Handbook of Experimental Pharmacology
Part I: Physiology of HDL
Structure of HDL: Particle Subclasses and Molecular Components
2 Molecular Components of HDL
2.1.1 Major Protein Components
Acute-Phase Response Proteins
Heterogeneity in HDL Proteins
2.1.2 Protein Isoforms, Translational and Posttranslational Modifications
3.1 Introduction/Brief History
3.3 ``Real´´ HDL Particles
Conclusions and Perspectives
HDL Biogenesis, Remodeling, and Catabolism
1.1 ATP-Binding Cassette Transporter A1 (ABCA1)
1.1.1 Structure of apoA-I and Its Interactions with ABCA1 In Vitro
1.1.2 Interaction of apoA-I with ABCA1 In Vivo Initiates the Biogenesis of HDL
1.1.3 Unique Mutations in apoA-I May Affect apoA-I/ABCA1 Interactions and Inhibit the First Step in the Pathway of HDL Biogene...
1.2 Lecithin/Cholesterol Acyltransferase (LCAT)
1.2.1 Interactions of Lipid-Bound ApoA-I with LCAT
1.2.2 ApoA-I Mutations that Affect apoA-I/LCAT Interactions
1.3 ApoA-I Mutations May Induce Hypertriglyceridemia and/or Hypercholesterolemia
1.3.1 Potential Mechanism of Dyslipidemia Resulting from apoA-I Mutations
1.4 ApoE and apoA-IV Participate in the Biogenesis of HDL Particles Containing the Corresponding Proteins
1.5 Clinical Relevance of the Aberrant HDL Phenotypes
2 Remodeling and Catabolism of HDL
2.1 ATP-Binding Cassette Transporter G1
2.2 Phospholipid Transfer Protein
2.4 Hepatic Lipase and Endothelial Lipase
2.5 Cholesteryl Ester Transfer Protein
2.6 Scavenger Receptor BI
2.6.1 Role of SR-BI in HDL Remodeling Based on Its In Vitro Interactions with Its Ligands
2.6.2 In Vivo Functions of SR-BI
2.7 Role of Ecto-F1-ATPase/P2Y13 Pathway in Hepatic HDL Clearance
2.8 Transcytosis of apoA-I and HDL by Endothelial Cells
2.9 The Role of Cubilin in apoA-I and HDL Catabolism by the Kidney
3.1 The Origin and Metabolism of Prebeta-HDL Subpopulations
Regulation of HDL Genes: Transcriptional, Posttranscriptional, and Posttranslational
1 Regulation of Genes Involved in HDL Metabolism at the Transcriptional Level
1.1 General Introduction to Hormone Nuclear Receptors
1.2 Transcriptional Regulation of the apoA-I Gene in the Liver
1.2.1 The Role of the Distal Enhancer in apoA-I Gene Transcription
1.2.2 Other Factors Regulating apoA-I Gene Transcription
1.3 Transcriptional Regulation of the ABCA1 Gene
1.3.1 Upregulatory Mechanisms of ABCA1 Gene Expression
1.3.2 Negative Regulation of ABCA1 Gene Transcription
1.4 Transcriptional Regulation of the ABCG1 Gene
1.5 Transcriptional Regulation of the Apolipoprotein E Gene
1.5.1 Proximal Regulatory Binding Sites Involved in the apoE Gene Expression
1.5.2 Distal Regulatory Binding Sites That Modulate apoE Gene Expression in Macrophages
1.6 Transcriptional Regulation of the Human apoM Gene in the Liver
1.7 Transcriptional Regulation of the CETP Gene
