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Papers In Press, published online ahead of print November 30, 2005
Laboratory Medicine, Karolinska Institutet, Stockholm 14186
Corresponding Author: ingemar.bjorkhem{at}karolinska.se
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 to heterozygous littermates there was no statistically significant difference in the mRNA levels of Cyp46a1. During the first two weeks of life in the wild-type mouse, however, a significant increase of Cyp46a1 mRNA levels were 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.
J. Biol. Chem, 10.1074/jbc.M505179200
Submitted on May 11, 2005
Revised on November 29, 2005
Accepted on November 30, 2005
Studies on the transcriptional regulation of cholesterol 24-hydroxylase (CYP46A1): Marked insensitivity towards different regulatory axes
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