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 transcriptional level by the quantity of bile salts fluxing through the enterohepatic circulation. Whether bile salts directly suppress 7 alpha-hydroxylase expression at the level of the hepatocyte or do so indirectly by promoting the release or absorption of an intestinal factor has not been resolved. We have investigated the ability of primary bile salts to suppress hepatic 7 alpha-hydroxylase expression in bile-diverted hamsters, Biliary diversion was accompanied by derepression of both hepatic 7 alpha-hydroxylase activity (4-5-fold) and bile salt secretion (similar to 3-fold). Derepression of hepatic 7 alpha-hydroxylase expression could be prevented by several interventions that increase the availability of bile salts within the hepatocyte including 1) overexpression of an exogenous 7 alpha-hydroxylase gene by adenovirus-mediated gene transfer, 2) obstruction of the common bile duct, and 3) intravenous infusions of taurocholate. In contrast, none of these interventions prevented derepression of hepatic cholesterol synthesis or significantly down-regulated hepatic low density lipoprotein receptor expression over the relatively short time course (24 h) of these studies. Together, these data indicate that primary bile salts contribute to the regulation of bile salt synthesis through feedback repression of 7 alpha-hydroxylase expression at the level of the hepatocyte.