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Link to original content: http://pubmed.ncbi.nlm.nih.gov/29731282/
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Review
. 2018 Jul-Aug;12(4):849-856.
doi: 10.1016/j.jacl.2018.04.001. Epub 2018 Apr 12.

Rethinking reverse cholesterol transport and dysfunctional high-density lipoproteins

Baiba K Gillard  1 , Corina Rosales  1 , Bingqing Xu  2 , Antonio M Gotto Jr  1 , Henry J Pownall  3
Affiliations
Review

Rethinking reverse cholesterol transport and dysfunctional high-density lipoproteins

Baiba K Gillard et al. J Clin Lipidol. 2018 Jul-Aug.

Abstract

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.

Keywords: ATP-binding cassette transporter A1; Atherogenesis; Cholesterol bioavailability; HDL biogenesis; Lipoprotein receptors; Reverse cholesterol transport.

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Figures

Figure 1
Figure 1
Traditional Model of RCT in the Context of Atheroprotection (Adapted from Glomset and Ross).(2) 1) FC efflux from macrophages initiates the formation of discoidal nHDL, which contains FC, PL, and apo AI. 2) LCAT catalyzes the conversion of FC to CE, which forms a central core within spherical HDL. 3) SR-B1 selectively extracts lipids, especially FC and CE, from the mature HDL particle leaving an apo-rich remnant HDL (remHDL) particle and lipid-free apo AI that returns to another RCT cycle.
Figure 2
Figure 2
Revised RCT Model. ABCA1-expressing cells extrude FC and PL via the interaction of apo AI with ABCA1 giving nHDL (1). nHDL-apo AI and some nHDL-FC and PL rapidly transfer to HDL, t1/2 < 2 min (2); concurrently some nHDL-FC and PL transfer to LDL (3). Over the same time frame, nHDL- and HDL-FC and PL transfer mainly to the liver (5, 6, 7) while some nHDL-apo AI is recycled to ABCA1 (8). Over time, FC and PL equilibrate among erythrocytes (4), extra-hepatic tissues, and lipoproteins. nHDL- and HDL-FC and PL accretion in the liver occurs via spontaneous transfer and SR-B1 (5, 6, 7), the latter being promoted by PLTP (6). Modified from Xu et al. (1).
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