CETP Inhibitor Torcetrapib Promotes Reverse Cholesterol Transport in Obese Insulin‐Resistant CETP‐ApoB100 Transgenic Mice

Abstract

Insulin resistance and type 2 diabetes are associated with low HDL‐cholesterol (HDL‐c) levels, which would impair reverse cholesterol transport (RCT). A promising therapeutic strategy is to raise HDL with cholesteryl ester transfer protein (CETP) inhibitors, but their effects on RCT remains to be demonstrated in vivo. We therefore evaluated the effects of CETP inhibitor torcetrapib in CETP‐apolipoprotein (apo)B100 mice made obese and insulin resistant with a 60% high‐fat diet. High‐fat diet over 3 months increased body weight and homeostasis model of insulin resistance index by 30% and 846%, respectively ( p < 0.01 for both vs. chow‐fed mice). Total cholesterol (TC) increased by 46% and HDL‐c/TC ratio decreased by 28% (both p < 0.05). Compared to vehicle, high‐fat‐fed mice treated with torcetrapib (30 mg/kg/day, 3 weeks) showed increased HDL‐c levels and HDL‐c/TC ratio by 41% and 37% (both p < 0.05). Torcetrapib increased in vitro macrophage cholesterol efflux by 22% and in vivo RCT through a 118% increase in ³H‐bile acids fecal excretion after ³H‐cholesterol labeled macrophage injection ( p < 0.01 for both). Fecal total bile acids mass was also increased by 158% ( p < 0.001). In conclusion, CETP inhibition by torcetrapib improves RCT in CETP‐apoB100 mice. These results emphasize the potential of CETP inhibition to prevent cardiovascular diseases. Clin Trans Sci 2011; Volume 4: 414–420