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Originally published In Press as doi:10.1074/jbc.M001811200 on March 27, 2000

J. Biol. Chem., Vol. 275, Issue 22, 16536-16542, June 2, 2000
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Disruption of the Oxysterol 7alpha -Hydroxylase Gene in Mice*

Jia Li-HawkinsDagger , Erik G. LundDagger , Stephen D. Turley§, and David W. RussellDagger

From the Departments of Dagger  Molecular Genetics and § Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75235-9046

Mice without oxysterol 7alpha -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 in Cyp7b1-/- 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 versus controls. We conclude that the major physiological role of the CYP7B1 oxysterol 7alpha -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.

* This work was supported by National Institutes of Health Grants HL 20948 and HL 09610, Robert A. Welch Foundation Grant I-0971, the Perot Family Foundation, and the William M. Keck Foundation.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Molecular Genetics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75235-9046. Tel.: 214-648-2007; Fax: 214-648-6899; E-mail: Russell@utsw.swmed.edu.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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