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J. Biol. Chem., Vol. 277, Issue 37, 34036-34041, September 13, 2002

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Human Sterol 27-Hydroxylase (CYP27) Overexpressor Transgenic Mouse Model
EVIDENCE AGAINST 27-HYDROXYCHOLESTEROL AS A CRITICAL REGULATOR OF CHOLESTEROL HOMEOSTASIS^*

Karen Meir^§, Daniel Kitsberg^§, Irit Alkalay^§, Fanny Szafer^§, Haim Rosen^¶, Shoshanna Shpitzen^§, Liat Ben Avi^§, Bart Staels, Catherine Fievet, Vardiella Meiner^**, Ingemar Björkhem, and Eran Leitersdorf^§§§¶¶

From the Departments of  Pathology, ^** Human Genetics, and ^§§ Medicine B and the ^§ Center for Research, Prevention, and Treatment of Atherosclerosis, Hadassah University Hospital, 91120 Jerusalem, Israel, the ^¶ Department of Molecular Virology, Faculty of Medicine, Hebrew University, 91120 Jerusalem, Israel, the  Department of Atherosclerosis, Institut Pasteur de Lille, 59000 Lille, France, and the  Department of Medical Laboratory Sciences and Technology, Division of Clinical Chemistry, Karolinska Institutet, Huddinge University Hospital, SE-141 86 Huddinge, Sweden

CYP27-overexpressed transgenic mice were generated with the use of a human full-length CYP27 coding region cloned into a ubiquitous expression vector. Positive transgenic mice were identified by tail DNA genotyping and high fecal 27-hydroxycholesterol content. The levels of 27-hydroxycholesterol were found to be 3-5 times higher in the circulation and the tissues of the overexpressed mice when compared with littermate controls. There were no gross morphological differences between the overexpressed mice and their controls. Total cholesterol and triglyceride levels were not affected by overexpression of CYP27. Serum lathosterol was also normal, suggesting a normal rate of cholesterol synthesis. Serum levels of 7-hydroxycholesterol were unaffected, suggesting a normal rate of bile acid formation in the pathway involving cholesterol 7-hydroxylase. Biliary bile acid composition was slightly affected by CYP27 overexpression in female but not in male mice. Fecal levels of neutral steroids were slightly but significantly increased in overexpressor female mice but not in male mice. Levels of 24-hydroxycholesterol in the circulation were significantly reduced in the overexpressed mice, probably as a consequence of a recently described catabolic pathway involving CYP27. Combined with the results of our previous work on mice with a disruption of the CYP27 gene, the present results suggest that the levels of 27-hydroxycholesterol are not of critical importance for cholesterol homeostasis in mice.

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