Comparative regulation of hepatic sterol 27-hydroxylase and cholesterol 7 alpha-hydroxylase activities in the rat, guinea pig, and rabbit: Effects ofcholesterol and bile acids

The regulation of the classic and alternative bile acid synthetic pathways by key hepatic enzyme activities (microsomal cholesterol 7 alpha-hydroxylas e and mitochondrial sterol 27-hydroxylase, respectively) was examined in bi le acid depletion and replacement and cholesterol-feeding experiments with rats, guinea pigs, and rabbits. The bile acid pool was depleted by creating a bile fistula (BF) and collecting bile for 2 to 5 days, and it was replac ed by intraduodenal infusion of the major biliary bile acids (taurocholic a cid [TCA], glycochenodeoxycholic acid [GCDCA], and glycocholic acid [GCA] i n the rat, guinea pig, and rabbit, respectively) at rates equivalent to the measured hepatic flux of the bile acids. To study the effects of cholester ol, the animals were fed for 7 days on a basal diet with and without 2% cho lesterol. Cholesterol 7 alpha-hydroxylase and sterol 27-hydroxylase activit ies, measured by isotope incorporation assays, were related to bile acid ou tput and composition and hepatic cholesterol concentrations Intraduodenal i nfusion of bile acids increased the output of the tested bile acids, but di d not significantly change hepatic cholesterol concentrations and had no ef fect on sterol 27-hydroxylase activity. Neither bile acid depletion nor rep lacement affected sterol 27-hydroxylase activity when three different subst rates (cholesterol, 5 beta-cholestane-3 alpha,7 alpha-diol, and 5 beta-chol estane-3 alpha,7 alpha,12 alpha-triol) were tested. In contrast, feeding 2% cholesterol increased hepatic cholesterol concentrations in rats, guinea p igs, and rabbits threefold, twofold, and eightfold, respectively, and incre ased hepatic mitochondrial sterol a;l-hydroxylase activity (conversion of c holesterol to 27-hydroxycholesterol) in all three animal models. The stimul ation and feedback inhibition of cholesterol 7 alpha-hydroxylase activity b y bile acid depletion and replacement were observed in all three animal mod els, whereas the effect of cholesterol feeding was species-dependent (chole sterol 7 alpha-hydroxylase activity increased in the rat, did not change in the guinea pig, and was inhibited in the rabbit). Thus, in contrast to ste rol 27-hydroxylase, which was upregulated by cholesterol but not affected b y bile acid depletion and replacement in all three animal models, cholester ol 7 alpha-hydroxylase activity was controlled consistently and inversely b y the hepatic flux of bile acids, but was species-dependent in its response to a 1-week feeding with 2% cholesterol. Copyright(C) 1999 by W.B. Saunder s Company.