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Originally published In Press as doi:10.1194/jlr.M700268-JLR200 on November 21, 2007

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Journal of Lipid Research, Vol. 49, 543-549, March 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

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

John S. Millar1,*, Margaret E. Brousseau{dagger}, Margaret R. Diffenderfer{dagger}, P. Hugh R. Barrett§, Francine K. Welty{dagger},**, Jeffrey S. Cohn{dagger}{dagger}, Aisha Wilson§§, Megan L. Wolfe§§, Chorthip Nartsupha{dagger}, Peter M. Schaefer{dagger}, Andres G. Digenio***, James P. Mancuso***, Gregory G. Dolnikowski{dagger}{dagger}{dagger}, Ernst J. Schaefer{dagger} and Daniel J. Rader§§

* Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA
§§ Department of Medicine Center for Translational Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA
{dagger} Lipid Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University and Tufts-New England Medical Center, Boston, MA
§ Schools of Medicine and Pharmacology, University of Western Australia, Perth, Australia
** Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, MA
{dagger}{dagger} Nutrition and Metabolism Group, Heart Research Institute, Sydney, Australia
*** Clinical Research and Development, Pfizer, Inc., Groton, CT
{dagger}{dagger}{dagger} Mass Spectrometry Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA

Published, JLR Papers in Press, November 21, 2007.

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

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 D3-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.

Supplementary key words very low density lipoproteins • triglyceride • low density lipoproteins • lipoprotein kinetics


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