Future therapeutic directions in reverse cholesterol transport - PubMed (original) (raw)

Review

Future therapeutic directions in reverse cholesterol transport

Amit V Khera et al. Curr Atheroscler Rep. 2010 Jan.

Abstract

Despite a robust inverse association between high-density lipoprotein (HDL) cholesterol levels and atherosclerotic cardiovascular disease, the development of new therapies based on pharmacologic enhancement of HDL metabolism has proven challenging. Emerging evidence suggests that static measurement of HDL levels has inherent limitations as a surrogate for overall HDL functionality, particularly with regard to the rate of flux through the macrophage reverse cholesterol transport (RCT) pathway. Recent research has provided important insight into the molecular underpinnings of RCT, the process by which excess cellular cholesterol is effluxed from peripheral tissues and returned to the liver for ultimate intestinal excretion. This review discusses the critical importance and current strategies for quantifying RCT flux. It also highlights therapeutic strategies for augmenting macrophage RCT via three conceptual approaches: 1) improved efflux of cellular cholesterol via targeting the macrophage; 2) enhanced cholesterol efflux acceptor functionality of circulating HDL; and 3) increased hepatic uptake and biliary/intestinal excretion.

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Conflict of interest statement

Disclosure Dr. Rader serves as a consultant to several companies that market or are developing therapies targeting HDL or RCT, including Abbott, AstraZeneca, Bristol-Myers-Squibb, Eli Lilly, Johnson & Johnson, Merck & Co, Novartis, and Resverlogix. No other potential conflicts of interest relevant to this article were reported.

Figures

Fig. 1

Fig. 1

Physiology of macrophage reverse cholesterol transport. Both the liver and intestine synthesize apolipoprotein A-I (ApoA-I), which is secreted in lipid-poor form. These particles are lipidated with both phospholipids and free cholesterol via the hepatocyte ATP-binding cassette A1 (ABCA1) transporter to form nascent high-density lipoprotein (HDL). In peripheral tissues, these HDL particles obtain additional free cholesterol via the macrophage ABCA1 transporter. Lecithin cholesterol acyltransferase (LCAT) esterifies free cholesterol to cholesteryl esters, generating mature HDL. These larger HDL particles serve as additional acceptors of cholesterol efflux via the macrophage ATP-binding cassette G1 (ABCG1) pathway. Liver X receptor (LXR) regulates the expression of both ABCA1 and ABCG1 in the macrophage. HDL can be remodeled by lipases such as hepatic lipase and endothelial lipase (EL), which hydrolyze HDL triglyceride and phospholipid, respectively. Mature HDL can transport its cholesterol directly to the liver via the hepatic scavenger receptor class B type 1 (SR-B1) receptor. Alternatively, cholesteryl ester transfer protein (CETP) can mediate transfer of cholesteryl esters from HDL particles to apoB-containing lipoproteins with subsequent uptake in the liver via the low-density lipoprotein receptor (LDLR). This “indirect” pathway is thought to predominate in humans. Hepatic cholesterol is secreted into the bile via the ABCG5 and ABCG8 transporters. Some reenters the circulation via intestinal reabsorption, and the remainder is excreted into the feces. Recent evidence suggests that the intestine may be able to directly excrete cholesterol, bypassing the liver entirely. VLDL—very low density lipoprotein

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