1.8 Transcriptional Regulation of the PLTP Gene
1.9 Transcriptional Regulation of the Bile Acid Transporters ABCG5/ABCG8
1.10 Transcriptional Regulation of the HDL Receptor SR-BI
2 Posttranscriptional Regulation of HDL Genes by Noncoding RNAs and microRNAs
2.1 miRNAs: Biogenesis and Function
2.2 Posttranscriptional Modulation of HDL Metabolism by miRNAs
2.2.1 Targeting ABCA1 and ABCG1
2.2.3 Targeting Other miRNAs Related to HDL Biogenesis and Function
3 Posttranslational Mechanisms of HDL Regulation
Cholesterol Efflux and Reverse Cholesterol Transport
1 Cholesterol Efflux as the First Step of Reverse Cholesterol Transport (RCT)
1.1 ABCA1-Mediated Lipid Efflux to Lipid-Poor apoA-I
1.2 Cholesterol Efflux to Lipidated HDL
2 HDL Quality and Cholesterol Efflux
3.1.1 Methodological Approaches to Quantify RCT In Vivo
3.1.2 Factors Impacting In Vivo RCT
3.2.2 Nuclear Receptor Activation
3.2.3 Cholesterol Absorption Inhibitors
3.2.4 Augmenting or Mimicking apoA-I
4 Serum Cholesterol Efflux Capacity (CEC)
Functionality of HDL: Antioxidation and Detoxifying Effects
1 High-Density Lipoproteins and Oxidative Stress
1.1 High-Density Lipoproteins: Antioxidative Function
1.2 Mechanisms of Protection
1.3 Heterogeneity of Antioxidant Activity of HDL Particles
2 High-Density Lipoproteins, Paraoxonase-1
2.1 PON1 as an Antioxidant
2.2 PON1 and Bacterial Pathogens
3 High-Density Lipoproteins, Environmental Pathogens and Toxins
3.3 Hepatitis, Dengue and Other Viruses
3.4 Metal Oxides, Carbon Nanotubes and PLGA Nanoparticles
3.5 PON1 and Organophosphates
3.6 Detoxification of Plasma and External Fluids
Signal Transduction by HDL: Agonists, Receptors, and Signaling Cascades
2 ApoA-I-Induced Cell Signaling Directly Mediated by ABCA1
3 ApoA-I-Induced Cell Signaling Indirectly Mediated by beta-ATPase and P2Y12/13 ADP Receptor
4 ApoA-I- and HDL-Induced Cell Signaling Indirectly Mediated by ABCA1 and/or ABCG1
5 HDL-Induced Cell Signaling Mediated by SR-BI
6 HDL-Induced Cell Signaling Mediated by S1P
7 HDL-Induced Cell Signaling: Future Challenges and Opportunities
Part II: Pathology of HDL
Epidemiology: Disease Associations and Modulators of HDL-Related Biomarkers
1 Protective Role of HDL: Evidence from Epidemiological Studies
2 HDL Cholesterol as a Risk Factor for Atherosclerosis and Its Complications
3 HDL Cholesterol as a Risk Factor for Other Diseases
4 Total HDL-C in Various Populations
5 Total HDL-C Modulated by Environmental Factors
6 HDL-C in Diseases and Conditions
7 High HDL Levels Do Not Add to the Protection
8 Effect of HDL on Stroke
10 Are There Other Biomarkers than the Total HDL-C?
9 Time Trends in Total HDL-C
19 Future Approaches of Epidemiological Studies
Beyond the Genetics of HDL: Why Is HDL Cholesterol Inversely Related to Cardiovascular Disease?
