INCREASED BILE-ACID POOL INHIBITS CHOLESTEROL 7-ALPHA-HYDROXYLASE IN CHOLESTEROL-FED RABBITS

Background & Aims: Cholesterol feeding unexpectedly inhibits cholester ol 7 alpha-hydroxylase in rabbits. The aim of this study was to explor e the mechanism. Methods: Twenty male New Zealand white rabbits were f ed regular chow with and without 2% cholesterol for 10 days followed b y 7 days of bile drainage. The activities of hepatic cholesterol 7 alp ha-hydroxylase and sterol 27-hydroxylase that control bile acid synthe sis in classic and alternative pathways were related to the size and c omposition of bile acid pool. Results: After feeding cholesterol, plas ma and hepatic cholesterol concentrations increased, the bile acid poo l doubled (from 254 +/- 44 to 533 +/- 51 mg; P < 0.001), cholesterol 7 alpha-hydroxylase activity decreased 68% (P < 0.01), but sterol 27-hy droxylase activity increased 66% (P < 0.05) with increased cholic acid synthesis (P < 0.01). Bile drainage in the cholesterol-fed rabbits de pleted the bile acid pool and stimulated down-regulated cholesterol 7 alpha-hydroxylase activity 11.4-fold (P < 0.001), although hepatic cho lesterol remained elevated. Hepatic sterol 27-hydroxylase activity was unaffected. Conclusions: Feeding cholesterol increased hepatic choles terol and stimulated sterol 27-hydroxylase and alternative bile acid s ynthesis, which expanded the bile acid pool and inhibited cholesterol 7 alpha-hydroxylase in rabbits. In distinction, hepatic sterol 27-hydr oxylase was insensitive to changes in the bile acid pool.