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J. Biol. Chem., Vol. 281, Issue 7, 3810-3820, February 17, 2006

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Studies on the Transcriptional Regulation of Cholesterol 24-Hydroxylase (CYP46A1)

MARKED INSENSITIVITY TOWARD DIFFERENT REGULATORY AXES^*

Yoshihiko Ohyama¹, Steve Meaney¹, Maura Heverin, Lena Ekström^¶, Anat Brafman^||, Millicent Shafir^||, Ulla Andersson, Maria Olin, Gösta Eggertsen, Ulf Diczfalusy, Elena Feinstein^||, and Ingemar Björkhem²

From the Divisions of Clinical Chemistry and ^¶Clinical Pharmacology, Department of Laboratory Medicine, Karolinska University Hospital, Huddinge, S-141 86 Stockholm, Sweden, the Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Higashi-Hiroshima 739-8526, Japan, and ^||Quark Biotech, Fremont, California 94555

Mammalian CNS contains a disproportionally large and remarkably stable pool of cholesterol. Despite an efficient recycling there is some requirement for elimination of brain cholesterol. Conversion of cholesterol into 24S-hydroxycholesterol by the cholesterol 24-hydroxylase (CYP46A1) is the quantitatively most important mechanism. Based on the protein expression and plasma levels of 24S-hydroxycholesterol, CYP46A1 activity appears to be highly stable in adults. Here we have made a structural and functional characterization of the promoter of the human CYP46A1 gene. No canonical TATA or CAAT boxes were found in the promoter region. Moreover this region had a high GC content, a feature often found in genes considered to have a largely housekeeping function. A broad spectrum of regulatory axes using a variety of promoter constructs did not result in a significant transcriptional regulation. Oxidative stress caused a significant increase in transcriptional activity. The possibility of a substrate-dependent transcriptional regulation was explored in vivo in a sterol-deficient mouse model (Dhcr24 null) in which almost all cholesterol had been replaced with desmosterol, which is not a substrate for CYP46A1. Compared with heterozygous littermates there was no statistically significant difference in the mRNA levels of Cyp46a1. During the first 2 weeks of life in the wild-type mouse, however, a significant increase of Cyp46a1 mRNA levels was found, in parallel with an increase in 24S-hydroxycholesterol level and a reduction of cholesterol synthesis. The failure to demonstrate a significant transcriptional regulation under most conditions is discussed in relation to the turnover of brain and neuronal cholesterol.

Received for publication, May 11, 2005 , and in revised form, November 29, 2005.

^* This work was supported by the Swedish Science Council, Heart-Lung Foundation, Karolinska Institutet Research Fund, Osterman's foundation for geriatric research, Gun and Bertil Stohne's Foundation, Fredrik and Ingrid Thuring's Foundation, the Foundation for Old Servants, the Swedish Brain Foundation, Swedish Brain Power and in part by Pfizer. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Tel.: 46-8-585-81235; Fax: 46-8-585-81260; E-mail: ingemar.bjorkhem{at}karolinska.se.

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