Inhibition of cholesteryl ester transfer protein activity in hamsters alters HDL lipid composition

Abstract

We investigated the role of cholesteryl ester transfer protein (CETP) in hamsters by using a monoclonal antibody (MAb) that inhibited hamster CETP activity. MAbs were prepared against partially purified human CETP and screened for inhibition of 3H-cholesterol oleate (CE) transfer from LDL to HDL in the presence of human plasma bottom fraction ( d > 1.21 g/ml). Antibody 1C4 inhibited CE transfer activity in both human plasma bottom fraction (IC 50 = ∼4 μg/ml) and in whole plasma from male Golden Syrian hamsters (IC 50 = ∼30 μg/ml). Purified MAb I C4 was injected into chow- and cholesterol-fed hamsters, and blood was collected for analysis of plasma CETP activity and HDL lipid composition. Plasma CETP activity was inhibited by 70%–80% at all times up to 24 h following injection of 500 μg MAb 1C4 (∼3.7 mg/kg). The amount of antibody required for 50% inhibition at 24 h post-injection was 200 μg (∼ 1.5 mg/kg). Inhibition of hamster CETP activity in vivo increased hamster HDL cholesterol by 33% ( P < 0.0001), increased HDL-CE by 31% ( P < 0.0001) and decreased HDL-triglyceride by 42% ( P < 0.0001) ( n = 36) as determined following isolation of HDL by ultracentrifugation. An increase in HDL cholesterol and a redistribution of cholesterol to a larger HDL particle were also observed following fast protein liquid chromatography (FPLC) gel filtration of plasma lipoproteins. These results demonstrate that inhibition of CETP activity in hamsters alters HDL lipid composition and particle size and further demonstrate the utility of hamsters as a model for CETP inhibition.