction Cholesterol structure Cholesterol action at membrane and receptor level Renin-Angiotensin system (RAS) and Hypertension Cyclodextrins and liposomes as drug delivery systems Role of the membrane in cholesterol action Experimental results and their discussion AT1R antagonists and cholesterol rafts Cholesterol influence on the physicochemical properties of the cell membrane in the presence of AT1R and sartans Molecular dynamics (MD) simulations on AT1R embedded in a DPPC:Cholesterol (60:40  mol%) bilayer reveal a putative binding ... Conclusions References Chapter 9 Principles of cholesterol regulation of ion channels Introduction Lipids as structural components and functional regulators of membrane proteins A thermodynamic consideration of lipid-binding sites on ion channels and their generic effects on the gating of the channel ... Cholesterol-binding sites on ion channels Cholesterol recognition motifs Molecular docking of cholesterol to channel proteins Molecular dynamics simulations to identify cholesterol-binding sites and differentiate structural and regulatory sites Functional impact of cholesterol on the activities of ion channels Experimental techniques and systems for studying cholesterol-channel interactions Cholesterol-regulation of a set of typical ion channels Large-conductance Ca-sensitive K + channels (BK) Inwardly rectifying K + channels (Kir) Functional regulations of AChR by cholesterol in membranes Cholesterol-dependent gating effects on voltage-gated ion channels Technical limitations and potential solutions for further developments Conclusions Acknowledgments References Chapter 10 Fluorescent probes for microscopy visualization of cholesterol topography and dynamics in membranes Introduction The elusive ideal probe Cholesterol probes Indirect cholesterol probes Filipin Perfringolysin O Direct imaging of intrinsic fluorescent cholesterol analogs Dehydroergosterol and cholestanetriol Organic dye Chol probes NBD-Chol fPEG derivatives Pyrene derivatives BODIPY derivatives TopFluor cholesterol Dansyl-cholestanol Rhodamine-cholestanol Imidazolium-based cholesterol (CHIM) analogs Concluding remarks Acknowledgments Author contributions Declaration of interests References Chapter 11 Cholesterol transport in blood, lipoproteins, and cholesterol metabolism Introduction Lipoproteins an overview Exogenous cholesterol metabolism: Cholesterol derived from diet Endogenous cholesterol metabolism: Synthesized cholesterol Low-density lipoprotein cholesterol High-density lipoprotein cholesterol How does aging impact cholesterol metabolism? Obesity and aging: Two sides of the same coin? Using mathematical modeling to explore cholesterol metabolism Discussion of future perspectives Author contributions References Chapter 12 Common laboratory research methods for detection and quantification of cholesterol Introduction to cholesterol detection and quantification The early era of cholesterol detection and quantification: Colorimetric approaches MS-based approaches Gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS) Electrospray ionization tandem mass spectrometry (ESI-MS/MS) Matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS) Ambient ionization mass spectrometry (AIMS), desorption electrospray ionization mass spectrometry (DESI-MS), and direct ana ... Imaging-based approaches The Liebermann-Burchard reaction-based visualization of cholesterol MS-based imaging Cholesterol-sensitive fluorescent dye filipin Cytolysins Antibody-based approaches Enzymatic methods Colorimetric sensing Fluorometric sensing Summary and concluding remarks References Chapter 13 Approaches for modifying cellular cholesterol levels and their application to mechanistic studies: Examples from .. Introduction In vitro methods for modifying cholesterol levels in cell membranes Alteration of cholesterol levels in Xenopus oocytes Phospholipid-based liposomes as a means to increasing the level of cholesterol in Xenopus oocytes The use of methyl- β -cyclodextrin (M β CD) to alter the level of cholesterol in Xenopus oocytes Alteration of cholesterol levels in tissues and cells other than Xenopus oocytes β -cyclodextrins as means for altering cholesterol content in tissues and cells other than Xenopus oocytes Lipoproteins: Preincubated plasma, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) Water-soluble cholesterol In vivo modification of cholesterol levels Cholesterol altering diets High-cholesterol/high-fat diet Plant sterol/plant stanol diet Cholesterol-lowering drugs Statins Cholesterol absorption inhibitors (ezetimibe) Bile acid sequestrants Fibric acid derivatives Applications to mechanistic studies on the