MECHANISM OF THE GEMFIBROZIL-INDUCED DECREASE IN THE TRANSFER OF CHOLESTEROL ESTERS FROM HIGH-DENSITY-LIPOPROTEINS TO VERY-LOW AND LOW-DENSITY LIPOPROTEINS

To better understand the effects of lipid-lowering drugs on the transf er of esterified cholesterol (EC) between lipoproteins, we investigate d the changes induced by gemfibrozil administration on the unidirectio nal transfer of radiolabeled EC from high density lipoproteins (HDL) t o very low (VLDL) and low density lipoproteins (LDL) in 10 normolipide mic subjects. HDL, VLDL/LDL, and the d > 1.21 g/ml fraction containing cholesterol ester transfer protein (CETP) were isolated from plasma b efore and after 8 weeks of gemfibrozil administration. The same fracti onation procedure was applied to aliquots of a control plasma pool to permit different recombination experiments. When the CETP fractions of the subjects studied were incubated in the presence of control HDL an d VLDL/LDL, no effect of gemfibrozil was observed on the rate of EC tr ansfer, indicating that the drug did not induce any change in the plas ma transfer activity. When HDL of the subjects studied were recombined with the CETP fraction and VLDL/LDL isolated from the control plasma pool, the rate of EC transfer was decreased by 43% after gemfibrozil a dministration. Thus, the drug induced a decrease in the HDL-dependent transfer of EC. This effect was accompanied by a decrease of the trigl yceride (TG)/EC ratio in HDL, a decrease of the Stokes radius of large HDL determined after gradient gel electrophoresis, and an increase of the HDL viscosity. Since both HDL size and viscosity are in part depe ndent upon their TG/EC ratio, further investigations will be necessary to answer the question as to whether one of these structural criteria is predominant for the regulation of the HDL dependent transfer of EC . (C) 1994 Academic Press, Inc.