2 Determinants of Plasma HDL Cholesterol Levels
2.1 Established Primary Regulators of Plasma HDL Cholesterol
2.2 Established Secondary Regulators of Plasma HDL Cholesterol
3 Novel Insight into HDL Biology
3.1 De Novo Synthesis of HDL and HDL Binding
3.1.1 Bone Morphogenetic Protein-1 and Procollagen C-Proteinase Enhancer-2
3.1.3 CTP:Phosphocholine Cytidylyltransferase Alpha (CT Alpha)
3.1.5 Glucuronic Acid Epimerase
3.1.6 Beta-Chain of ATP Synthase
3.2 HDL Conversion and Remodeling
3.2.1 Angptl Family of Proteins
3.2.3 Tetratricopeptide Repeat Domain/Glycogen-Targeting PP1 Subunit G(L)
3.2.5 Glucokinase (Hexokinase 4) Regulator
Conclusions and Perspectives
Mouse Models of Disturbed HDL Metabolism
3 ATP-Binding Cassette Transporter A1
4 ATP-Binding Cassette Transporter G1
5 Lecithin-Cholesterol Acyltransferase
6 Phospholipid Transfer Protein
8 Insights from Intercrossing of the Different Knockout Mice
9 Conclusions from the Gene Knockout Mouse Studies
10 Cholesterol Ester Transfer Protein Transgenic Mice
Dysfunctional HDL: From Structure-Function-Relationships to Biomarkers
2 HDL and Reverse Cholesterol Transport
2.1 Mechanisms Under Physiological Conditions
2.2 Alterations of the Cholesterol Efflux Capacity of HDL in Cardiovascular Disease
3 Effects of HDL on LDL Oxidation
3.1 Mechanisms Under Physiological Conditions
3.2 Impairment of the Anti-Oxidative Effects of HDL in Patients After Surgery and With Cardiovascular Disease
4 Effects of HDL on Endothelial Nitric Oxide Bioavailability
4.1 Mechanisms Under Physiological Conditions
4.2 Impaired HDL Capacity to Stimulate NO Production in Patients with Cardiovascular Disease
5 Endothelial Anti-Inflammatory Effects of HDL
5.1 Mechanisms Under Physiological Conditions
5.2 Impaired Endothelial Anti-Inflammatory Effects of HDL in Patients with CAD, Diabetes, or Chronic Kidney Dysfunction
6 Effects of HDL on Endothelial Cell Apoptotic Pathways
6.1 Mechanisms Under Physiological Conditions
6.2 Impairment of the Endothelial Anti-Apoptotic Effects of HDL in Patients with Cardiovascular Disease
7 HDL Protein Cargo and Prognostic Biomarkers
Conclusion and Perspectives
Part III: Possible Indications and Target Mechanisms of HDL Therapy
HDL and Atherothrombotic Vascular Disease
2 Interactions of HDLs with the Endothelium
2.1 Preservation of Endothelial Integrity
2.2 Preservation of Endothelial Function
3 Anti-inflammatory Effects
3.1 Suppression of Myelopoiesis
3.2 Suppression of Monocyte Extravasation
3.3 Interference with Macrophage Differentiation and Activation
4 Effects of HDLs on Vascular Lipid and Lipoprotein Homeostasis
4.1 From LDL Retention to Atheroma Formation
4.1.1 Initial Lipid Accumulation in Atherosclerosis-Prone Arterial Intima: A Sign of LDL Retention
4.1.2 Formation of a Fatty Streak
4.1.3 Development of an Atheroma
4.2 Inhibition of LDL Modification by HDLs
4.3 Macrophage Cholesterol Efflux and Reverse Cholesterol Transport
4.3.1 Transendothelial HDL Transport
4.3.2 Cholesterol Efflux from Macrophages
4.3.3 Exit from the Arterial Wall
4.3.4 Delivery of Cholesterol to the Liver and Intestine
5.1 Effects of HDLs on Smooth Muscle Cells
5.2 Antithrombotic Effects of HDLs
5.2.2 HDLs and Coagulation
HDLs, Diabetes, and Metabolic Syndrome
1 Type 2 Diabetes Mellitus and the Metabolic Syndrome
2 Low HDL Cholesterol Levels in Diabetes and Metabolic Syndrome
2.1 Insulin Resistance, Hypertriglyceridemia, and Decreased HDL Cholesterol Levels
2.2 FFAs and Decreased HDL Levels
2.3 HDL Metabolism, Subclasses, and Catabolism
3 Does HDL Play a Causal Role in the Pathogenesis of Diabetes?
3.1 Effects of HDL on Obesity
3.2 Effects of HDL on Insulin Sensitivity and Glucose Utilization by Skeletal Muscle