effect of cholesterol on ion channel targets Applying controls in studies on the effect of cholesterol on protein function: Specific examples from the potassium channel ... Establishing the effect of cholesterol on G-protein gated inwardly rectifying potassium channels using different approaches ... Establishing the effect of mutations on the sensitivity of inwardly rectifying potassium channels in Xenopus oocytes (lip ... Controlling for M β CD treatment through the application of M β CD/cholesterol: Effect of cholesterol depletion on atrial G ... Establishing the effect of in vivo modifications of cholesterol levels: Effect of a high-cholesterol diet and cholesterol l ... Establishing the effect of cholesterol in whole organ: Application of lipoproteins and cyclodextrins in studies of ion cha ... Outlook References Section 2 Cholesterol homeostasis and its disruption Chapter 14 Diet-induced hypercholesterolemia in small laboratory animal models Introduction Mouse models Rat models Hamsters Guinea pigs Rabbits Additional diet considerations Control diets References Chapter 15 Nutrition and cholesterol metabolism Introduction Cholesterol structure Nutritional recommendations for maintaining healthy blood cholesterol levels Dietary Guidelines for Americans Dietary cholesterol intake Saturated fat intake Cholesterol functions Digestion and absorption of cholesterol Transport of cholesterol Endogenous cholesterol synthesis Blood cholesterol and atherosclerosis Guinea pigs as a preclinical model Advances in cholesterol research Dietary cholesterol and heart disease Patients with prediabetes, diabetes, or metabolic syndrome Patients with cardiovascular disease Populations with hypercholesterolemia Healthy individuals Findings from systematic reviews and metaanalysis Explanatory and predictive models approach Conclusions Acknowledgments References Chapter 16 Cholesterol and early development Introduction The fetus and cholesterol Fetal cholesterol synthesis Cholesterol and fetal development Fetal cholesterol derivates and metabolites Steroid hormones Calcitriol Oxysterols Bile acids Steroid hormones in reproduction and early life Sex steroid hormones and selected reproductive organs Ovaries Uterus Testes Fetal adrenal glands and steroid hormone production Extraembryonic structures, secondary yolk sac and placenta, and materno-fetal cholesterol transport Vitelline circulation Chorionic circulation Maternal cholesterol levels in healthy pregnancies, maternal hyper- and hypocholesterolemia, and consequences for the fetus Maternal cholesterol levels in healthy pregnancies Supraphysiological hypercholesterolemia Hypocholesterolemia Effect of selected medicines related to cholesterol metabolism on the fetal development Ursodeoxycholic acid (UDCA) Colesevelam Statins Ezetimibe Fibrates Niacin Summary References Chapter 17 Clinical and biochemical diagnostic methods: What do blood lipid levels tell us? Introduction Separation of plasma lipoproteins Use of conventional laboratory methods to measure lipoproteins by determining their cholesterol content Beyond standard lipid profiles: Determination of atherogenic lipoproteins by advanced lipoprotein testing Triglyceride-rich lipoprotein remnants and ASCVD risk Determination of lipoprotein (a) cholesterol Determination of lipoprotein X Fasting versus nonfasting lipid measurements Lipid and lipoprotein testing in laboratory animals What do lipid/lipoprotein levels tell us? References Chapter 18 Familial hypobetalipoproteinemia and abetalipoproteinemia Introduction ApoB gene mutations causing familial hypobetalipoproteinemia Familial hypobetalipoproteinemia (FHBL) and coronary heart disease (CHD) FHBL and hepatic steatosis FHBL and insulin sensitivity FHBL, hepatic cirrhosis, and hepatocarcinoma FHBL and psychiatric disease Heterozygous FHBL and neurological manifestations Proprotein convertase subtilisin kexin 9 gene (PCSK9) mutations Familial combined hypolipidemia (FHBL2) Angptl3 S17x Abetalipoproteinemia (ABL) and homozygous hypobetalipoproteinemia (HHBL) Diagnosis and management Homozygous FHBL, compound heterozygous FHBL and abetalipoproteinemia Heterozygous FHBL Pregnancy management Conclusion References Chapter 19 Critical illness and cholesterol levels Introduction Cholesterol is crucial for several reasons The mechanisms of cholesterol depletion Clinical implications of hypocholesterolemia Cholesterol metabolism and trauma The complex character of hypocholesterolemia in trauma Cholesterol metabolism and inflammation Depletion of serum cholesterol in surgical patients and in sepsis Cholesterol metabolism during bleeding and fluid resuscitation Hypocholesterolemia