Two uniquely arranged thyroid hormone response elements in the far upstream 5′ flanking region confer direct thyroid hormone regulation to the murine cholesterol 7α hydroxylase gene

Dong Ju Shin, Michelina Plateroti, Jacques Samarut, Timothy Osborne

Research output: Contribution to journalArticle

Abstract

Cholesterol 7α 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.

Original languageEnglish (US)
Pages (from-to)3853-3861
Number of pages9
JournalNucleic Acids Research
Volume34
Issue number14
DOIs
StatePublished - Sep 21 2006
Externally publishedYes

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Cholesterol 7-alpha-Hydroxylase
5' Flanking Region
Response Elements
Thyroid Hormones
Cholesterol
Genes
Binding Sites
Retinoid X Receptors
Thyroid Hormone Receptors
Transcription Initiation Site
Bile Acids and Salts
Protein Isoforms
Gene Expression
Liver
Enzymes
Serum

ASJC Scopus subject areas

  • Genetics

Cite this

Two uniquely arranged thyroid hormone response elements in the far upstream 5′ flanking region confer direct thyroid hormone regulation to the murine cholesterol 7α hydroxylase gene. / Shin, Dong Ju; Plateroti, Michelina; Samarut, Jacques; Osborne, Timothy.

In: Nucleic Acids Research, Vol. 34, No. 14, 21.09.2006, p. 3853-3861.

Research output: Contribution to journalArticle

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