Regulation of classic and alternative bile acid synthesis in hypercholesterolemic rabbits: effects of cholesterol feeding and bile acid depletion

The effect of cholesterol feeding (3 g/day) on bile acid synthesis was examined in 10 New Zealand white rabbits (NZW), 8 Watanabe heterozygous and 10 homozy- gous rabbits with partial and complete deficiencies of LDL receptors. After 10 days of cholesterol feeding, bile fistulas were constructed and bile acid pool sizes were measured. Cholesterol feeding increased plasma and hepatic choles- terol levels in all rabbit groups. Baseline bile acid pool sizes were smaller ( P , 0.01) in heterozygotes (139 6 3 mg) and homozygotes (124 6 30 mg) than NZW rabbits (254 6 44 mg). After feeding cholesterol, bile acid pool sizes doubled with increased cholic acid synthesis in NZW and, to a lesser extent, in Watanabe heterozygous rabbits but not in ho- mozygotes. Baseline cholesterol 7 a -hydroxylase activity in NZW and heterozygotes declined 69% and 53% ( P , 0.001), respectively, after cholesterol feeding. Sterol 27-hydroxylase activity reflecting alternative bile acid synthesis increased 66% ( P , 0.01) in NZW and 37% in Watanabe heterozygotes but not in homozygotes after feeding cholesterol. Bile fistula drainage stimulated cholesterol 7 a -hydroxylase activity but not sterol 27-hydroxylase activity in all thr ee rabbit groups. These results demonstrated that dietary choles- terol increased hepatic sterol 27-hydroxylase activity and al- ternative bile acid synthesis to expand the bile acid pool and inhibited cholesterol 7 a -hydroxylase in NZW and in Watanabe heterozygous rabbits but not in homozygotes with absent hepatic LDL receptor function. Thus, in rabbits, sterol 27-hydroxylase is up-regulated by the increased hepatic choles- terol that enters the liver via LDL receptors whereas cho- lesterol 7 a -hydroxylase is controlled by the circulating hepatic bile acid flux.— Xu, G., G. Salen, S. Shefer, G. S. Tint, L. B. Nguyen, T. T. Parker, T. S. Chen, J. Roberts, X. Kong, and D. Greenblatt. Regulation of classic and alternative bile acid syn- thesis in hypercholesterolemic rabbits: effects of choles- terol feeding and bile acid depletion. J. Lipid Res. 1998. 39: 1608-1615.