FEEDBACK-REGULATION OF HEPATIC 7-ALPHA-HYDROXYLASE EXPRESSION BY BILE-SALTS IN THE HAMSTER

Hepatic 7 alpha-hydroxylase activity appears to be regulated at the tr anscriptional level by the quantity of bile salts fluxing through the enterohepatic circulation. Whether bile salts directly suppress 7 alph a-hydroxylase expression at the level of the hepatocyte or do so indir ectly by promoting the release or absorption of an intestinal factor h as not been resolved. We have investigated the ability of primary bile salts to suppress hepatic 7 alpha-hydroxylase expression in bile-dive rted hamsters, Biliary diversion was accompanied by derepression of bo th hepatic 7 alpha-hydroxylase activity (4-5-fold) and bile salt secre tion (similar to 3-fold). Derepression of hepatic 7 alpha-hydroxylase expression could be prevented by several interventions that increase t he availability of bile salts within the hepatocyte including 1) overe xpression of an exogenous 7 alpha-hydroxylase gene by adenovirus-media ted gene transfer, 2) obstruction of the common bile duct, and 3) intr avenous infusions of taurocholate. In contrast, none of these interven tions prevented derepression of hepatic cholesterol synthesis or signi ficantly down-regulated hepatic low density lipoprotein receptor expre ssion over the relatively short time course (24 h) of these studies. T ogether, these data indicate that primary bile salts contribute to the regulation of bile salt synthesis through feedback repression of 7 al pha-hydroxylase expression at the level of the hepatocyte.