Principles and Treatment of Lipoprotein Disorders

Section A: Physiology and Pathophysiology of Lipid Metabolism.- 1 An Introduction to the Biochemistry and Biology of Blood Lipids and Lipoproteins.- A. Introduction.- B. Blood Lipid Transport: Historical Aspects.- C. Blood Lipids, Apolipoproteins, and Lipoproteins.- I. Lipids.- II. Apolipoproteins.- III. Lipoproteins.- D. Enzymes and Transfer Factors Involved in the Biochemistry of Blood Lipid Regulation.- E. Lipoprotein Metabolism.- I. Transport of Exogenous Lipids.- II. Transport of Endogenous Lipids.- F. Cholesterol and Atherosclerosis.- G. High-Density Lipoprotein Cholesterol and Reverse Cholesterol Transport.- H. Triglycerides, High-Density Lipoprotein Cholesterol, and Coronary Artery Disease.- I. Conclusion.- References.- 2 Lipoprotein Metabolism.- A. Introduction.- B. Plasma Apolipoproteins.- C. Cellular Receptors.- I. Low-Density Lipoprotein Receptor.- II. Scavenger Receptor(s).- III. Chylomicron Remnant Receptor.- IV. High-Density Lipoprotein Receptor.- D. Lipoprotein Metabolism.- I. ApoB Metabolic Cascade.- II. High-Density Lipoprotein Metabolism.- III. Lp(a).- E. Major Plasma Atherogenic and Antiatherogenic Lipoproteins.- I. Low-Density Lipoproteins.- II. ? Very Low Density Lipoproteins.- III. Lp(a).- IV. High-Density Lipoproteins.- F. Summary.- References.- 3 Lipoprotein Receptors.- A. Introduction.- B. The Low-Density Lipoprotein Receptor.- I. Functions of the Low-Density Lipoprotein Receptor in the Body.- II. Structure of the Low-Density Lipoprotein Receptor.- 1. Domains.- 2. Evolution.- 3. Low-Density Lipoprotein Receptor Polymorphisms.- III. Low-Density Lipoprotein Receptor Endocytosis, Recycling and Turnover.- IV. Low-Density Lipoprotein Receptor Mutations and Familial Hypercholesterolaemia.- 1. Classes of Low-Density Lipoprotein Receptor Mutations.- a) Class I Mutations (Null Alleles).- b) Class II Mutations (Transport-Defective Alleles).- c) Class III Mutations (Binding-Defective Alleles).- d) Class IV Mutations (Internalization-Defective Alleles).- e) Class V Mutations (Recycling-Defective Alleles).- 2. Clinical Variability in Familial Hypercholesterolaemia.- V. Low-Density Lipoprotein Receptor Regulation.- 1. Low-Density Lipoprotein Receptor Promoter.- 2. Control in the Liver.- VI. Low-Density Lipoprotein Receptor and Therapy.- 1. Drug Therapy.- 2. Liver Transplantation.- 3. Gene Therapy.- C. Chylomicron Remnant Receptor.- I. Receptor-Mediated Clearance of Chylomicron Remnants.- II. Low-Density Lipoprotein Receptor Related Protein: Candidate Chylomicron Remnant Receptor.- III. Structure of Low-Density Lipoprotein Receptor Related Protein.- IV. Properties of Low-Density Lipoprotein Receptor Related Protein.- 1. Binding of Ligands.- 2. Regulation of Ligand Binding.- D. High-Density Lipoprotein Receptor.- I. Cholesterol Efflux.- II. High-Density Lipoprotein Endocytosis.- E. The Scavenger Receptor.- I. The Modified Low-Density Lipoprotein Hypothesis.- II. Scavenger Receptor Structure.- III. Scavenger Receptor Function.- IV. Human Scavenger Receptor Gene.- V. Expression and Regulation.- VI. Scavenger Receptor and Atherogenesis.- F. Conclusion.- References.- 4 Genetic Disorders of Lipoprotein Metabolism.