Identification and characterization of a mouse oxysterol 7α-hydroxylase cDNA

Abstract

The synthesis of essential 7α-hydroxylated bile acids in the liver is mediated by two pathways that involve distinct 7α-hydroxylases. One pathway is initiated in the endoplasmic reticulum by cholesterol 7α-hydroxylase, a well studied cytochrome P450 enzyme. A second pathway is initiated by a less well defined oxysterol 7α-hydroxylase. Here, we show that a mouse hepatic oxysterol 7α-hydroxylase is encoded by Cyp7b1, a cytochrome P450 cDNA originally isolated from the hippocampus. Expression of a Cyp7b1 cDNA in cultured cells produces an enzyme with the same biochemical and pharmacological properties as those of the hepatic oxysterol 7α-hydroxylase. Cyp7b1 mRNA and protein are induced in the third week of life commensurate with an increase in hepatic oxysterol 7α-hydroxylase activity. In the adult mouse, dietary cholesterol or colestipol induce cholesterol 7α-hydroxylase mRNA levels but do not affect oxysterol 7α-hydroxylase enzyme activity, mRNA, or protein levels. Cholesterol 7α-hydroxylase mRNA is reduced to undetectable levels in response to bile acids, whereas expression of oxysterol 7α-hydroxylase is modestly decreased. The liver thus maintains the capacity to synthesize 7α-hydroxylated bile acids regardless of dietary composition, underscoring the central role of 7α-hydroxylated bile acids in lipid metabolism.