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 heterozygo us and 10 homozygous rabbits with partial and complete deficiencies of LDL receptors, After 10 days of cholesterol feeding, bile fistulas we re constructed and bile acid pool sizes were measured. Cholesterol fee ding increased plasma and hepatic cholesterol levels in ail rabbit gro ups. Baseline bile acid pool sizes were smaller (P < 0.01) in heterozy gotes (139 +/- 3 mg) and homozygotes (124 +/- 30 mg) than NZW rabbits (254 +/- 44 mg). After feeding cholesterol, bile acid pool sizes doubl ed with increased cholic acid synthesis in NZW and, to a lesser extent , in Watanabe heterozygous rabbits but not in homozygotes. Baseline ch olesterol 7 alpha-hydroxylase activity in NZW and heterozygotes declin ed 69% and 53% (P < 0.001), respectively, after cholesterol feeding, S terol 27-hydroxylase activity reflecting alternative bile acid synthes is increased 66% (P < 0.01) in NZW and 37% in Watanabe heterozygotes b ut not in homozygotes after feeding cholesterol. Bile fistula drainage stimulated cholesterol 7 alpha-hydroxylase activity but not sterol 27 -hydroxylase activity in all three rabbit groups. These results demons trated that dietary cholesterol increased hepatic sterol 27-hydroxylas e activity and alternative bile acid synthesis to expand the bile acid pool and inhibited cholesterol 7 alpha-hydroxylase in NZW and in Wata nabe heterozygous rabbits but not in homozygotes with absent hepatic L DL receptor function, Thus, in rabbits, sterol 27-hydroxylase is up-re gulated by the increased hepatic cholesterol that enters the liver via LDL receptors whereas cholesterol 7 alpha-hydroxylase is controlled b y the circulating hepatic bile acid flux.