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Aryl hydrocarbon receptor regulates the cholesterol biosynthetic pathway in a dioxin response element‐independent manner
Author(s) -
Tanos Rachel,
Patel Rushang D.,
Murray Iain A.,
Smith Philip B.,
Patterson Andrew D.,
Perdew Gary H.
Publication year - 2012
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.25571
Subject(s) - aryl hydrocarbon receptor , biology , transcription factor , aryl hydrocarbon receptor nuclear translocator , microbiology and biotechnology , response element , transcriptional regulation , transgene , gene , gene expression , promoter , biochemistry
The aryl hydrocarbon receptor (AhR) is a ligand‐activated transcription factor. Activation of AhR mediates the expression of target genes (e.g., CYP1A1 ) by binding to dioxin response element (DRE) sequences in their promoter region. To understand the multiple mechanisms of AhR‐mediated gene regulation, a microarray analysis on liver isolated from ligand‐treated transgenic mice expressing a wild‐type (WT) Ahr or a DRE‐binding mutant Ahr (A78D) on an ahr ‐null background was performed. Results revealed that AhR DRE binding is not required for the suppression of genes involved in cholesterol synthesis. Quantitative reverse‐transcription polymerase chain reaction performed on both mouse liver and primary human hepatocyte RNA demonstrated a coordinated repression of genes involved in cholesterol biosynthesis, namely, HMGCR , FDFT1 , SQLE , and LSS after receptor activation. An additional transgenic mouse line was established expressing a liver‐specific Ahr‐A78D on a Cre Alb / Ahr flox/flox background. These mice displayed a similar repression of cholesterol biosynthetic genes, compared to Ahr flox/flox mice, further indicating that the observed modulation is AhR specific and occurs in a DRE‐independent manner. Elevated hepatic transcriptional levels of the genes of interest were noted in congenic C57BL/6J‐ Ah d allele mice, when compared to the WT C57BL/6J mice, which carry the Ah b allele. Down‐regulation of AhR nuclear translocator levels using short interfering RNA in a human cell line revealed no effect on the expression of cholesterol biosynthetic genes. Finally, cholesterol secretion was shown to be significantly decreased in human cells after AhR activation. Conclusion: These data firmly establish an endogenous role for AhR as a regulator of the cholesterol biosynthesis pathway independent of its DRE‐binding ability, and suggest that AhR may be a previously unrecognized therapeutic target. (H EPATOLOGY 2012;55:1994–2004)