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32 Dyslipidemias 32 Dyslipidemias Annabelle Rodriguez-Oquendo, Peter O. Kwiterovich, Jr. 32.1 Overview of Plasma Lipid and Lipoprotein Metabolism – 391 32.1.1 Exogenous Lipoprotein Metabolism – 391 32.1.2 Endogenous Lipoprotein Metabolism – 392 32.1.3 Reverse Cholesterol Transport and High Density Lipoproteins – 393 32.1.4 Lipid Lowering Drugs – 394 32.2 Disorders of Exogenous Lipoprotein Metabolism – 394 32.2.1 Lipoprotein Lipase Deficiency – 394 32.2.2 Apo C-II Deficiency – 395 32.3 Disorders of Endogenous Lipoprotein Metabolism – 395 32.3.1 Disorders of VLDL Overproduction – 396 32.3.2 Disorders of LDL Removal – 397 32.4 Disorders of Endogenous and Exogenous Lipoprotein Transport – 399 32.4.1 Dysbetalipoproteinemia (Type III Hyperlipoproteinemia) – 399 32.4.2 Hepatic Lipase Deficiency – 400 32.5 Disorders of Reduced LDL Cholesterol Levels – 400 32.5.1 Abetalipoproteinemia – 400 32.5.2 Hypobetalipoproteinemia – 401 32.5.3 Homozygous Hypobetalipoproteinemia – 401 32.6 Disorders of Reverse Cholesterol Transport – 401 32.6.1 Familial Hypoalphalipoproteinemia – 401 32.6.2 Apolipoprotein A-I Mutations – 401 32.6.3 Tangier Disease – 402 32.6.4 Lecithin-Cholesterol Acyltransferase Deficiency – 402 32.6.5 Cholesteryl Ester Transfer Protein Deficiency – 402 32.6.6 Elevated Lipoprotein (a) – 403 32.7 Guidelines for the Clinical Evaluation and Treatment of Dyslipidemia – 403 32.7.1 Clinical Evaluation – 403 32.7.2 Dietary Treatment, Weight Reduction and Exercise – 404 32.7.3 Goals for Dietary and Hygienic Therapy – 405 32.7.4 Low Density Lipoprotein-Lowering Drugs – 406 32.7.5 Triglyceride Lowering Drugs – 407 32.7.6 Combination Pharmacotherapy – 408 Abbreviations – 408 References – 408 390 Chapter 32 · Dyslipidemias Lipoprotein Metabolism Lipids are transported in plasma on lipoproteins, spher- for lipoprotein biosynthesis, or to downregulate LDL ical particles that consist of a hydrophobic core of trig- receptors and cholesterol biosynthesis. lycerides and cholesteryl esters, surrounded by an am- (2) The endogenous (hepatic) pathway transports phiphilic coating of apolipoproteins, phospholipids and triglycerides and cholesterol from the liver as VLDL unesterified cholesterol. The human plasma lipopro- (. Fig. 32.1). In the capillaries of muscle and fat, VLDL teins are classified according to their density and elec- are also hydrolyzed by lipoprotein lipase, yielding free trophoretic mobility (. Table 32.1), and a number of fatty acids for uptake. Their remnants, IDL, are in part species of apolipoproteins are known (. Table 32.2). Li- cleared from the circulation by the liver LDL receptor, poprotein metabolism involves three major pathways, and in part converted into LDL. LDL are taken up via which are briefly summarized here and reviewed in LDL receptors by a variety of extrahepatic tissues, where more detail in the first section of the chapter. they supply cholesterol mainly for membrane synthesis. (1) The exogenous (intestinal) pathway transports Liver also takes up LDL via LDL receptors and uses their mainly triglycerides from the diet, but also cholesterol cholesterol for the synthesis of bile acids or lipopro- of both dietary and biliary origin, as chylomicrons teins. (. Fig. 32.1). Lipoprotein lipase, an enzyme on the sur- (3) Reverse cholesterol transport involves release face of capillary endothelial cells that requires apo C-II of unesterified cholesterol from cells into plasma, fol- VII as cofactor, hydrolyzes chylomicron triglycerides into lowed by binding to HDL, conversion by LCAT of un- free fatty acids for uptake by muscle and fat. The result- esterified into esterified cholesterol, and transfer of the ant chylomicron remnants are taken up by the LDL re- latter via cholesteryl ester transfer protein to VLDL and ceptor-related protein (LRP) in liver, where they deliver ultimately IDL and LDL. HDL can also deliver choles- cholesterol that can be converted into bile acids, used teryl esters directly to the liver (. Fig. 32.2). Major Nonhepatic Lipoprotein apolipoproteins capillary Uptake of Chylomicron B-48, E, C endothelium cholesterol ase Chylomicron B-48, E lip remnant Endogenous in te ro 6 pathway p o p Free i IDL VLDL B-100, C, E fatty acids L IDL B-100 E Peripheral LDL tissues HTGL LDL B-100 (adipose VLDL 5 VLDL and muscle) remnant 4 Acetyl-CoA e MVA as 1 p Cholesterol li HMG- in 2 e Chyclomicron t CoA o r remnant p Liver o p Bile acids i 6 L Free Chyclomicron fatty acids Bile Portal Exogenous duct vein pathway 3 Cholesterol Triglycerides 2 Bile acids Dietary Intestines fat . Fig. 32.1. Pathways of exogenous and endogenous lipopro- inhibitor (3) all induce LDL receptors (4). Niacin (5), inhibits VLDL, tein metabolism. The metabolism of the apoB containing lipo- IDL and LDL production. The fibric acid derivatives (6) enhance li- proteins from the intestine and the liver are depicted. The site of poprotein lipase activity. See text for abbreviations. Modified and action of the lipid-lowering drugs are also shown. The statins (1), reproduced with permission from Braunwald E (ed) Essential atlas the bile acid sequestrants (2) and the cholesterol absorption of heart diseases, Appleton and Lange, Philadelphia, 1997, p 1.28 391 32 32.1 · Overview of Plasma Lipid and Lipoprotein Metabolism 32.1.1 Exogenous Lipoprotein Metabolism Conversion Factors The exogenous pathway of lipoprotein metabolism trans- mg/dl o mmol/l o mg/dl ports dietary fats from intestine to muscle, adipose tissue Cholesterol x 0.0259 x 38.6 and liver. After a meal is consumed, dietary lipids, mainly Triglycerides x 0.0114 x 87.7 triglycerides (TG), cholesteryl esters, and phospholipids, are Phospholipids x 0.323 x 77.5 emulsified by bile acids and hydrolyzed by pancreatic lipases into their component parts, monoglyceride and free fatty acids (FFA), and unesterified cholesterol and FFA, respec- tively. After absorption into the intestinal cells, the mono- 32.1 Overview of Plasma Lipid glycerides are reconverted into TG, and incorporated to- and Lipoprotein Metabolism gether with cholesterol into chylomicrons, which contain apolipoproteins A-I, A-II, A-IV, and B-48. The assembled Lipoproteins play an essential role in the delivery of free chylomicrons are secreted into the thoracic duct, a process fatty acids to muscle and adipose tissue where they, respec- that requires apo B-48. Thereafter, they enter the peripheral tively, serve as a fuel and are stored as triglycerides. Lipo- cir culation, where they acquire apo E and apo C-I, apo C-II proteins also intervene in the transfer of cholesterol from and apo C-III by transfer from HDL. When they enter the intestine to liver, from liver to other tissues, and from the capillaries of skeletal muscle and adipose tissue, the chylo- latter back to the liver. The lipoprotein structure resembles microns are exposed to the enzyme lipoprotein lipase (LPL), a plasma membrane bilayer with hydrophilic phospholipids, located on the surface of the endothelial cells (. Table 32.3). apolipoproteins and some cholesterol on the outer surface, Apo C-II is necessary for activation of LPL, provoking hy- and hydrophobic triglycerides and cholesteryl esters in the drolysis of the TG into FFA which enter muscle and adipose core. The physical-chemical properties and composition of tissue. the major human plasma proteins are given in . Table 32.1. The resulting chylomicron remnants, still containing The plasma apolipoproteins are amphipathic proteins cholesterol, apo B-48 and apo E, the latter acting as a ligand that interact with both the polar aqueous environment of for the hepatic chylomicron remnant receptor, are taken blood, and the nonpolar core lipids. They serve various up into the liver, where they deliver dietary and biliary chol- functions such as ligands for receptors, cofactors for en- esterol (. Fig. 32.1). zymes, and structural proteins for packaging. The main characteristics of human plasma apolipoproteins are given in . Table 32.2. Table 32.1. Physical-chemical properties of human plasma lipoproteins Class Density (g/ml) Electrophoretic Surface components Core lipids mobility Cholesterol Phospho- Apolipo- Triglycerides Cholesteryl lipids protein esters Chylomicrons <0.95 Remains at origin 2 7 2 86 3 VLDL 0.950–1.006 Pre-β lipoproteins 7 18 8 55 12 IDL 1.006–1.019Slow pre-β lipo- 9 19 19 23 29 proteins LDL 1.019–1.063 β-Lipoproteins 8 22 22 6 42 HDL-2 1.063–1.125 α-Lipoproteins 5 33 40 5 17 HDL-3 1.125–1.210 α-Lipoproteins 4 35 55 3 13 Lp(a) 1.040–1.090 Slow pre-β-lipo- proteins VLDL, very low-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low density lipoprotein; HDL, high density lipoprotein. HDL- 2 and HDL-3 are the two major subclasses of HDL. Lp(a) consists of a molecule of LDL covalently attached to a molecule of apo(a), a protein homologous to plasminogen. Its lipid composition is similar to that of LDL. Compositions are given in % (by weight). 392 Chapter 32 · Dyslipidemias . Table 32.2. Characteristics of human plasma apolipoproteins Apolipoproteins Major tissue sources Functions Molecular weight Apo A-I Co-factor LCAT 29,016 Apo A-II · Liver and intestine Not known 17,414 Apo A-IV Activates LCAT 44,465 Apo B-48 Intestine Secretion TG from intestine 240,800 Apo B-100 Liver Secretion TG from liver; binding ligand to LDL receptor 512,723 Apo C-I Activates LCAT; inhibits CETP 6,630 Apo C-II · Liver Cofactor LPL 8,900 Apo C-III Inhibits LPL 8,800 Apo D Many sources Reverse cholesterol transport 19,000 Apo E Liver Ligand for uptake of chylomicron remnants and IDL 34,145 LCAT, lecithin cholesterol acyl transferase;
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