DIFFERENT FEEDBACK-REGULATION OF HEPATIC CHOLESTEROL AND BILE-ACID SYNTHESIS BY GLYCODEOXYCHOLIC ACID IN RABBITS

Background: To explore the sexual difference in the feedback regulation of hepatic bile acid synthesis, glycodeoxycholic acid (GDCA) was administered to 15 male and 14 female rabbits. Methods: After bile diversion, GDCA equivalent to the hepatic bile acid influx was infused intraduodenally. Biliary cholic acid output represented bile acid synthesis. Hepatic 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase and cholesterol 7α-hydroxylase activities and steady state messenger RNA (mRNA) levels were determined. Results: GDCA inhibited bile acid synthesis less in female than in male rabbits. Hepatic HMG-CoA reductase activity decreased 39% in males, but increased 48% in females. Hepatic cholesterol 7α-hydroxylase activity decreased similarly in males and females, and mRNA levels decreased 86% in males but were unchanged in females. Conclusions: (1) Total bile diversion stimulated both hepatic cholesterol and bile acid synthesis by activating the rate-controlling enzymes and increasing mRNA levels. (2) GDCA decreased mRNA levels of HMG-CoA reductase and cholesterol 7α-hydroxylase in males, but mRNA levels did not decrease in females. (3) Bile acid synthesis was sustained in females because continued biosynthesis of cholesterol provided a substrate for cholesterol 7α-hydroxylase and stimulus for enzyme formation. © 1993.