in critical conditions and on artificial pulmonary ventilation resulting from pneumonia Acknowledgments References Chapter 20 Familial hypercholesterolemia Introduction Genetic and molecular background of FH Low-density lipoprotein receptor (LDLR) Apolipoprotein B (APOB) Protein convertase subtilisin kexin (PCSK9) Low-density lipoprotein receptor adaptor protein-1 (LDLRAP1) Other genes Polygenic familial hypercholesterolemia Familial hypercholesterolemia diagnosis Familial hypercholesterolemia treatments Statins Nonstatin treatments Ezetimibe PCSK9 inhibitors Bile acid sequestrants Niacin Low-density lipoprotein aphaeresis Lomitapide and Mipomersen Other therapies Nutrition and familial hypercholesterolemia Management of homozygous familial hypercholesterolemia Familial hypercholesterolemia-related diseases Familial hypercholesterolemia and cardiovascular disease Familial hypercholesterolemia and type 2 diabetes mellitus Familial hypercholesterolemia and risk of chronic kidney disease Familial hypercholesterolemia current status and future perspectives References Chapter 21 Niemann-Pick type C disease (NPC) Introduction Structure and function of the lysosome: The term of a lysosomal disease Clinical picture of NPC disease Genetic background of NPC NPC1 gene NPC2 gene Genotype-phenotype correlation Biochemical aspects of NPC1 and NPC2 proteins Pathomechanisms underlying NPC disease Diagnostics Histologic findings Filipin staining Oxysterols Lysosphingolipids Metabolites of bile acids Chitotriosidase Heat shock protein 70 (HSP70) Genetic analyses Treatment Acknowledgment References Chapter 22 Rare monogenic disorders of cholesterol metabolism Introduction Monogenic hypercholesterolemia Autosomal dominant hypercholesterolemia Familial hypercholesterolemia Rare forms of autosomal dominant hypercholesterolemia APOE gene STAP1 gene Recessive hypercholesterolemia Autosomal recessive hypercholesterolemia (ARH) Sterol storage diseases Plasma noncholesterol sterols Sitosterolemia Bile acid biosynthesis disorders Major pathways for excretion of cholesterol into bile Inborn errors of bile acid synthesis Cerebrotendinous xanthomatosis Hypercholesterolemia due to cholesterol 7 α -hydroxylase deficiency Hypocholesterolemia Primary hypobetalipoproteinemia Abetalipoproteinemia Familial hypobetalipoproteinemia PCSK9 deficiency Chylomicron retention disease Familial combined hypolipidemia Other inherited disorders associated with hypocholesterolemia Primary bile acid malabsorption Smith-Lemli-Opitz syndrome Other potential genetic causes of hypocholesterolemia NPC1L1 gene IDOL gene LIMA1 gene References Chapter 23 Secondary (acquired) hypercholesterolemia Introduction Causes of secondary hyperlipidemias and their treatment Diet and lifestyle Insulin resistance, metabolic syndrome, and obesity Diabetes mellitus Hypothyroidism Nephrotic syndrome Chronic kidney disease Multiple myeloma Medications Conclusions References Chapter 24 Blood lipids and molecular pathways of atherogenesis Introduction Cholesterol metabolism Pathophysiology of atherosclerosis Low-density lipoprotein cholesterol and cardiovascular disease Oxidized low-density lipoprotein cholesterol and cardiovascular disease Small dense low-density lipoprotein cholesterol and cardiovascular disease High-density lipoprotein cholesterol: Marker or risk factor? Triglycerides and cardiovascular disease Genetics and dyslipidemia Conclusions References Chapter 25 Lysosomal acid lipase: Roles in rare deficiency diseases, myeloid cell biology, innate immunity, and common neut... Historical background: Lysosomal acid lipase (LAL) Structure, properties, and biology of LAL LAL homology with other lipases and structure Cellular expression of LAL Central nervous system cholesterol metabolism Roles of LAL in visceral neutral lipid metabolism, inflammation, and immune system Roles of LAL in catabolic and anabolic cellular networks Critical role(s) of LAL in myeloid cell differentiation and function The role of LAL in T cell development, function, and T cell responses to graft versus host disease (GVHD) LAL roles in disease states Lysosomal acid lipase deficiency diseases (LALDs) Rpi-Lald Ca-Lald Pathology Liver Molecular biology and genetics Population prevalence LIPA mutations and function LIPA mutations and effects Treatment of LALD variants Diet and supportive care Rpi-Lald Ca-Lald Specific LAL therapy in LALDs LAL in diseases beyond the LALDs LAL and nonobese nonalcoholic fatty liver disease, NAFLD/NASH The role of LAL on endothelial cell proliferation, migration, and angiogenesis LAL: Tumor progression, metastasis, and tumor microenvironment LAL hydrolyzes retinyl