Review Articles| Volume 12, ISSUE 4, P849-856, July 2018

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Rethinking reverse cholesterol transport and dysfunctional high-density lipoproteins

Published:April 12, 2018DOI:


      • Nascent high-density lipoprotein–free cholesterol (nHDL-FC) and human and mouse HDL-FC are cleared faster than apolipoprotein AI and HDL-cholesteryl ester.
      • FC esterification by lecithin:cholesterol acyltransferase plays a minor role in reverse cholesterol transport.
      • Mouse plasma nHDL-phospholipid rapidly transfers to the liver via a phospholipid transfer protein-dependent mechanism.
      • Mol% HDL-FC and plasma HDL levels may contribute to dysfunctional HDL.
      • High plasma FC bioavailability may be a marker of cardiovascular disease risk.


      Human plasma high-density lipoprotein cholesterol concentrations are a negative risk factor for atherosclerosis-linked cardiovascular disease. Pharmacological attempts to reduce atherosclerotic cardiovascular disease by increasing plasma high-density lipoprotein cholesterol have been disappointing so that recent research has shifted from HDL quantity to HDL quality, that is, functional vs dysfunctional HDL. HDL has varying degrees of dysfunction reflected in impaired reverse cholesterol transport (RCT). In the context of atheroprotection, RCT occurs by 2 mechanisms: one is the well-known trans-hepatic pathway comprising macrophage free cholesterol (FC) efflux, which produces early forms of FC-rich nascent HDL (nHDL). Lecithin:cholesterol acyltransferase converts HDL-FC to HDL-cholesteryl ester while converting nHDL from a disc to a mature spherical HDL, which transfers its cholesteryl ester to the hepatic HDL receptor, scavenger receptor B1 for uptake, conversion to bile salts, or transfer to the intestine for excretion. Although widely cited, current evidence suggests that this is a minor pathway and that most HDL-FC and nHDL-FC rapidly transfer directly to the liver independent of lecithin:cholesterol acyltransferase activity. A small fraction of plasma HDL-FC enters the trans-intestinal efflux pathway comprising direct FC transfer to the intestine. SR-B1−/− mice, which have impaired trans-hepatic FC transport, are characterized by high plasma levels of a dysfunctional FC-rich HDL that increases plasma FC bioavailability in a way that produces whole-body hypercholesterolemia and multiple pathologies. The design of future therapeutic strategies to improve RCT will have to be formulated in the context of these dual RCT mechanisms and the role of FC bioavailability.

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