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  • Plasma high-density lipoproteins (HDL) consist of about 50 percent protein and 50 percent lipids. The principal apolipoproteins of HDL, apo A-I and apo A-II, are synthesized in the liver (apo A-I and apo A-II) or small intestine (apo A-I), secreted as components of triglyceride (TG)-rich lipoproteins (TRL), and then transferred into HDL during lipolysis, along with phospholipid and cholesterol. Alternatively, they may be secreted as free apoproteins, then acquire lipids by interaction with the cellular ATP binding cassette transporter, ABC1. The plasma cholesterol-esterifying enzyme lecithin: cholesterol acyltransferase (LCAT) circulates bound to HDL and uses free cholesterol and phospholipids as substrates in the generation of cholesteryl esters (CE). HDL also contains a phospholipid transfer protein (PLTP) and a cholesteryl ester transfer protein (CETP), which mediate the transfer of phospholipid and cholesterol into HDL and the removal of cholesteryl esters from HDL, respectively. CETP mediates a hetero-exchange of HDL CE for TG of TRL, and the HDL TG is subsequently hydrolyzed by hepatic lipase (HL). The coordinate activities of PLTP, CETP, LCAT, and HL promote the formation and turnover of HDL CE, which is a central event in the transport of cholesterol from peripheral tissues to the liver, that is, reverse cholesterol transport. The return of plasma HDL CE to the liver may involve transfer to TRL by CETP, selective uptake of free and esterified cholesterol (i.e., cellular uptake of HDL lipid without protein degradation), or uptake of holo-HDL particles. An authentic HDL receptor, scavenger receptor BI (SR-BI), is highly expressed in the liver and steroidogenic tissues, where it mediates the selective uptake of HDL lipids.

  • Plasma HDL levels show an inverse relationship to atherosclerotic cardiovascular disease. Underlying this relationship is the ability of HDL to promote the efflux of cholesterol from foam cells in the arterial wall and to mediate reverse cholesterol transport. Transgenic mouse studies strongly support an antiatherogenic role of HDL, and are consistent with increased reverse cholesterol transport as the underlying mechanism. Antiatherogenic properties of HDL may also be related to its ability to inhibit the retention, aggregation, and oxidation of LDL in the arterial wall. Humans with low HDL often have increased levels of TRL; in some cases, low HDL is likely a marker for a metabolic predisposition to accumulate atherogenic remnants of TRL. Subjects with low HDL typically have increased catabolism of apo A-I, a process that may be driven by increased core lipid exchange between HDL and TRL. In other cases low HDL may be a marker of an inflammatory state involving the vessel wall.

  • Transgenic mouse models have proven invaluable in elucidating the metabolism of HDL and its relationships to atherosclerosis. Human apo A-I transgenic mice show increased HDL cholesterol and have human-like subspecies of HDL in plasma. Importantly, apo A-I transgenic mice are resistant to the development of early atherosclerotic lesions in response to an atherogenic diet. Moreover, the apo A-I transgene inhibits the development of both early and late complex atherosclerotic lesions in ...

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