Nucleic Acids Research Advance Access published online on August 9, 2006
Nucleic Acids Research, doi:10.1093/nar/gkl506
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© 2006 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commerical use, distribution, and reproduction in any medium, provided the original work is properly cited.
Article |
Two uniquely arranged thyroid hormone response elements in the far upstream 5' flanking region confer direct thyroid hormone regulation to the murine cholesterol 7
hydroxylase gene
Department of Molecular Biology and Biochemistry University of California, Irvine CA, USA 1 Laboratoire de Biologie Moléculaire de la Cellule UMR5161, Ecole Normale Supérieure de Lyon IFR128 Biosciences, 46, Allée d' Italie 69364 Lyon, France 2 Université Claude Bernard Lyon 1 France
*To whom correspondence should be addressed. Tel: +1 949 824 2979; Fax: +1 949 824 8551; Email: tfosborn{at}uci.edu
Received May 22, 2006. Revised June 26, 2006. Accepted July 3, 2006.
Cholesterol 7
hydroxlyase (CYP7A1) is a key enzyme in cholesterol catabolism to bile acids and its activity is important for maintaining appropriate cholesterol levels. The murine CYP7A1 gene is highly inducible by thyroid hormone in vivo and there is an inverse relationship between thyroid hormone and serum cholesterol. Eventhough gene expression has been shown to be upregulated, whether the induction was mediated through a direct effect of thyroid hormone on the CYP7A1 promoter has never been established. Using gene targeted mice, we show that either of the two TR isoforms are sufficient to maintain normal hepatic CYP7A1 expression but a loss of both results in a significant decrease in expression. We also identified two new functional thyroid hormone receptor-binding sites in the CYP7A1 5' flanking sequence located 3 kb upstream from the transcription start site. One site is a DR-0, which is an unusual type of TR response element, and the other consists of only a single recognizable half site that is required for TR/retinoid X receptor (RXR) binding. These two independent TR-binding sites are closely spaced and both are required for full induction of the CYP7A1 promoter by thyroid hormone, although the DR-0 site was more crucial.
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