Disruption of the oxysterol 7 alpha-hydroxylase gene in mice

Mice without oxysterol 7 alpha-hydroxylase, an enzyme of the alternate bile acid synthesis pathway with a sexually dimorphic expression pattern, were constructed by the introduction of a null mutation at the Cyp7b1 locus. Ani mals heterozygous (Cyp7b1(+/-)) and homozygous (Cyp7b1(-/-)) for this mutat ion were grossly indistinguishable from wild-type mice. Plasma and tissue l evels of 25- and 27-hydroxycholesterol, two oxysterol substrates of this en zyme with potent regulatory actions in cultured cells, were markedly elevat ed in Cyp7b1(-/-) knockout animals. Parameters of bile acid metabolism as w ell as plasma cholesterol and triglyceride levels in male and female Cyp7b1 (-/-) mice were normal. The cholesterol contents of major tissues mere not altered. In vivo sterol biosynthetic rates were unaffected in multiple tiss ues with the exception of the male kidney, which showed a similar to 40% de crease in de novo synthesis versus controls. We conclude that the major phy siological role of the CYP7B1 oxysterol 7 alpha-hydroxylase is to metaboliz e 25- and 27-hydroxycholesterol and that loss of this enzyme in the liver i s compensated for by increases in the synthesis of bile acids by other path ways. A failure to catabolize oxysterols in the male kidney may lead to a d ecrease in de novo sterol synthesis.