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(Received for publication, June 4, 1997, and in revised form, July 15, 1997)
From the The synthesis of essential 7
Volume 272, Number 38,
Issue of September 19, 1997
pp. 23995-24001
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
-Hydroxylase cDNA
,
,
Department of Molecular Genetics, University
of Texas Southwestern Medical Center, Dallas, Texas 75235-9046, the
§ Center for Genome Research, University of Edinburgh,
King's Buildings, West Mains Road, Edinburgh EH9 3JQ, United Kingdom,
and the ¶ Department of Clinical Chemistry, Karolinska Institute,
Huddinge Hospital, Huddinge S-14186, Sweden
-hydroxylated bile
acids in the liver is mediated by two pathways that involve distinct
7-hydroxylases. One pathway is initiated in the endoplasmic
reticulum by cholesterol 7-hydroxylase, a well studied cytochrome
P450 enzyme. A second pathway is initiated by a less well defined
oxysterol 7-hydroxylase. Here, we show that a mouse hepatic
oxysterol 7-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 7-hydroxylase. Cyp7b1 mRNA and protein are induced in
the third week of life commensurate with an increase in hepatic
oxysterol 7-hydroxylase activity. In the adult mouse, dietary
cholesterol or colestipol induce cholesterol 7-hydroxylase mRNA
levels but do not affect oxysterol 7-hydroxylase enzyme activity,
mRNA, or protein levels. Cholesterol 7-hydroxylase mRNA is
reduced to undetectable levels in response to bile acids, whereas
expression of oxysterol 7-hydroxylase is modestly decreased. The
liver thus maintains the capacity to synthesize 7-hydroxylated bile
acids regardless of dietary composition, underscoring the central role
of 7-hydroxylated bile acids in lipid metabolism.
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