3.3 The Beneficial Effects of HDL in Pancreatic Beta Cells
3.3.1 Beneficial Effects of HDL on Insulin Secretion
3.3.2 Effects of HDL on Pancreatic Beta Cell Survival and ER Stress
High-Density Lipoprotein: Structural and Functional Changes Under Uremic Conditions and the Therapeutic Consequences
2 Chronic Kidney Disease: Epidemiology and Pathophysiology
3 Dyslipidemia, Lipid-Modulating Therapy, and Cardiovascular Risk in CKD Patients
3.1 Dyslipidemia in CKD Patients
3.2 Lipid-Modulating Therapy in CKD Patients
3.3 Protective Effects of HDL on the Kidney
4 Structural and Functional Modifications of HDL in CKD Patients
4.1 Dysregulation of Proteins in HDL Metabolism
4.2 Changes of HDL Apolipoproteins (Modifications and Levels)
4.3 Loss of Protective Proteins or Lipids
4.4 Increase of Molecules within HDL with a Fatal Function in the Vascular Wall
5 Possibility of Functional Restoration of HDL
6 Laboratory Tests to Measure HDL Function
Conclusion and Perspective
Impact of Systemic Inflammation and Autoimmune Diseases on apoA-I and HDL Plasma Levels and Functions
2 HDL/apoA-I Structure and Function
3 HDL and apoA-I as Members of the Innate Immune System
4 Relationship Between Lipid Raft Modulation and Lymphocyte Function
5 Modulation of Spinghosine-1-Phosphate (S1P)/S1P-Receptor Axis and Lymphocyte Function
6.1 Inflammatory Bowel Diseases
7 Autoimmune Diseases: The Role of Autoantibodies
7.1 Systemic Lupus Erythematosus (SLE)
7.2 Rheumatoid Arthritis (RA)
8 Impact of Anti-inflammatory Treatments
HDL in Infectious Diseases and Sepsis
2 HDL and Bacterial Infections
2.1 Interaction of HDL with LPS and Gram-Negative Bacteria
2.2 Interaction of HDL with LTA and Gram-Positive Bacteria
2.4 General Innate Host Defense Mechanisms Exerted by HDL After Bacterial Infection
3 HDL and Parasitic Infections
4 HDL and Viral Infections
High-Density Lipoproteins in Stroke
2 Pleiotropic Effects of HDLs
3 HDL Potential Effects on the Blood-Brain Barrier
3.1 Reconstituted HDLs and HDL Mimetics
4 Part 1: Pleiotropic Effects of HDLs-In Vitro and In Vivo Data
4.1 HDLs and Nitric Oxide (NO)
4.2 HDLs and Sphingosine 1-Phosphate
4.4 Anti-inflammatory and Antiprotease Properties
4.5 Endothelial Cell Integrity, EPCs and Antiapoptotic Action
4.6 Antithrombotic Actions
5 HDLs in the Cerebral Compartment
5.1 Lipoproteins in the Brain
5.2 Plasma HDLs in the Brain
6 Part 2: HDLs and Acute Stroke (In Vivo Data)
6.1 HDLs and Acute Stroke: Experimental Models
Therapeutic Potential of HDL in Cardioprotection and Tissue Repair
2 In Vitro Effects of HDL on Cardiomyocytes
2.1 Effects of HDL in Rat Neonatal Cardiomyocytes
2.2 Adult Mouse Cardiomyocytes
2.3 Apo A-I and Sphingosine-1-Phosphate Mediate the Cytoprotective Effects of HDL
3 HDL Confer Protection Against Ischaemia Reperfusion Injury
3.1 IRI in the Isolated Heart Model
3.2 IRI in In Vivo Models
3.3 Apo A-I and S1P Confer Cardioprotective Effects on HDL
4 Human Apo A-I Gene Transfer Attenuates Diabetic Cardiomyopathy
4.1 Human Apo A-I Gene Transfer Influences Metabolic Parameters in Streptozotocin-Induced Diabetes Mellitus
4.2 Human Apo A-I Gene Transfer Attenuates Diabetes-Associated Oxidative Stress, Cardiac Fibrosis, and Endothelial Dysfunction
4.3 Human Apo A-I Gene Transfer Reduces Diabetes-Induced Cardiac Inflammation
4.4 Human Apo A-I Gene Transfer Reduces Diabetes-Associated Cardiac Apoptosis and Improves the Cardiac Endothelial Integrity
5 HDL and Tissue Repair: Modulation of EPC Biology via SR-BI
6 Development of Topical HDL Therapy for Cutaneous Wound Healing
7 Beneficial Effects of Selective HDL-Raising Gene Transfer on Cardiac Remodelling and Cardiac Function After Myocardial Infar...
