MODULATION OF LIPOPROTEIN PRODUCTION IN HEP G2 CELLS BY FENOFIBRATE AND CLOFIBRATE

Fenofibrate and other fibrate derivatives are commonly used to treat hyperlipidemia. It is not yet clear how they exert their modulatory effects on plasma lipoproteins. To investigate whether these drugs act on the liver to primarily inhibit very low density lipoprotein production, we utilized the highly differentiated human hepatoma cell line, Hep G2. At concentrations greater than 15-mu-g/mL, fenofibrate caused a 30% decrease in secreted apolipoprotein B (apo B) after 4 days of treatment. Pulse-chase studies demonstrated that this was not due to inhibition of apo B synthesis. Triglyceride synthesis by fenofibrate-treated Hep G2 cells was decreased by 30%, and the amount secreted into the medium was reduced by 50%. At a low concentration of drug (5-mu-g/mL), triglyceride secretion was reduced markedly while apo B secretion remained unchanged. Thus, apo B secretion is less sensitive to fenofibrate than the synthesis and secretion of triglyceride, and may be secondary to changes in the latter. Fenofibrate has also been shown to raise plasma high density lipoprotein concentrations. We found that low concentrations of fenofibrate caused a 20-101% increase in secreted apolipoprotein AI (apo AI), and pulse-chase immunoprecipitation studies showed that this was due to an increase in apo AI synthesis. Fenofibrate was compared to clofibrate to investigate whether their relative effects on lipoprotein production in Hep G2 cells were comparable to their relative effects on plasma lipoproteins. Both fibrates decreased the secretion of apo B to the same extent, but only fenofibrate increased apo AI secretion. Fenofibrate was more effective than clofibrate in inhibiting the secretion of lipids by these cells. Thus, the known effects of fenofibrate on plasma lipoproteins can be attributed to its direct modulation of lipoprotein synthesis in the liver cell. Hep G2 cells may thus be useful in testing the relative efficacy of fibric acid derivatives in vitro.