Increased bile acid pool inhibits cholesterol 7 alpha-hydroxylase in cholesterol-fed rabbits.

BACKGROUND & AIMS: Cholesterol feeding unexpectedly inhibits cholesterol 7 alpha-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 7 alpha-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 7 alpha-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 7 alpha-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 7 alpha-hydroxylase in rabbits. In distinction, hepatic sterol 27-hydroxylase was insensitive to changes in the bile acid pool.

Treatment of the cholesterol biosynthetic defect in Smith-Lemli-Opitz syndrome reproduced in rats by BM 15.766.

BACKGROUND & AIMS: The Smith-Lemli-Opitz syndrome is a recessive inherited disorder characterized by neurological developmental defects and dysmorphic features with a defect in cholesterol synthesis at the conversion of 7-dehydrocholesterol to cholesterol. BM 15.766 inhibits 7-dehydrocholesterol-delta 7-reductase and reproduces the biochemical defect. The aim of this study was to investigate the effects of cholesterol, cholic acid, and lovastatin feeding on rats fed BM 15.766. METHODS: Plasma cholesterol and 7-dehydrocholesterol concentrations were related to the hepatic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. RESULTS: With the inhibitor treatment, plasma cholesterol concentrations decreased 67%; 7-dehydrocholesterol concentrations increased from trace to 17 mg/dL; and hepatic HMG-CoA reductase activity and messenger RNA levels were stimulated 74% and two times, respectively. In inhibitor-treated rats, feeding cholesterol increased plasma cholesterol concentrations 3.7 times, decreased 7-dehydrocholesterol concentrations 88%, and reduced elevated HMG-CoA reductase activity and messenger RNA levels 74% and 49%. Feeding cholic acid increased plasma cholesterol without reducing 7-dehydrocholesterol concentrations. The combination of cholic acid and cholesterol enhanced plasma cholesterol 9.5 times without decreasing 7-dehydrocholesterol levels. Feeding lovastatin depressed plasma cholesterol further without reducing 7-dehydrocholesterol levels. CONCLUSIONS: Cholesterol is essential to correct abnormal cholesterol synthesis induced by BM 15.766 in rats by expanding the pool and inhibiting HMG-CoA reductase. Neither cholic acid nor lovastatin are effective separately, but cholic acid plus cholesterol may offer some additional benefit.