RT Journal Article
SR Electronic
T1 REGULATION OF HEPATIC CHOLESTEROL BIOSYNTHESIS BY CLOFIBRATE ADMINISTRATION
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 361
OP 370
VO 178
IS 2
A1 LAWRENCE W. WHITE
YR 1971
UL http://jpet.aspetjournals.org/content/178/2/361.abstract
AB Clofibrate decreases plasma cholesterol concentration and inhibits hepatic cholesterol biosynthesis. However, the biochemical site of inhibition of cholesterol synthesis has not been defined. To localize the site of action of clofibrate, liver slices and cell-free fractions were prepared from control rats and rats fed a diet containing 0.3% clofibrate for 1 to 18 days. Clofibrate administration was associated with depressed incorporation of (14C)pyruvate or (14C)acetate into cholesterol or mevalonate by liver slices. There was no effect on incorporation of substrate into CO2 or fatty acids and no influence on steps between mevalonate and cholesterol. In fractionated liver homogenates, incorporation of (14C)acetate, (14C)acetyl-CoA, or (14C)3-hydroxy-3-methylglutaryl (HMG-CoA) into mevalonate was depressed by clofibrate treatment. HMG-CoA condensing enzyme was not affected. Changes in 14C incorporation into 11MG and mevalonate corresponded to changes in product synthesis. These findings indicate that clofibrate regulates hepatic cholesterol biosynthesis by inhibiting microsomal reduction of HMG-CoA to mevalonate. Additional changes, dependent on soluble factors, include depression of acetate activation and increased acetoacetate formation. © 1971 by The Williams & Wilkins Co.