SIMVASTATIN-INDUCED DECREASE IN THE TRANSFER OF CHOLESTEROL ESTERS FROM HIGH-DENSITY-LIPOPROTEINS TO VERY LOW AND LOW-DENSITY LIPOPROTEINS IN NORMOLIPIDEMIC SUBJECTS

Hyperlipidemic patients often have an accelerated esterified cholester ol transfer (ECT) from high density lipoproteins (HDL) to very low (VL DL) and low density lipoproteins (LDL). We investigated the effect of simvastatin on ECT in twelve normolipidemic subjects. After 6 weeks of simvastatin administration, ECT was decreased by 23%. To determine th e mechanism of action of simvastatin, we measured ECT in different rec ombination experiments, using an isotopic assay in which the transfer of labelled EC from HDL to VLDL/LDL was determined. When HDL of the tr eated subjects were incubated with VLDL/LDL and CETP fractions isolate d from control plasma, no effect of simvastatin was observed, indicati ng that the drug did not alter the HDL-dependent ECT. This might be ex pected since simvastatin induced only minor modifications of HDL struc ture. When HDL and VLDL/LDL of control plasma were incubated with CETP fractions of the treated subjects, a clear reduction of ECT occurred after simvastatin administration. The decrease of plasma transfer acti vity was correlated to that of CETP concentration and accounted for th e simvastatin-induced lowering of ECT. The diminution of plasma CETP w as correlated to that of the apo B-containing lipoproteins concentrati on. This finding confirms previous reports suggesting a relationship b etween LDL level and CETP activity. In conclusion, our work shows that simvastatin administration results in a decrease of ECT and that this effect occurs through a lowering of plasma CETP activity.