- A. Introduction.- B. Familial Hyperchylomicronemia.- I. Lipoprotein Lipase Deficiency.- II. Apolipoprotein C-II Deficiency.- C. Familial Hypercholesterolemia.- I. Heterozygous Familial Hypercholesterolemia.- 1. Low-Density Lipoprotein.- 2. Pathophysiology and Clinics of Familial Hypercholesterolemia.- 3. Diagnosis of Familial Hypercholesterolemia.- II. Homozygous Familial Hypercholesterolemia.- III. Familial Defective ApoB-100.- 1. Population Genetics of Familial Defective ApoB-100.- 2. Diagnosis of Familial Defective ApoB-100.- 3. The Familial Defective ApoB-100 Phenotype.- D. Lp(a) Hyperlipoproteinemia.- I. Structure and Evolution.- II. Genetics.- III. Genetics of Lp(a) and of Lp(a) Hyperlipoproteinemia.- IV. Lp(a) Hyperlipoproteinemia and Atherosclerotic Vascular Disease.- E. Hyperlipoproteinemia Type III.- I. ApoE Polymorphism.- II. Multifactorial Type III Hyperlipoproteinemia.- III. Dominant Type III Hyperlipoproteinemia.- IV. Pathophysiology of Type III Hyperlipoproteinemia.- F. Familial Combined Hyperlipoproteinemia.- G. Polygenic Hypercholesterolemia.- H. Familial Hypertriglyceridemia.- I. Familial Hyperalphalipoproteinemia and Familial Hypoalphalipoproteinemia.- References.- 5 Interactions Between Lipoproteins and the Arterial Wall.- A. The Molecular Mechanisms of Atherogenesis Are Not Known.- B. The Low-Density Lipoprotein Receptor Pathway and the Pathogenesis of Atherosclerosis.- C. Is Low-Density Lipoprotein Atherogenic?.- D. The Low-Density Lipoprotein Receptor is a Member of a Family of Lipoprotein Receptors: The Low-Density Lipoprotein Receptor Related Proteins, a Very Low-Density Lipoprotein Receptor, and Glycoprotein 330.- E. The Low-Density Lipoprotein Receptor Dependent-Arachidonic Acid Pathway.- F. The Oxidation and Scavenger Receptor Hypotheses.- G. High-Density Lipoproteins and the Reverse Cholesterol Transport Hypothesis.- H. Arterial Wall Cells Form Biologically Active Mediators of Inflammation in Response to Cholesterol Feeding.- I. Adhesion Molecules Are Involved in Leukocyte-Endothelial Cell Interactions.- J. Proto-oncogenes Are Expressed in Atherosclerotic Lesions.- References.- 6 Lipoprotein Lipase and Hepatic Lipase.- A. Introduction.- B. Gene Structures.- C. Molecular Structure.- D. Effects of Apolipoproteins on Lipase Action.- E. Lipoprotein Lipase and Hepatic Lipase — What Are the Functional Differences?.- F. Actions of Lipoprotein Lipase.- G. Sites of Synthesis.- H. Maturation into Active Lipoprotein Lipase.- I. Transfer to the Endothelium.- J. Transport in Blood.- K. Lipases in Pre- and Postheparin Plasma.- L. Regulation.- M. Lipoprotein Lipase as Ligand for Binding of Lipoproteins to Cells and Receptors.- N. Is Lipoprotein Lipase Rate-Limiting for Catabolism of Triglyceride-Rich Lipoproteins?.- O. Impact on Lipoprotein levels.- References.- 7 Animal Models of Lipoprotein Metabolism.- A. Introduction.- B. Animal Models.- C. Lipoproteins.- I. Rabbit.- II. Monkey.- D. Conclusion.- References.- Section B: Lipid Lowering Therapy.- 8 Rationale to Treat.- A. Introduction.- B. Mortality- and Morbidity-Based Drug Trials.- C. Mortality- and Morbidity-Based Diet Trials.- D. Atherosderotic Regression Trials — Uncontrolled Case Series and Case Reports.