Hypolipidemic Agents

ISBN-13: 9783642661921 / Angielski / Miękka / 2011 / 490 str.

W.L. Bencze;M.E. Dempsey;S. Eisenberg

Opis

The major cause of death in the Western world is some form of vascular disease; and principal among these forms is atherosclerotic heart disease (ASHD). Although much is known about the etiology and treatment of ASHD, there is, as yet, no specific means of prognosis of an impending coronary episode. There are, however, several indications of susceptibility to coronary disease, generally known as risk factors, the foremost of which is hyperlipidemia. Hyperlipidemia is more commonly designated as hypercholesteremia or triglyceridemia, depending upon which moiety is elevated, but since lipids are transported in the blood as members of a lipoprotein complex, the most descriptive general term would be hyperlipoproteinemia. This volume represents an effort to elucidate the origins and metabolic behavior of lipoproteins and their components, to describe aspects of the morphology, biochemistry and experimental induction of ASHD, and to describe modalities of treatment. The contributions to this book include descriptions of cholesterol synthesis and metabolism, as well as the metabolism of bile acids, the principal products of cholesterol metabolism. There are also chapters on the mechanisms of hyperlipidemia and on lipoprotein metabolism. The induction of experimental atherosclerosis and the aortic structural changes caused by this disease are discussed.

Spis treści

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.