Part IV: Treatments for Dyslipidemias and Dysfunction of HDL
HDL and Lifestyle Interventions
1.1 Effects of Substituting Dietary Saturated Fatty Acids
1.3 n-3 Polyunsaturated Fatty Acids
1.4 Carbohydrate and Extrinsic Sugars
1.5 Effects of Dietary Fatty Acids and Cholesterol on HDL Function
2.1 Impact of Adiposity on HDL Concentration and Function
2.2 Effect of Weight-Loss Therapies on HDL Concentration and Function
3 Effects of Regular Aerobic Exercise
3.1 Effects of Exercise on HDL
3.2 Effects of Exercise on Prevention and Treatment of Cardiometabolic Risk
4.1 Smoking and HDL-C Concentration
4.2 Potential Mechanisms for the Smoking-Related Reduction in HDL-C
4.3 Smoking Cessation Intervention to Increase Plasma HDL Concentration
5 Effects of Alcohol on HDL and Cardiovascular Risk
5.1 Alcohol Intake and HDL-C
5.2 Effects of Alcohol on HDL Atheroprotective Functions
Effects of Established Hypolipidemic Drugs on HDL Concentration, Subclass Distribution, and Function
1 Effects on Plasma HDL-C Concentration
2 Effects on HDL Subclass Distribution
3 Effects on Cholesterol Efflux Capacity
4 Effect on HDL Ability to Preserve Endothelial Cell Homeostasis
5 Effect on HDL Antioxidant Properties
Conclusions and Perspectives
Emerging Small Molecule Drugs
2 Cholesteryl Ester Transfer Protein Inhibitors
2.1 Biological Mechanisms
3.1 Biological Mechanisms
4.1 Biological Mechanisms
5.1 Biological Mechanisms
2 ApoA-I Mimetic Peptides
3 ApoA-I-Based Infusion Therapy
3.2 Purified ApoA-I Infusions
3.3 ApoA-IMilano Infusions
3.4 CSL-111 and CSL-112 Infusions
Antisense Oligonucleotides, microRNAs, and Antibodies
1 Antisense Oligonucleotides
1.1 Making Sense of Antisense
1.2 Therapeutic Antisense Oligonucleotides to Treat Dyslipidemia
1.3 Therapeutic Antisense Oligonucleotides for the Increase of HDL-Cholesterol Levels and Improvement of HDL Function
1.3.1 Cholesteryl Ester Transfer Protein
2.1.1 Therapeutic miRNA Mimics or miRNA Replacement Therapy
2.1.2 Therapeutic miRNA Inhibition or Anti-miR Therapy
2.2 Micromanaging Cholesterol Efflux, RCT, HDL Levels, and HDL Function
2.2.2 miR-758 and miR-106b
2.2.4 miR-10b, miR-128-2, miR-145
2.2.5 Other miRNA Related to Cholesterol Efflux and Cholesterol Homeostasis
3.1 LDL-Cholesterol Lowering Approaches: Proprotein Convertase Subtilisin/Kexin Type 9 Blocking Antibodies
3.2 Approaches to Antibody Therapy for the Increase of HDL-Cholesterol Levels
3.2.1 Cholesteryl Ester Transfer Protein
3.3 Effect of Antibodies Used for the Treatment of Chronic Inflammatory Diseases on HDL Antiatherogenic Functions
3.4 Vaccines Against Atherosclerosis
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