INHIBITION OF CHOLESTERYL ESTER TRANSFER PROTEIN-ACTIVITY IN HAMSTERSALTERS HDL LIPID-COMPOSITION

We investigated the role of cholesteryl ester transfer protein (CETP) in hamsters by using a monoclonal antibody (MAb) that inhibited hamste r CETP activity. MAbs were prepared against partially purified human C ETP and screened for inhibition of H-3-cholesteryl oleate (CE) transfe r 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 (IC50 = similar to 4 mu g/ml) and in whole pla sma from male Golden Syrian hamsters (IC50 = similar to 30 mu g/ml). P urified MAb 1C4 was injected into chow- and cholesterol-fed hamsters, and blood was collected for analysis of plasma CETP activity and HDL l ipid composition. Plasma CETP activity was inhibited by 70%-80% at all times up to 24 h following injection of 500 mu g MAb 1C4 (similar to 3.7 mg/kg). The amount of antibody required for 50% inhibition at 24 h post-injection was 200 mu g (similar to 1.5 mg/kg). Inhibition of ham ster CETP activity in vivo increased hamster HDL cholesterol by 33% (P < 0.0001), increased HDL-CE by 31% (P < 0.0001) and decreased HDL-tri glyceride by 42% (P < 0.0001) (n = 36) as determined following isolati on of HDL by ultracentrifugation. An increase in HDL cholesterol and a redistribution of cholesterol to a larger HDL particle were also obse rved following fast protein liquid chromatography (FPLC) gel filtratio n of plasma lipoproteins. These results demonstrate that inhibition of CETP activity in hamsters alters HDL lipid composition and particle s ize and further demonstrate the utility of hamsters as a model for CET P inhibition.