Published Online
on August 20, 2007

A more recent version of this article appeared on September 11, 2007

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Submitted on March 21, 2007
Accepted on June 29, 2007

Expression of Cholesteryl Ester Transfer Protein in Mice Promotes Macrophage Reverse Cholesterol Transport

Hiroyuki Tanigawa MD, PhD, Jeffrey T. Billheimer PhD, Jun-ichiro Tohyama MD, YuZhen Zhang MD, PhD, George Rothblat PhD, and Daniel J. Rader MD^*

From the Institute for Translational Medicine and Therapeutics and the Cardiovascular Institute (H.T., J.T.B., J.-i.T., Y.Z.Z., D.J.R.), University of Pennsylvania School of Medicine, Philadelphia, and the Children’s Hospital of Philadelphia (G.R.), Pa.

^* To whom correspondence should be addressed. E-mail: rader{at}mail.med.upenn.edu.

Background—Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from high-density lipoproteins to apolipoprotein (apo) B–containing lipoproteins and in humans plays an important role in lipoprotein metabolism. However, the role that CETP plays in mediation of reverse cholesterol transport (RCT) remains unclear. We used a validated in vivo assay of macrophage RCT to test the effect of CETP expression in mice (which naturally lack CETP) on macrophage RCT, including in mice that lack the low-density lipoprotein receptor or the scavenger receptor class B, type I.

Method and Results—A vector based on adeno-associated virus serotype 8 (AAV8) with a liver-specific thyroglobulin promoter was used to stably express human CETP in livers of mice and was compared with an AAV8-lacZ control vector. The RCT assay was performed 4 weeks after vector injection and involved the intraperitoneal injection of acetylated low-density lipoprotein cholesterol–loaded and ³H-cholesterol–labeled J774 macrophages in mice with plasma sampling at several time points, liver and bile sampling at 48 hours, and continuous fecal collection to measure ³H-sterol as an integrated readout of macrophage RCT. In apobec-1–null mice, CETP expression reduced plasma high-density lipoprotein cholesterol levels but significantly increased fecal ³H-sterol excretion. In low-density lipoprotein receptor/apobec-1 double-null mice, CETP expression reduced high-density lipoprotein cholesterol levels and had no effect on fecal ³H-sterol excretion. Finally, in scavenger receptor class B, type I–null mice, CETP expression reduced high-density lipoprotein cholesterol levels and significantly increased fecal ³H-sterol excretion.

Conclusion—The present results demonstrate that CETP expression promotes macrophage RCT in mice, that this effect is dependent on the low-density lipoprotein receptor, and that CETP expression restores to normal the impaired RCT in mice deficient in scavenger receptor class B, type I.

Key words: atherosclerosis • cholesterol • lipids • lipoproteins • macrophages

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