Rapid modulation of lipogenesis by clofibrate in rat and monkey hepatocytes.
Previous studies have proposed various possible mechanisms for the hypolipidemic actions of clofibrate. In the present study, isolated liver cells freshly prepared from rats and squirrel monkeys were used to investigate the acute effects of sodium clofibrate (sodium chlorophenoxyisobutyrate) on hepatic lipogenesis. Incubation of liver cells with levels of the drug (1 mM) known to lower plasma lipid level in vivo produced a rapid inhibition of [14C]acetate incorporation into cellular lipids. The degree of inhibition caused by the drug was not diminished by preincubation with an excess of unlabeled acetate. Conversion of [14C]acetate to 14CO2 was not significantly altered by sodium clofibrate at 1--3 mM levels, but was decreased at 5--10 mM levels. Incorporation of [14C]acetate into all lipid classes was suppressed by this agent, but inhibition of sterol synthesis was more pronounced than that of fatty acids. Sodium clofibrate (1 mM) reduced the synthesis of sterols from either labeled acetate or labeled mevalonate to a similar degree, but the decline was augmented in each case by a 30-min preincubation of the cells with sodium clofibrate. Addition of fatty acids to cell incubations stimulated sterol generation from [14C] acetate or from [3H] mevalonate, but did not reverse the inhibitory effects of the drug. These results suggest (a) the sodium clofibrate rapidly interferes with hepatic fatty acid and sterol synthesis by direct or indirect actions at diverse loci; (b) that these effects probably occur after acetyl-CoA formation and do not stem from precursor pool dilution; (c) that sodium clofibrate diminishes sterol production at post-mevalonic and perhaps also at pre-mevalonic sites; (d) that a similar pattern of inhibition occurs with sodium clofibrate in  the presence of added fatty acids; and (e) that rat and primate livers demonstrate similar metabolic responses to the drug.
D000085:Acetates / Q000378:metabolism; D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis; D002994:Clofibrate / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D000882:Haplorhini; D008055:Lipids / Q000096:biosynthesis*; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D008798:Mevalonic Acid / Q000378:metabolism; D010169:Palmitic Acids / Q000494:pharmacology; D051381:Rats; D012453:Saimiri; D013261:Sterols / Q000096:biosynthesis
D000085:Acetates; D008055:Lipids; D010169:Palmitic Acids; D013261:Sterols; D002784:Cholesterol; D002994:Clofibrate; D008798:Mevalonic Acid