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Regulation of cholesterol biosynthetic gene expression by the Ah receptor
Author(s) -
Tanos Rachel,
Patel Rushang D.,
Perdew Gary H.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.472.2
Subject(s) - aryl hydrocarbon receptor , transcription factor , downregulation and upregulation , biology , transcriptional regulation , gene , microarray analysis techniques , gene expression , psychological repression , regulation of gene expression , nuclear receptor , receptor , transgene , aryl hydrocarbon receptor nuclear translocator , microbiology and biotechnology , biochemistry
The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor known to drive expression of target genes. Activation of AHR by xenobiotic agonists such as dioxin or TCDD (2,3,7,8‐tetrachlorodibenzo‐p‐dioxin) is known to have toxic consequences. Interestingly, ahr‐null mice exhibit a defined set of physiological phenotypes that indicate an endogenous role for AHR. Recent microarray studies performed in mice and rats treated with TCDD have shown a decrease in the expression of lipid metabolism genes. In our effort to understand the mechanisms of this regulation, we conducted a microarray analysis on liver samples from ligand‐treated transgenic mice expressing a DNA‐binding mutant AHR and showed that AHR DNA‐binding is not essential for the observed repression. In addition, real‐time qPCR performed on mice and human hepatocytes confirmed repression of cholesterol biosynthesis genes namely HMGCR, SQLE and LSS following receptor activation. Using real‐time qPCR and western blot, we showed that absence of the receptor in liver‐specific AHR Cre‐Flox mice leads to upregulation of those genes in the absence of an exogenous ligand. These data firmly establish the role of AHR as regulator of cholesterol biosynthesis independently of its DNA‐binding ability and suggest that AHR may be a previously unrecognized therapeutic target. Funding: NIH ES04869 and Bristol Myers Squibb