esters (RE) LAL in atherosclerosis References Further reading Chapter 26 Cholesterol and pathogens Introduction The role of cholesterol-rich membrane microdomains in infectious diseases Cholesterol recruitment to pathogen-containing vacuoles Targeting cellular cholesterol metabolism Systemic cholesterol levels and pathogens Cholesterol-lowering agents as potential therapeutics in infectious diseases Cholesterol and immune response Summary Acknowledgments References Chapter 27 Involvement of cholesterol and β -amyloid in the initiation and progression of Alzheimer’s disease Neurodegenerative diseases are a significant health problem: Alzheimer’s disease (AD) The amyloid cascade as a central cause for Alzheimer’s disease Cellular domains important for the formation of A β and cholesterol Interactions of A β with the neuronal membrane and the initiation of synaptic failure Participation of membrane lipids in the initiation of A β -mediated neurotoxicity How A β and cholesterol might lead to neurodegeneration Cholesterol affects a number of membrane proteins that fine tune neuronal excitability The ε 4 isoform (ApoE4) factor in disease onset and progression References Chapter 28 Cholesterol and alcohol Introduction Alcohol pharmacology Alcohol use disorder Alcohol and cholesterol interactions Alcohol and lipoproteins Vldl Ldl Hdl Alcohol and PCSK9 PCSK9 biology PCSK9 and cholesterol regulation PCSK9 and alcohol effects Fetal alcohol spectrum disorders (FASDs) and cholesterol Targeting lipids for treatment of alcohol-related diseases Statin therapy PCSK9 monoclonal antibody therapy PCSK9 RNAi therapy Conclusion References Section 3 Pharmacological considerations and perspectives Chapter 29 Cholesterol stiffening of lipid membranes and drug interactions: Insights from neutron spin echo and deuterium N... Introduction Neutron spin echo spectroscopy of lipid membranes Neutron spin echo principles Neutron spin echo technique Membrane undulations Membrane thickness fluctuations Solid-state 2 H NMR spectroscopy of lipid membranes Solid-state 2 H NMR spectroscopic principles Membrane dynamics and structural properties by solid-state 2 H NMR spectroscopy Membrane stiffening effect of cholesterol from molecular dynamics simulations Cholesterol effects on drug uptake and drug delivery applications Conclusions Acknowledgment References Chapter 30 Cholesterol in drug delivery systems Introduction The common synthesis chemistry of modifying cholesterol into the polymers Polymerization of cholesterol-based monomers Postpolymerization modification strategy to introduce cholesterol Cholesterol in the form of drug delivery vehicles Cholesterol and its derivatives in liposomes PEGylation and dePEGylation Ligand modification Cationic modification Self-assembling cholesterol amphiphilic polymers into nanostructures Cholesteryl albumins Cholesteryl natural carbohydrate nanostructures Cholesteryl synthetic polymer conjugates Cholesteryl drug on gene conjugates Cholesteryl derivatives for macromolecules delivery Conclusion References Chapter 31 Modification of vascular receptor pharmacology by cholesterol: From molecular determinants to impact on arterial... Introduction Cholesterol modulation of vasoactive drug action in which the underlying pharmacodynamic process(es) is not fully determine ... Cholesterol modulation of vasoactive drug action occurring at the cell membrane where the vasoactive drug receptor of inter ... Cholesterol modulation of vasoactive drug action occurring at the vasoactive drug receptor protein itself Metabolotropic receptors: The human β 2 -adrenergic receptor Ionotropic receptors: BK channels Conclusions and prospective References Chapter 32 Clinical strategies for reducing cholesterol levels Introduction Epidemiology Risk factors for hyperlipidemia Modifiable risk factors Nonmodifiable risk factors Secondary causes of elevated LDL-C (some examples appear below; refer to the “ Clinical pearls ” section of this chapter fo ... Further risk assessment Genetics Major guidelines for lipid-lowering therapy in the United States National Lipid Association (NLA) recommendations for patient-centered management of dyslipidemia: Parts 1 and 2 (2015) Part 1 Part 2 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: Executive su ... A report of the American College of Cardiology (ACC)/American Heart Association (AHA) Task Force on Clinical Practice Guide ... 