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Journal of Lipid Research, Vol. 50, S189-S194, April 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Lipoprotein Metabolism

The role of reverse cholesterol transport in animals and humans and relationship to atherosclerosis

Daniel J. Rader^1,*,, Eric T. Alexander^*,, Ginny L. Weibel, Jeffrey Billheimer^* and George H. Rothblat

^* Institute for Translational Medicine and Therapeutics and Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, PA
Children's Hospital of Philadelphia, Philadelphia, PA

This work was supported by P01-HL22633 from the NHLBI.

Published, JLR Papers in Press, December 8, 2008.

¹ To whom correspondence should be addressed. e-mail: rader{at}mail.med.upenn.edu

ABSTRACT

Reverse cholesterol transport (RCT) is a term used to describe the efflux of excess cellular cholesterol from peripheral tissues and its return to the liver for excretion in the bile and ultimately the feces. It is believed to be a critical mechanism by which HDL exert a protective effect on the development of atherosclerosis. In this paradigm, cholesterol is effluxed from arterial macrophages to extracellular HDL-based acceptors through the action of transporters such as ABCA1 and ABCG1. After efflux to HDL, cholesterol may be esterified in the plasma by the enzyme lecithin:cholesterol acyltransferase and is ultimately transported from HDL to the liver, either directly via the scavenger receptor BI or after transfer to apolipoprotein B-containing lipoproteins by the cholesteryl ester transfer protein. Methods for assessing the integrated rate of macrophage RCT in animals have provided insights into the molecular regulation of the process and suggest that the dynamic rate of macrophage RCT is more strongly associated with atherosclerosis than the steady-state plasma concentration of HDL cholesterol. Promotion of macrophage RCT is a potential therapeutic approach to preventing or regressing atherosclerotic vascular disease, but robust measures of RCT in humans will be needed in order to confidently advance RCT-promoting therapies in clinical development.

Supplementary key words high density lipoproteins • macrophage • cholesterol efflux

Abbreviations: apo, apolipoprotein; CETP, cholesteryl ester transfer protein; HDL-C, HDL cholesterol; LCAT, lecithin:cholesterol acyltransferase; LXR, liver X receptor; RCT, reverse cholesterol transport; PPAR, peroxisome proliferator-activated receptor; SR-BI, scavenger receptor class B type I

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