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,Peter M Schaefer,Andres G Digenio,James P Mancuso,Gregory G Dolnikowski,Ernst J Schaefer,Daniel J Rader

doi:10.1194/jlr.m700268-jlr200

Abstract

Cholesteryl ester transfer protein (CETP) inhibition leads to changes in lipoprotein metabolism. We studied the effect of the CETP inhibitor torcetrapib on VLDL apolipoprotein E (apoE) metabolism. Subjects, pretreated with atorvastatin (n = 9) or untreated (n = 10), received placebo followed by torcetrapib (4 weeks each). After each treatment, subjects underwent a primed-constant infusion of D(3)-leucine to determine the VLDL apoE production rate (PR) and fractional catabolic rate (FCR). Torcetrapib alone reduced the VLDL apoE pool size (PS) (-28%) by increasing the VLDL apoE FCR (77%) and leaving the VLDL apoE PR unchanged. In subjects pretreated with atorvastatin, torcetrapib increased the VLDL apoE FCR (25%) and PR (21%). This left the VLDL apoE PS unchanged but increased the VLDL apoE content, likely enhancing VLDL clearance and reducing LDL production in this group. Used alone, torcetrapib reduces the VLDL apoE PS by increasing the apoE FCR while leaving the VLDL apoE content unchanged. In contrast, torcetrapib added to atorvastatin treatment increases both the VLDL apoE FCR and PR, leaving the VLDL apoE PS unchanged. Adding torcetrapib to atorvastatin treatment increases the VLDL apoE content, likely leading to decreased conversion of VLDL to LDL, reduced LDL production, and lower levels of circulating VLDL and LDL.

Highlights

Cholesteryl ester transfer protein (CETP) inhibition leads to changes in lipoprotein metabolism
The change in lipoprotein mass and composition might be expected to alter the distribution of exchangeable apolipoproteins, including apolipoprotein E, between VLDL and HDL, because the affinity of these proteins for lipoproteins is affected by lipoprotein size and composition [4]
Consistent with this hypothesis, we previously reported that the apolipoprotein E (apoE) content of newly secreted VLDL can influence the LDL production rate (PR), with a reduced VLDL apoE content being associated with increased LDL apoB-100 production [6]

Summary

Introduction

Cholesteryl ester transfer protein (CETP) inhibition leads to changes in lipoprotein metabolism. We studied the effect of the CETP inhibitor torcetrapib on VLDL apolipoprotein E (apoE) metabolism. In subjects pretreated with atorvastatin, torcetrapib increased the VLDL apoE FCR (25%) and PR (21%). This left the VLDL apoE PS unchanged but increased the VLDL apoE content, likely enhancing VLDL clearance and reducing LDL production in this group. Adding torcetrapib to atorvastatin treatment increases the VLDL apoE content, likely leading to decreased conversion of VLDL to LDL, reduced LDL production, and lower levels of circulating VLDL and LDL.—Millar, J. Effects of the cholesteryl ester transfer protein inhibitor torcetrapib on VLDL apolipoprotein E metabolism. CETP inhibitors alter lipoprotein metabolism by reducing the CETP-mediated transfer of cholesteryl ester and triglyceride between HDL and VLDL [1]. This article is available online at http://www.jlr.org

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