Disruption of the Oxysterol 7α-Hydroxylase Gene in Mice

Mice without oxysterol 7α-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. Animals heterozygous (Cyp7b1+/−) and homozygous (Cyp7b1−/−) for this mutation were...

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Bibliographic Details
Published in:The Journal of biological chemistry 2000-06, Vol.275 (22), p.16536-16542
Main Authors: Li-Hawkins, Jia, Lund, Erik G., Turley, Stephen D., Russell, David W.
Format: Article
Language:English
Subjects:
27-hydroxycholesterol
bile acids
Cyp7b1 gene
oxysterol 7^a-hydroxylase
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Summary:Mice without oxysterol 7α-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. Animals heterozygous (Cyp7b1+/−) and homozygous (Cyp7b1−/−) for this mutation were grossly indistinguishable from wild-type mice. Plasma and tissue levels of 25- and 27-hydroxycholesterol, two oxysterol substrates of this enzyme with potent regulatory actions in cultured cells, were markedly elevated inCyp7b1−/− knockout animals. Parameters of bile acid metabolism as well as plasma cholesterol and triglyceride levels in male and female Cyp7b1−/− mice were normal. The cholesterol contents of major tissues were not altered.In vivo sterol biosynthetic rates were unaffected in multiple tissues with the exception of the male kidney, which showed a ∼40% decrease in de novo synthesis versuscontrols. We conclude that the major physiological role of the CYP7B1 oxysterol 7α-hydroxylase is to metabolize 25- and 27-hydroxycholesterol and that loss of this enzyme in the liver is compensated for by increases in the synthesis of bile acids by other pathways. A failure to catabolize oxysterols in the male kidney may lead to a decrease in de novo sterol synthesis.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M001811200