Hypolipidemic Agents

1 Cholesterol Biosynthesis in vitro.- I. Cell-Free Homogenates.- II. Microsomal and Soluble Enzymes; Squalene and Sterol Carrier Protein Applications.- A. Enzymes in the Early Stages of Cholesterol Synthesis.- B. Enzymes in the Later Stages of Cholesterol Synthesis.- C. Characteristics of ?5-Dehydrogenase and ?7-Reductase; Role of Squalene and Sterol Carrier Protein (SCP).- D. Inhibition of the Later Stages of Cholesterol Synthesis.- III. Preparations and Activity Assays.- A. HMG-CoA Reductase.- B. ?5-Dehydrogenase and ?7-Reductase.- C. Squalene and Sterol Carrier Protein (SCP).- D. Method 1.- E. Method 2.- F. Assay of HMG-CoA Reductase.- G. Assay of ?5-Dehydrogenase.- H. Assay of ?7-Reductase.- I. Linearity of Enzymic Assays; Optimum Substrate Levels.- J. Binding of Compounds to SCP and Microsomal Enzymes.- References.- 2 Cholesterol Metabolism in Man.- I. Introduction.- II. Distribution of Cholesterol in the Body.- III. Functions of Cholesterol.- IV. Synthesis of Cholesterol.- A. Synthesis of Cholesterol in Various Tissues of the Body.- B. Control of Endogenous Synthesis of Cholesterol.- C. Diurnal Variation.- D. Methods to Study Synthesis of Cholesterol in Man.- V. Absorption of Dietary Cholesterol.- A. Control Mechanisms Regulating Absorption of Cholesterol from the Intestinal Lumen.- B. Methods to Study Absorption of Dietary Cholesterol.- VI. Catabolism of Cholesterol and Its Losses from the Body Pools.- A. Factors Influencing Catabolism of Endogenous Cholesterol.- B. Skin.- C. Adrenal Glands.- VII. Plasma Cholesterol.- VIII. Relationship of Cholesterol in Plasma and Tissue Pools.- IX. Homeostasis of Plasma Cholesterol.- Turnover of Cholesterol in Exchangeable Pools.- X. Plasma Cholesterol Esters.- XI. Proposed Model for Cholesterol Metabolism in Man.- XII. Cholesterol Metabolism in Hyperlipoproteinemias.- References.- 3 Bile Acid Metabolism.- I. Introduction.- II. Enterohepatic Circulation.- III. Different Parameters of Bile Acid Metabolism.- A. Pool Size.- B. Biliary Secretion.- C. Intestinal Concentration.- D. Reabsorption.- E. Number of Enterohepatic Circulations.- F. Faecal Excretion.- G. Serum Bile Acids.- H. Urinary Bile Acids.- Daily Synthesis.- IV. Regulation of Cholesterol Catabolism via Bile Acids.- V. Physiological Factors Influencing Bile Acid Metabolism.- Diet.- VI. Effects of Hormones on Bile Acids.- A. Pituitary Hormones.- B. Sex Hormones.- C. Thyroid Hormones.- VII. Hyperlipidaemia.- A. Chylomicronaemia (Type I).- B. Hypercholesterolaemia (Type II).- C. Familial Hyperlipoproteinaemia (Type III).- D. Hypertriglyceridaemia (Type IV).- E. Hyperglyceridaemia (Type V).- References.- 4 Mechanisms of Hyperlipidemia.- I. Introduction.- II. Normal Levels of Plasma Triglycerides and Cholesterol.- III. The Plasma Lipoprotein Spectrum.- A. Techniques of Analysis.- 1. Separation on the Basis of Density.- a) The Analytical Ultracentrifuge.- b) The Preparative Ultracentrifuge.- 2. Separation on the Basis of Charge by Zonal Electrophoresis.- 3. Gel Filtration Chromatography.- 4. Precipitation with Polyanion-Metal Complexes.- B. Structure and Chemical Composition of Plasma Lipoproteins.- C. Free Fatty Acids (FFA).- IV. The Metabolism of Constituents of Plasma Lipoproteins.- A. Triglyceride Transport in Chylomicrons and VLDL.- 1. Intestinal Mucosal Cell.- 2. Liver.- B. Cholesterol Transport in Chylomicrons and VLDL.- 1. Intestinal Mucosal Cell.- 2. Liver.- C. Triglyceride Assimilation Mechanisms.- 1. Role of Liver.- 2. Role of Lipoprotein Lipase.- D. Cholesterol Assimilation Mechanisms.- V. Classification of Hyperlipidemias.- A. Primary Hyperlipoproteinemias.- 1. Familial Type I Hyperlipoproteinemia (Familial Hyperchylomicronemia, Fat Induced Hyperlipidemia, Idiopathic Hyperlipemia).- 2. Familial Type II Hyperlipoproteinemia (Familial Hypercholesterolemia; Familial Hypercholesterolemic Xanthomatosis.- 3. Familial Type III Hyperlipoproteinmia (Broad-Beta Diesease, Remnant Disease).- 4. Familial Type IV Hyperlipoproteinemia (Hyperprebetalipoproteinemia, Familial Hyperlipemia, Carbohydrate-Induced Hyperlipemia, Endogenous Hyperglyceridemia).- 5. Familial Type V Hyperlipoproteinemia [Familial Mixed (Endogenous and Exogenous) Hyperlipemia, Familial Hyperprebetalipo- proteinemia with Hyperchylomicronemia].- B. Secondary Hyperlipoproteinemias.