Identification and characterization of a mouse oxysterol 7alpha-hydroxylase cDNA.
The synthesis of essential 7alpha-hydroxylated bile acids in the liver is mediated by two pathways that involve distinct 7alpha-hydroxylases. One pathway is initiated in the endoplasmic reticulum by cholesterol 7alpha-hydroxylase, a well studied cytochrome P450 enzyme. A second pathway is initiated by a less well defined oxysterol 7alpha-hydroxylase. Here, we show that a mouse hepatic oxysterol 7alpha-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 7alpha-hydroxylase. Cyp7b1 mRNA and protein are induced in the third week of life commensurate with an increase in hepatic oxysterol 7alpha-hydroxylase activity. In the adult mouse, dietary cholesterol or colestipol induce cholesterol 7alpha-hydroxylase mRNA levels but do not affect oxysterol 7alpha-hydroxylase enzyme activity, mRNA, or protein levels. Cholesterol 7alpha-hydroxylase mRNA is reduced to undetectable levels in response to bile acids, whereas expression of oxysterol 7alpha-hydroxylase is modestly decreased. The liver thus maintains the capacity to synthesize 7alpha-hydroxylated bile acids regardless of dietary composition, underscoring the central role of 7alpha-hydroxylated bile acids in lipid metabolism.
Schwarz
M
M
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75235-9046, USA.
Lund
E G
EG
Lathe
R
R
Björkhem
I
I
Russell
D W
DW
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D018076:DNA, Complementary; D008401:Gas Chromatography-Mass Spectrometry; D015971:Gene Expression Regulation, Enzymologic; D008099:Liver / Q000201:enzymology; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics; D013045:Species Specificity; D013250:Steroid Hydroxylases / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism
D018076:DNA, Complementary; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; C115867:oxysterol 7-alpha-hydroxylase