- I. Femoral Artery.- II. Popliteal Artery.- III. Renal Artery.- IV. Carotid Artery.- V. Coronary Artery and Aorta.- E. Controlled Coronary Angiographic Studies of Drug Therapy.- F. Coronary Angiographic Studies of Diet Therapy.- G. Femoral Angiographic Drug Studies.- H. Atherosclerosis Regression in Experimental Animal Models.- I. Summary.- References.- 9 The Dietary Therapy of Hyperlipidemia: Its Important Role in the Prevention of Coronary Heart Disease.- A. Introduction.- B. Dietary Cholesterol.- C. Effects of Dietary Fats Upon the Plasma Lipids and Lipoproteins.- D. The Cholesterol-Saturated Fat Index of Foods.- E. Polyunsaturated Fatty Acids.- F. Carbohydrate.- G. Fiber, Saponins, and Antioxidants.- H. Protein.- I. Calories.- J. Alcohol.- K. Coffee and Tea.- L. The Dietary Design to Achieve Optimal Plasma Lipid-Lipoprotein Levels.- M. A Phased Approach to the Dietary Treatment of Hyperlipidemia.- N. Predicted Plasma Cholesterol Lowering from Three Phases of the Low-Fat, High Complex Carbohydrate Diet.- O. The Applicability of the Low-Cholesterol, Low-Fat, High-Carbohydrate Diet in the Treatment of the Various Phenotypes and Genotypes of Hyperlipidemia.- P. The Use of the Low-Fat, High Complex Carbohydrate Diet in Diabetic Patients, Pregnant Patients, Children, and Hypertensive Patients.- Q. Interrelationship Between Dietary and Pharmaceutical Therapy of Hyperlipidemic States.- R. Summary.- References.- 10 Lipid Apheresis.- A. Introduction.- B. Low-Density Lipoprotein Apheresis Procedures.- C. The Heparin-Induced Extracorporeal Low-Density Lipoprotein Plasmapheresis System.- D. Clinical Experience with the Heparin-Induced Extracorporeal Low-Density Lipoprotein Plasmapheresis System.- E. Experience with Combined Heparin-Induced Extracorporeal Low-Density Lipoprotein Plasmapheresis and 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitor Therapy.- F. Treatment Tolerance and Safety of Heparin-Induced Extracorporeal Low-Density Lipoprotein Plasmapheresis.- G. Typical Case Reports.- I. Case 1.- II. Case 2.- H. The Heparin-Induced Extracorporeal Low-Density Lipoprotein Plasmapheresis Treatment in Heart-Transplant Patients with Severe Hypercholesterolemia: Report of an Ongoing Study.- I. The Heparin-Induced Extracorporeal Low-Density Lipoprotein Plasmapheresis U System for a Simultaneous Hemodialysis: Low-Density Lipoprotein Apheresis.- I. Case Report.- J. Comparison of Techniques to Lower Low-Density Lipoprotein Levels by Apheresis.- K. Indication for Heparin-Induced Extracorporeal Low-Density Lipoprotein Apheresis.- L. Conclusion.- References.- Section C: Lipid Lowering Drugs.- 11 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitors.- A. Introduction.- B. Structure and Mechanism of Action of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitors.- I. Structure.- II. Pharmacokinetic Properties of Lovastatin, Pravastatin, and Simvastatin.- III. Mechanism of Action.- IV. Effects on Lipoprotein Metabolism.- V. Other Potential Effects of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitors.- C. Clinical Efficacy of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitors in the Treatment of Hyperlipidemia.- I. Effects in Primary Hypercholesterolemia.