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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1132.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Inhibition of Cholesteryl Ester Transfer Protein by Torcetrapib Modestly Increases Macrophage Cholesterol Efflux to HDL

Laurent Yvan-Charvet; Fumihiko Matsuura; Nan Wang; Mark J. Bamberger; Tu Nguyen; Franz Rinninger; Xian-Cheng Jiang; Charles L. Shear; Alan R. Tall

From the Division of Molecular Medicine, Department of Medicine (L.Y.C., F.M., N.W., A.R.T.), Columbia University, New York; University Hospital Hamburg Eppendorf (F.R.), Hamburg, Germany; Department of Anatomy and Cell Biology and Scientific Computing Center (X.C.J.), State University of New York, Downstate Medical Center, Brooklyn; and Pfizer Global Research and Development (M.B., T.N., C.L.S.), New London, Conn.

Correspondence to Laurent Yvan-Charvet, Division of Molecular Medicine, Department of Medicine, Columbia University, 630 West 168^th St, New York, NY 10032. E-mail ly2159{at}columbia.edu

Objective— This study examines the effects of pharmacological inhibition of cholesteryl ester transfer protein (CETP) on the ability of high-density lipoprotein particles (HDL) to promote net cholesterol efflux from human THP-1 macrophage foam cells.

Methods and Results— Two groups of 8 healthy, moderately hyperlipidemic subjects received the CETP inhibitor torcetrapib at 60 or 120 mg daily for 8 weeks. Torcetrapib increased HDL cholesterol levels in both groups by 50% and 60%, respectively. Compared with baseline, torcetrapib 60 mg daily increased HDL-mediated net cholesterol efflux from foam cells primarily by increasing HDL concentrations, whereas 120 mg daily torcetrapib increased cholesterol efflux both by increasing HDL concentration and by causing increased efflux at matched HDL concentrations. There was an increased content of lecithin:cholesterol acyltransferase (LCAT) and apolipoprotein E (apoE) in HDL-2 only at the 120 mg dose. ABCG1 activity was responsible for 40% to 50% of net cholesterol efflux to both control and T-HDL.

Conclusions— These data indicate that inhibition of CETP by torcetrapib causes a modest increase in the ability of HDL to promote net cholesterol efflux at the 60 mg dose, and a more dramatic increase at the 120 mg dose in association with enhanced particle functionality.

This study shows that CETP inhibition via torcetrapib has a dose-related effect on the ability of HDL to promote cholesterol efflux from macrophage foam cells in an ABCG1-dependent fashion.

Key Words: CETP • torcetrapib • high-density lipoprotein • ABC transporters • macrophages

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