Increase in hepatic expression of SREBP-2 by gemfibrozil administration torats

It is well known that gemfibrozil increases the biliary output of cholester ol and phospholipids, but we have little knowledge about the impact these c hanges have on liver cholesterol and phospholipid biosynthetic pathways. In the present study, no changes were detected in liver lipids and CTP:phosph ocholine cytidylyltransferase after gemfibrozil administration to rats. On the contrary, 3-hydroxy-3-methylglutaryl-CoA reductase mRNA (9.9-fold) and Rd activity (16.7-fold) and phosphatidate phosphohydrolase activity (1.7-fo ld) increased, while plasma apo B-cholesterol (40%) and triglyceride (43%) levels decreased. As a part of a compensatory homeostatic response, we repo rt for the first time that gemfibrozil administration to rats increased the hepatic sterol regulatory element binding protein-2 (SREBP-2) mRNA (2.9-fo ld) and mature protein (2.2-fold) levels. An early increase in the transcri ptional activity of SREBP-2 elicited by gemfibrozil administration might be responsible for the observed changes in HMG-CoA reductase, phosphatidate p hosphohydrolase, and SREBP-2 expression. (C) 2001 Elsevier Science Inc. All rights reserved.