- II. Effects in Combined Hyperlipidemia.- III. Effects in Hypertriglyceridemia and Hypoalphalipoproteinemia.- IV. Potential Utility of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitors in Patients with Secondary Causes of Hyperlipidemia.- D. Safety and Side-Effect Profile of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitors.- E. Contraindications and Inappropriate Uses of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitors.- F. Use of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitors in Combination Drug Therapy.- G. Conclusions.- References.- 12 Fibrates.- A. Introduction.- I. Clinical Use.- II. History and Development.- III. Helsinki Heart Study.- B. Comparative Pharmacology of the Fibrates.- I. Clofibrate.- II. Bezafibrate.- III. Ciprofibrate.- IV. Fenofibrate.- V. Gemfibrozil.- C. Mechanism of Action.- I. Effects on Very Low-Density Lipoprotein Metabolism.- II. Effects on Chylomicron Metabolism.- III. Effects on Low-Density Lipoprotein Metabolism.- IV. Effects on Low-Density Lipoprotein Composition and Subfraction Profile.- V. Effects on Cholesterol Synthesis.- VI. Effects on High-Density Lipoprotein Metabolism.- D. Toxicology.- I. Hepatomegaly and Carcinogenicity.- II. Bile Lithogenicity.- E. Adverse Clinical Effects.- I. Side Effects.- II. Drug Interactions.- F. Special Uses.- I. Combination Therapy.- II. Paediatric Use of the Fibrates.- G. Conclusions.- References.- 13 Nicotinic Acid and Derivatives.- A. Introduction.- B. The Vitamin.- I. Biochemistry and Requirements.- II. Mechanism of Action.- III. Deficiency.- C. The Drug.- I. Pharmacology.- II. Effects in Lipid Metabolism.- 1. Free Fatty Acid Metabolism.- a) Extracellular Metabolism.- b) Intracellular Metabolism.- 2. Plasma Lipoprotein Metabolism.- a) Very Low-Density Lipoproteins and their Subfractions.- b) Low-Density Lipoprotein Concentrations and Subfractions.- c) Apolipoprotein B, C, and E.- d) Kinetic Studies of Apolipoprotein B-Containing Lipoproteins.- e) High-Density Lipoprotein Concentrations and Subfractions.- f) Lipoprotein Lp(a).- g) Postprandial Lipaemia.- 3. Enzyme Activities and Receptor Functions in Lipid Metabolism.- a) Hormone-Sensitive Lipase.- b) Lipoprotein Lipase and Plasma Triglyceride Removal.- c) Hepatic Lipase.- d) Other Enzymes and Receptors in Lipid Metabolism.- 4. Biliary Lipid Metabolism and Cholesterol Balance.- 5. Summary of the Mechanism of Hypolipidaemic Action of Nicotinic Acid.- 6. Prostanoid Metabolism.- III. Effects on Glucose Metabolism.- 1. Basal Mechanisms.- 2. Non-Insulin-Dependent Diabetes in Man.- a) Short-Term Studies.- b) Long-Term Studies.- 3. Differences Between Nicotinic Acid Derivatives.- 4. Conclusions About Effects on Glucose Metabolism.- D. Clinical Approach.- I. Side Effects.- 1. Flushing.- a) Symptoms.- b) Preventing Flushing.- 2. Gastrointestinal Side Effects.- 3. Hepatic Side Effects.- 4. Cutaneous Side Effects.- 5. Lactacidosis.- 6. Gout.- 7. Retinal Edema.- 8. Time-Release Nicotinic Acid.- II. Laboratory Safety Tests.- III. Start of Treatment.- 1. Fast Dosage Increase.- 2. Slow Dosage Increase.- IV. Treatment Compliance.- V. Combinations with Other Plasma Lipid-Lowering Drugs.- 1. Nicotinic Acid and Bile Acid Sequestrants.