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A more recent version of this article appeared on March 1, 2008

Papers In Press, published online ahead of print November 21, 2007
J. Lipid Res., doi:10.1194/jlr.M700268-JLR200
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Submitted on June 11, 2007
Revised on October 11, 2007
Accepted on November 20, 2007

Effects of the cholesteryl ester transfer protein inhibitor torcetrapib on VLDL apolipoprotein E metabolism

John S. Millar, Margaret E. Brousseau, Margaret R. Diffenderfer, P. Hugh R. Barrett, Francine K. Welty, Jeffrey S. Cohn, Aisha Wilson, Megan L. Wolfe, Chorthip Nartsupha, Andres G. Digenio, James P. Mancuso, Gregory G. Dolnikowski, Ernst J. Schaefer, and Daniel J. Rader

Pharmacology, University of Pennsylvania, Philadelphia, PA 19104

Corresponding Author: jsmillar{at}mail.med.upenn.edu

Cholesteryl ester transfer protein (CETP) inhibition alters the lipid and apolipoprotein content of lipoproteins leading to changes in lipoprotein metabolism. The goal of this study was to determine changes in the metabolism of apoE within VLDL fraction in response to treatment with the CETP inhibitor torcetrapib. Subjects, pretreated with atorvastatin (n=9) or untreated (n=10), received placebo followed by torcetrapib (4 weeks each phase). At the end of each phase, subjects underwent a primed-constant infusion of deuterated leucine to determine VLDL apoE production rate (PR) and fractional catabolic rate (FCR). Torcetrapib treatment alone significantly reduced the VLDL apoE pool size (-28%). This was associated with an enhanced VLDL apoE FCR (77%) with no change in the VLDL apoE PR. Torcetrapib treatment in subjects pretreated with atorvastatin also resulted in a significantly increased VLDL apoE FCR (25%) that was offset by a significant increase in the VLDL apoE PR (21%) resulting in no change in the VLDL apoE pool size, despite a reduction in the VLDL apoB pool size. This resulted in an increased VLDL apoE content which may have enhanced direct removal of VLDL leading to a reduced LDL apoB PR in this group. These data indicate that, used alone, torcetrapib reduces the VLDL apoE pool size primarily by increasing the apoE FCR while leaving the content of apoE on VLDL unchanged. In contrast, torcetrapib added to atorvastatin treatment leaves the VLDL apoE pool size unchanged due to increases in both the VLDL apoE FCR and PR. Adding torcetrapib to atorvastatin treament significantly increased VLDL apoE content which may lead to decreased conversion of VLDL to LDL, reduced LDL production and lower levels of circulating VLDL and LDL.


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