HDL metabolism and its role in lipid transport

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Abstract
High density lipoprotein (HDL) plays an essential role in plasma lipid transport. It provides a reservoir of C apolipoproteins, which are required for the metabolism of chylomicrons and very low density lipoproteins (VLDL), and acts as a scavenger of surplus unesterified cholesterol from these lipoproteins. HDL is also the major vehicle for the transport of cholesterol from peripheral cells to the liver for excretion and catabolism. This process, known as reverse cholesterol transport, occurs in three stages: extravascular, intravascular, and intrahepatic. In the extravascular phase, unesterified cholesterol is removed from cell membranes by small apoprotein (apo) A-I-containing particles in interstitial fluid. This may be facilitated by binding of the particles to cell surface receptors that recognize apo A-I. After entry into the blood via peripheral lymph, cholesterol in these and other HDL particles is esterified by the associated enzyme, lecithin: cholesterol acyltransferase. Some of the cholesteryl esters that are formed are transferred to chylomicrons and VLDL by a transfer protein. Others are incorporated into the core of HDL particles, which then increase in size and decrease in density. Ultimately these HDL particles associate with apo E, which is synthesized and secreted by some peripheral tissues at a rate regulated by their cell cholesterol content. Removal of cholesteryl esters from the circulation occurs in the liver by receptor-mediated uptake of HDL—with apo E, chylomicron remnants, VLDL remnants, and low density lipoprotein—and by direct transfer of cholesteryl esters from HDL particles into liver cells. Cholesterol is eliminated by hepatocytes by secretion into the bile, and by conversion to primary bile acids. Persuasive evidence indicates that the protective effect of HDL against atherogenesis reflects the function of this class of lipoproteins in reverse cholesterol transport. Numerous experimental and epidemiologic studies have indicated that plasma HDL-cholesterol is a major independent risk factor for coronary heart disease. This finding has stimulated further research into the metabolic factors that determine the concentration and composition of HDL.

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