- a) Nicotinic Acid and Colestipol.- b) Acipimox and Cholestyramine.- c) Nicotinic Acid and Lovastatin.- VI. Recommendations for Drug Treatment.- 1. Policy Statement of the European Atherosclerosis Society.- 2. The National Cholesterol Education Program.- E. Clinical Effects.- I. Coronary and Femoral Artery Disease.- 1. Mortality and Morbidity.- a) The Coronary Drug Project (CDP).- b) The Stockholm Ischaemic Heart Disease Study.- 2. Regression of Atherosclerosis.- a) Coronary Atherosclerosis.- b) Femoral Atherosclerosis.- 3. Conclusion on the Effect of Nicotinic Acid on Atherosclerosis.- II. Dementia.- F. General Conclusions.- References.- 14 Ion Exchange Resins.- A. Introduction.- B. Chemistry and Pharmacology.- C. Mode of Action.- D. Clinical Experience.- E. Pharmacodynamic and Pharmacokinetic Parameters.- F. Drug Interactions.- G. Adverse Effects of Resins.- H. Other Indications.- I. Children and Adolescents.- J. Combined Drug Treatment with Resins.- I. Bile Acid Sequestrants and Cholesterol Synthesis Enzyme Inhibitors.- II. Bile Acid Sequestrants and Nicotinic Acid or Analog.- III. Bile Acid Sequestrants plus Fibrates.- IV. Bile Acid Sequestrants plus Probucol.- V. Triple Drug Therapy.- References.- 15 Probucol.- A. Introduction.- B. Chemistry, Physical Properties, and Dosage.- C. Absorption, Metabolism, and Excretion.- D. Effects on Plasma Lipids, Lipoproteins, and Apolipoproteins.- I. Cholesterol and Low-Density Lipoproteins.- II. High-Density Lipoproteins and Reverse Cholesterol Transport.- III. Apolipoproteins, Lipoprotein Composition, and Enzymes.- IV. Effect of Combination Therapy with Probucol.- E. Antioxidant Properties and Antiatherogenic Effects.- I. Effect on Low-Density Lipoprotein.- 1. In Vitro Studies.- 2. In Vivo Studies.- a) The Watanabe Heritable Hyperlipidemic Rabbit.- b) Other Animal Models.- 3. Studies in Man.- II. Studies with Lipoprotein (a).- F. Mechanisms of Action.- I. Mechanism of Low-Density Lipoprotein-Lowering Effect.- II. Mechanism of High-Density Lipoprotein-Lowering Effect.- III. Antioxidant Effect.- G. Side Effects, Safety, Tolerance, and Drug Interactions.- H. Other Properties and Use of Probucol in Specific Diseases.- I. Anti-inflammatory Effect.- II. Probucol and Diabetes.- III. Probucol and Renal Disease.- IV. Probucol and the Heart.- I. Conclusions.- References.- 16 Miscellaneous Lipid-Lowering Drugs.- A. Introduction.- B. ?-Sitosterol.- I. Chemistry, Physical Properties, and Dosage Form.- II. Absorption, Metabolism, and Excretion.- III. Effects on Plasma Lipids and Lipoproteins.- 1. Treatment with ?-Sisterol Alone.- 2. Combined Drug Treatment.- IV. Mechanisms of Action.- V. Side Effects, Safety, Tolerance, and Drug Interactions.- VI. Conclusions.- C. Neomycin.- I. Chemistry, Physical Properties, and Dosage Form.- II. Absorption, Metabolism, and Excretion.- III. Effects on Plasma Lipids and Lipoproteins.- 1. Treatment with Neomycin Alone.- 2. Combined Drug Treatment.- a) Neomycin and Niacin.- b) Neomycin and Cholestyramine.- c) Neomycin and Clofibrate.- d) Neomycin and Lovastatin.- IV. Mechanisms of Action.- V. Side Effects, Safety, Tolerance, and Drug Interactions.- VI. Conclusions.- D. Ketoconazole.- E. d-Thyroxine.- References.