IDENTIFICATION AND CHARACTERIZATION OF A MOUSE OXYSTEROL 7-ALPHA-HYDROXYLASE CDNA

The synthesis of essential 7 alpha-hydroxylated bile acids in the live r is mediated by two pathways that involve distinct 7 alpha-hydroxylas es. One pathway is initiated in the endoplasmic reticulum by cholester ol 7 alpha-hydroxylase, a well studied cytochrome P450 enzyme. A secon d pathway is initiated by a less well defined oxysterol 7 alpha-hydrox ylase. Here, we show that a mouse hepatic oxysterol 7 alpha-hydroxylas e is encoded by Cyp7b1, a cytochrome P450 cDNA originally isolated fro m the hippocampus. Expression of a Cyp7b1 cDNA in cultured cells produ ces an enzyme with the same biochemical and, pharmacological propertie s as those of the hepatic oxysterol 7 alpha-hydroxylase. Cyp7b1 mRNA a nd protein are induced in the third week of life commensurate with an increase in hepatic oxysterol 7 alpha-hydroxylase activity. In the adu lt mouse, dietary cholesterol or colestipol induce cholesterol 7 alpha -hydroxylase mRNA levels but do not affect oxysterol 7 alpha-hydroxyla se enzyme activity, mRNA, or protein levels. Cholesterol 7 alpha-hydro xylase mRNA is reduced to undetectable levels in response to bile acid s, whereas expression of oxysterol 7 alpha-hydroxylase is modestly dec reased, The liver thus maintains the capacity to synthesize 7 alpha-hy droxylated bile acids regardless of dietary composition, underscoring the central role of 7 alpha-hydroxylated bile acids in lipid metabolis m.