- 1. Alcoholic Hyperlipoproteinemia.- 2. Diabetic Hyperlipoproteinemia.- 3. Hyperlipoproteinemia of the Nephrotic Syndrome.- 4. Hyperlipoproteinemia Associated with Myxedema.- 5. Hyperlipoproteinemia Associated with Obesity and Excess Caloric Intake.- References.- 5 Lipoproteins and Lipoprotein Metabolism.- I. Structure and Functions of Lipoproteins.- A. Physical Properties.- 1. Chylomicrons.- 2. Very Low Density Lipoprotein.- 3. Low Density Lipoprotein.- 4. High Density Lipoprotein.- B. Lipid Composition.- C. The Apoprotein Moiety of Lipoproteins.- D. Conclusion.- II. Synthesis of Lipoproteins.- A. Assembly, Intracellular Transport, and Release.- B. Synthesis of Apoproteins.- C. Regulation of Lipoprotein Synthesis.- III. Lipoprotein Metabolism.- A. Chylomicrons.- B. Very Low Density Lipoproteins.- C. Low Density Lipoprotein.- D. High Density Lipoprotein.- E. Conclusions.- IV. The Hyperlipoproteinemias.- Hyperlipoproteinemia Summary.- V. Treatment of Hyperpoproteinemia.- References.- 6 Animal Models for Atherosclerosis Research.- I. Rabbit.- II. Rat.- III. Chicken.- IV. Dog.- V. Pigeons.- VI. Swine.- VII. Primates.- References.- 7 Lipoprotein Formation in the Liver Cell (Ultrastructural and Functional Aspects Relevant to Hypolipidemic Action).- I. Introduction.- II. The Concept of Membrane Flow and Its Relevance to Secretion.- A. The Model.- B. Individuality of Membrane Compartments.- C. Directional Flow of Membranes.- D. Energy Requirements of Secretion.- III. Formation and Secretion of Lipoproteins.- A. Evidence of the Secretion of Lipoproteins by the Hepatocyte.- B. Synthesis of Lipoproteins on Ribosomes.- C. Stepwise Glycosylation of Exportable Proteins by the Membrane-Bound Multiglycosyl Transferase System.- D. Assembly of Protein and Lipid Moieties and Intracellular Transport.- E. The Role of the Golgi Complex.- F. Release from the Cell.- G. Recapitulation.- IV. Regulation of Lipoprotein Secretion.- A. Compositional Variability of Lipoproteins.- B. The Nature of Cytoplasmic Lipid Particles.- C. Effects of Lipid-Lowering Agents.- 1. Actions of Aryloxyacetic Acids.- 2. Liver Induction in the Rodent.- 3. The Peroxisome Problem.- 4. Effects on Mitochondria.- 5. Relationship between VLDL-Containing Secretion Granules and Lysosomes.- V. Concluding Remarks.- References.- 8 Vascular Metabolism, Vascular Enzymes, and the Effect of Drugs.- I. Notes on Vascular Metabolism.- Summary.- II. Vascular Enzyme Studies.- A. Enzymes in Venous Tissue.- B. Interspecies and Intraspecies Differences.- C. Effect of Age and Sex.- D. Enzyme Activities in Vascular Grafts.- E. Enzyme Activity in Atherosclerotic Vessels.- F. The Role of Vascular Injury.- G. Enzymes of Connective Tissue Metabolism.- H. Enzymes Related to Lipid Metabolism.- Summary.- III. The Effect of Drugs.- A. Bioflavonoids.- B. Pyridinolcarbamate.- C. Sex Hormones.- D. Drugs Affecting Vascular Lipolytic and Esterolytic Activity.- Summary.- Concluding Remarks.- Abbreviations.- References.- 9 Hypolipidemic Agents.- I. Introduction.- II. The Coronary Drug Project.- III. Nicotinic Acid and Analogs.- IV. Pyrazoles and Isoxazoles.- V. Diethyl Chelidonate.- VI. The Role of the Second Messenger in Lipolysis.- VII. Catecholamines, Adrenergic Blocking Agents.- VIII. Miscellaneous Inhibitors of Lipolysis.- IX. The Prostaglandins.- X. Thyroid Hormones.- XI. Estrogens, Progestagens, Anabolic, and Androgenic Compounds.- XII. Substituted Phenyl- and Phenyloxy-acetic Acids.- XIII. Hepatic Action of Clofibrate and Its Analogs.- A. Mitochondria.- B. Microsomes.- C. Peroxisomes (Mircrobodies).- D. Cytoplasm.- XIV. Extrahepatic Enzymes Influenced by Clofibrate.- XV. Potential Antiatherosclerotic Effect of Clofibrate.- XVI. Derivatives of Dialkylaminoethanol.- XVII. Unsaturated Fatty Acids.- XVIII. Compounds Containing Sulfur.- XIX. Indole-2-Carboxylic Acids.- XX. Hydroxylamine Derivatives.- XXI. Pyridinolcarbamate.- XXII. Eritadenine.- XXIII. Miscellaneous Compounds.- XXIV. Cholestyramine.- XXV. Neomycin.- XXVI. Rifampin.- XXVII. Concluding Remarks.- References.- 10 The Rationale for Hypolipemic Therapy.- Cholesterol Lowering by Diet.- Conclusions from the Dietary Trials.- Cholesterol Lowering with Clofibrate.- Extrapolations between Different Lipid Lowering Techniques.- Summary of Opinions.- Conclusions.- References.- Author Index.