Regulation of lipid metabolism and gene expression by fenofibrate in hamsters

Fenofibrate is a potent hypolipidemic agent that lowers plasma lipid levels and may thus decrease the incidence of atherosclerosis. Here we investigat ed the molecular mechanism of fenofibrate's hypolipidemic action by charact erizing its in vivo effects on the expression of mRNAs and the activities o f pivotal enzymes in cholesterol and triglyceride metabolism in the hamster . Treatment of hamsters with fenofibrate led to a dose-dependent reduction in serum cholesterol concentrations. Studies on the incorporation of [C-14] acetate and [C-14]mevalonate into cholesterol suggested that this effect oc curs primarily through inhibition of cholesterol biosynthesis at steps prio r to mevalonate. Fenofibrate decreased levels of hepatic enzyme activities and mRNAs for 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) synthase and HMG CoA reductase. A potential mechanism for transcriptional regulation of these enzymes is via SREBP-2 that we found to be suppressed 2-fold by fenof ibrate. Fenofibrate also lowered circulatory triglyceride levels. In keepin g with the effect, we observed strong suppression of fatty acid synthase, a cetyl-CoA carboxylase and apolipoprotein C-III mRNA and stimulation of lipo protein lipase and acyl-CoA oxidase mRNA in the liver of fenofibrate-treate d hamsters. These observations suggest that the effect of fenofibrate on tr iglyceride metabolism is likely to be a result of both decreased fatty acid synthesis and increased lipoprotein lipase and acyl-CoA oxidase gene expre ssion in the liver. Surprisingly, alterations in lipoprotein lipase, acyl-C oA oxidase, acetyl-CoA carboxylase, and apolipoprotein C-III could not be o bserved in hamster hepatocytes incubated with fenofibric acid in vitro. The se observations raise the possibility that changes in these genes may be se condary to the metabolic alterations occurring in animals but not in cultur ed cells and thus that the effect of fenofibrate on these genes may be indi rect. (C) 2001 Elsevier Science B.V. All rights reserved.