DISRUPTION OF CHOLESTEROL 7-ALPHA-HYDROXYLASE GENE IN MICE .2. BILE-ACID DEFICIENCY IS OVERCOME BY INDUCTION OF OXYSTEROL 7-ALPHA-HYDROXYLASE

Past experiments and current paradigms of cholesterol homeostasis sugg est that cholesterol 7 alpha-hydroxylase plays a crucial role in stero l metabolism by controlling the conversion of cholesterol into bile ac ids, Consistent with this conclusion, we show in the accompanying pape r that mice deficient in cholesterol 7 alpha-hydroxylase (Cyp7(-/-) mi ce) exhibit a complex phenotype consisting of abnormal lipid excretion , skin pathologies, and behavioral irregularities (Ishibashi, S., Schw arz, M., Frykman, P, K., Herz, J., and Russell, D. W. (1996) J. Biol. Chem, 261, 18017-18023), Aspects of lipid metabolism in the Cyp7(-/-) mice are characterized here to deduce the physiological basis of this phenotype. Serum lipid, cholesterol, and lipoprotein contents are indi stinguishable between wild-type and Cyp7(-/-) mice, Vitamin D-3 and E levels are low to undetectable in knockout animals, Stool fat content is significantly elevated in newborn Cyp7(-/-) mice and gradually decl ines to wild-type levels at 28 days of age, Several species of 7 alpha -hydroxylated bile acids are detected in the bile and stool of adult C yp7(-/-) animals, A hepatic oxysterol 7 alpha-hydroxylase enzyme activ ity that may account for the 7 alpha-hydroxylated bile acids is induce d between days 21 and 30 in both wild-type and deficient mice, An anom alous oily coat in the Cyp7(-/-) animals is due to the presence of exc ess monoglyceride esters in the fur, These data show that 7 alpha-hydr oxylase and the pathway of bile acid synthesis initiated by this enzym e are essential for proper absorption of dietary lipids and fat-solubl e vitamins in newborn mice, but not for the maintenance of serum chole sterol and lipid levels, In older animals, an alternate pathway of bil e acid synthesis involving an inducible oxysterol 7 alpha-hydroxylase plays a crucial role in lipid and bile acid metabolism.