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: Executive summary A report of the American College of Cardiology (ACC)/American Heart Association (AHA) Task Force on Clinical Practice Guide ... Consensus statement by the American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology ( ... Cardiovascular disease and risk management from the American Diabetes Association (ADA) 2021 standards of medical care in d ... Pharmacologic treatment of lipids Statins Limitations of statins Nonadherence to statin treatment Statin intolerance Statin resistance Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors Inclisiran (interfering RNA therapy directed against PCSK9) Icosapent ethyl Cholesterol absorption inhibitors (ezetimibe) Bile acid sequestrants Niacin Fibrates Adenosine triphosphate-citrate lyase (ACL) inhibitors (bempedoic acid) Cholesteryl ester transfer protein (CETP) inhibition Angiopoietin-like 3 (ANGPL3) inhibitors (evinacumab) Other lipid-lowering therapies Lomitapide Mipomersen Volanesorsen Lifestyle therapies Nonprescription and dietary supplements Omega-3 fatty acids Red yeast rice Soluble fiber Phytosterols Coenzyme Q Policosanol Resveratrol Patient education Clinical pearls Hypothyroidism Lysosomal acid lipase deficiency (LALD) Screening for lipid disorders Limitations of risk calculators Secondary causes of dyslipidemia Summary References General patient education resources for understanding cholesterol disorders and treatment options Clinician tools Further reading Chapter 33 Medicinal chemistry and pharmacology of statins Introduction Medicinal chemistry of statins Early search for inhibitors of cholesterol biosynthesis 3-Hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase) First-generation statins Second-generation statins Pharmacology Mechanism of action Pharmacokinetics (ADME) Adverse effects and drug interactions Decreasing efficacy with increased statin dose—Proprotein convertase subtilisin/kexin type 9 (PCSK9) induction Future drugs and concluding remarks References Chapter 34 Cyclodextrins as promising therapeutics against cholesterol overload Introduction Cyclodextrins in general Structure and major applications of cyclodextrins Cyclodextrins as compounds to selectively modify cholesterol levels of biological membranes Direct cyclodextrin actions on proteins Cyclodextrins in the treatment of Niemann-Pick type C disease Clinical symptoms and cellular pathophysiology of Niemann-Pick type C disease Possible mechanisms of CD actions in Niemann-Pick type C disease Clinical experience with HP β CD in NPC Alternatives of HP β CD in the treatment of NPC Future perspectives using new β CD-based variations in NPC Cyclodextrins with great potential in the treatment of neurodegenerative diseases Alzheimer’s disease Transmissible spongiform encephalopathies (prion diseases) Parkinson’s disease Cyclodextrins as promising therapeutics in atherosclerosis Role of cyclodextrins in the treatment of kidney diseases Role of cyclodextrins in the treatment of eye disorders Potential effects of cyclodextrins against coronavirus Concluding remarks Acknowledgments References Chapter 35 Hyperlipidemia and rheumatoid arthritis Introduction Pathophysiologic mechanisms in rheumatoid arthritis (RA) Articular and extra-articular manifestations of RA Rheumatoid arthritis treatment Comorbidities in RA CVD: A major comorbidity in RA CVD risk assessment in RA CVD and atherosclerosis in RA Lipid profile in RA patients Mechanisms related to dyslipidemia in RA Lipid concentration and inflammatory markers Atherosclerosis and inflammation Lipid metabolism and inflammation The impact of cytokines on LDL Lipid peroxidation Altered HDL function and structure Effects of antirheumatic therapy on serum lipid levels Glucocorticoids (GCs) DMARDs Antitumor necrosis factor-alpha (anti-TNF-a) agents Anti-interleukin-6 (IL-6) agents Janus kinase inhibitors (JAK inhibitors) Other agents Mediterranean diet and RA The role of exercise in RA Conclusions References Chapter 36 Management of hypercholesterolemia in individuals living with HIV/AIDS Introduction Antiretroviral therapy and hyperlipidemia Protease inhibitors (PIs) Nucleoside reverse transcriptase inhibitors (NRTIs) Nonnucleoside reverse transcriptase inhibitors (NNRTIs) Integrase inhibitors (INSTIs) Why management of HIV dyslipidemia needs the specialist’s input? Cardiovascular risk and HIV Diabetes mellitus, metabolic syndrome and HIV Nonalcoholic fatty liver disease and HIV Chronic kidney disease among HIV patients and associated dyslipidemia Hypothyroidism and HIV Excess alcohol intake Aging with HIV Solutions for hyperlipidemia in HIV patients Life style changes and intervention (weight loss, physical activity, and change in diet) Statin therapy, when to treat and interaction with ART medications Why HIV metabolic clinic should be integral part of HIV service? Conclusion References Index Back Cover