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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:2177.)
© 2005 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Cholesteryl Ester Transfer Protein Directly Mediates Selective Uptake of High Density Lipoprotein Cholesteryl Esters by the Liver

Andre Gauthier; Paulina Lau; Xiaohui Zha; Ross Milne; Ruth McPherson

From Lipoprotein and Atherosclerosis Research Group & Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Canada.

Address correspondence to Ruth McPherson, University of Ottawa Heart Institute, H453, 40 Ruskin St, Ottawa, ON Canada K1Y 4W7. E-mail rmcpherson{at}ottawaheart.ca

Objective— To determine whether cholesteryl ester transfer protein (CETP) directly mediates selective uptake of high-density lipoprotein (HDL)-cholesteryl ester (CE) by hepatocytes and to quantify the effects of the CETP inhibitor, torcetrapib, on this process.

Methods and Results— Using adenovirus-mediated CETP (ad-CETP) expression in primary mouse hepatocytes from either wild-type, low-density lipoprotein (LDL) receptor–/– or SR-BI–/– mice, we demonstrate that CETP enhances the selective accumulation of HDL-derived ³H-CE independently of known lipoprotein receptors. Addition of torcetrapib to the media did not impair the ability of cell-associated CETP to enhance CE uptake but reduced the ability of exogenously added CETP to increase selective uptake by up to 80%. When mice were infected with ad-CETP or ad-Luciferase and treated with daily intravenous injections of torcetrapib or vehicle, hepatic CETP expression resulted in a 50% decrease in HDL cholesterol in vehicle-treated animals versus a 33% decrease in HDL cholesterol in mice treated with torcetrapib.

Conclusions— CETP mediates selective uptake of HDL-CE by hepatocytes by both torcetrapib-sensitive (exogenous CETP) and torcetrapib-insensitive (cell-associated CETP) mechanisms. Hepatic expression of CETP in vivo results in a marked decrease in cholesterol in particles in the HDL density range, consistent with a physiological role for hepatocyte CETP in selective uptake.

These studies demonstrate that cholesteryl ester transfer protein (CETP) mediates the selective uptake of IIDL-derived cholesteryl esters by hepatocytes both in vitro and in vivo by a mechanism that is independent of other lipoprotein receptors and which is only partially sensitive to inhibition by torcetrapib.

Key Words: CETP • selective uptake • torcetrapib • lipoproteins • HDL

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