Stimulation of Bile Acid Biosynthesis by Clofibrate

Abstract

The hypocholesterolemic effect of clofibrate (ethyl p-chlorophenoxyisobutyrate) was investigated in rats under conditions of severe hypercholesterolemia produced by administering relatively large amounts of cholesterol. The rats were fed a normal chow (control rats) or a chow containing 0.25% clofibrate (treated rats) for 14 d, then Triton WR-1339 was administered intraperitoneally (100 mg/100 g body weight). Four days after this administration, the blood cholesterol level of the control rats was markedly higher at 9335 mg/dl serum, while the level of the treated rats was about 30% lower than that of the control. The bile acid level in pooled 24-h bile was proportionally higher (about 1.3-fold) in the treated rats than that in the control. In the initial bile (within 4 h after bile duct cannulation), the bile acid level in the treated bile was 2.4 times higher than in the control bile. [4-¹⁴C] Cholesterol and 100 mg non-labeled cholesterol were injected intraperitoneally into the control and clofibratetreated rats, and the radioactivities excreted into the bile were determined. The early bile (within 8 h) of the treated rats contained 5.6-fold higher radioactivity than the control bile, and the radioactivities were largely recovered in the bile acid fraction ; scarcely any radioactivity was found in the cholesterol fraction. From these results, we conclude that one of the mechanisms by which the hypocholesterolemic effect of clofibrate is mediated is stimulation of the degradation of cholesterol, that is, stimulation of the biosynthesis of bile acids.