Abstract
Hepatic 7alpha-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 7alpha-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 7alpha-hydroxylase expression in bile-diverted hamsters. Biliary diversion was accompanied by derepression of both hepatic 7alpha-hydroxylase activity (4-5-fold) and bile salt secretion (approximately 3-fold). Derepression of hepatic 7alpha-hydroxylase expression could be prevented by several interventions that increase the availability of bile salts within the hepatocyte including 1) overexpression of an exogenous 7alpha-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 7alpha-hydroxylase expression at the level of the hepatocyte.
Highlights
Exogenous 7␣-hydroxylase gene by adenovirus-medi- hydroxylase expression
Using adenovirus-mediated gene transfer, we recently noted that primary overexpression of an exogenous 7␣-hydroxylase gene in the hamster resulted in reciprocal down-regulation of the endogenous gene, suggesting that bile salts may directly regulate expression of the 7␣
Using adenovirus-mediated gene transfer, we recently noted that primary overexpression of an exogenous 7␣-hydroxylase gene in hamsters with an intact enterohepatic circulation resulted in reciprocal down-regulation of the endogenous gene
Summary
Exogenous 7␣-hydroxylase gene by adenovirus-medi- hydroxylase expression. obstruction of the common bile ated gene transfer, 2) obstruction of the common bile duct, which leads to an accumulation of bile salts within the duct, and 3) intravenous infusions of taurocholate. Paradoxically increases hepatic 7␣-hydroxylase activity 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␣-hydroxylase expression at the level of the hepatocyte. Using adenovirus-mediated gene transfer, we recently noted that primary overexpression of an exogenous 7␣-hydroxylase gene in the hamster resulted in reciprocal down-regulation of the endogenous gene, suggesting that bile salts may directly regulate expression of the 7␣-
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