Inhibition of cholesteryl ester transfer protein by torcetrapib modestly increases macrophage cholesterol efflux to HDL

被引:161
作者
Yvan-Charvet, Laurent
Matsuura, Fumihiko
Wang, Nan
Bamberger, Mark J.
Nguyen, Tu
Rinninger, Franz
Jiang, Xian-Cheng
Shear, Charles L.
Tall, Alan R.
机构
[1] Columbia Univ, Dept Med, Div Mol Med, New York, NY 10032 USA
[2] Univ Hamburg, Hosp Eppendorf, D-20246 Hamburg, Germany
[3] Suny Downstate Med Ctr, Dept Anat & Cell Biol, Brooklyn, NY 11203 USA
[4] Suny Downstate Med Ctr, Ctr Comp Sci, Brooklyn, NY 11203 USA
[5] Pfizer Global Res & Dev, New London, CT USA
关键词
CETP; torcetrapib; high-density lipoprotein; ABC transporters; macrophages;
D O I
10.1161/ATVBAHA.106.138347
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:1132 / 1138
页数:7
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