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.
Highlights
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 the feces
The primary biomedical interest in RCT has been with regard to atherosclerosis; it has long been believed that RCT is the major mechanism by which HDL protects against atherosclerotic cardiovascular disease
scavenger receptor class B type I (SR-BI) knockout mice, cholesteryl ester transfer protein (CETP) expression restored the rate of macrophage RCT to normal by providing a “bypass” route for HDL-cholesteryl ester to get to the liver
Summary
Lecithin:cholesterol acyltransferase (LCAT) converts newly effluxed free cholesterol associated with HDL into cholesteryl ester. Overexpression of LCAT modestly reduced macrophage RCT in vivo despite the marked increase in HDL-C levels, at least in part due to a reduction in lipid-poor apoA-I and cholesterol efflux via ABCA1 [23]. The likely explanation for these observations was provided by the experimental demonstration that overexpression of hepatic SR-BI promoted macrophage RCT, whereas ablation of SR-BI reduced macrophage RCT [31] This is probably the best example of the concept that “flux” of cholesterol through the RCT pathway is a more important determinant of atherosclerosis than steady-state HDL-C concentrations. SR-BI knockout mice, CETP expression restored the rate of macrophage RCT to normal by providing a “bypass” route for HDL-cholesteryl ester to get to the liver. Some HDL-C may be directly transferred to the intestine and excreted without first passing through the liver [40], which would represent a change in the classic RCT paradigm
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