Increased bile acid pool inhibits cholesterol 7 alpha-hydroxylase in cholesterol-fed rabbits
Xu, G.; Salen, G.; Shefer, S.; Tint, G.S.; Kren, B.T.; Nguyen, L.B.; Steer, C.J.; Chen, T.S.; Salen, L.; Greenblatt, D.
Gastroenterology 113(6): 1958-1965
Background and Aims: Cholesterol feeding unexpectedly inhibits cholesterol 7alpha-hydroxylase in rabbits. The aim of this study was to explore the mechanism. Methods: Twenty male New Zealand white rabbits were fed regular chow with and without 2% cholesterol for 10 days followed by 7 days of bile drainage. The activities of hepatic cholesterol 7alpha-hydroxylase and sterol 27-hydroxylase that control bile acid synthesis in classic and alternative pathways were related to the size and composition of bile acid pool. Results: After feeding cholesterol, plasma and hepatic cholesterol concentrations increased, the bile acid pool doubled (from 254 +- 44 to 533 +- 51 mg; P < 0.001), cholesterol 7alpha-hydroxylase activity decreased 68% (P < 0.01), but sterol 27-hydroxylase activity increased 66% (P < 0.05) with increased cholic acid synthesis (P < 0.01). Bile drainage in the cholesterol-fed rabbits depleted the bile acid pool and stimulated down-regulated cholesterol 7alpha-hydroxylase activity 11.4-fold (P < 0.001), although hepatic cholesterol remained elevated. Hepatic sterol 27-hydroxylase activity was unaffected. Conclusions: Feeding cholesterol increased hepatic cholesterol and stimulated sterol 27-hydroxylase and alternative bile acid synthesis, which expanded the bile acid pool and inhibited cholesterol 7alpha-hydroxylase in rabbits. In distinction, hepatic sterol 27-hydroxylase was insensitive to changes in the bile acid pool.