Activation of AhR mediates the expression of

Activation of AhR mediates the expression of NSC 683864 chemical structure 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 CreAlb/Ahrflox/flox background. These mice displayed a similar repression of cholesterol biosynthetic genes, compared to Ahrflox/flox BVD-523 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-Ahd allele mice, when compared to the WT C57BL/6J mice, which carry the Ahb allele. Down-regulation of AhR nuclear translocator levels using short interfering RNA in a human cell line MCE公司 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. (HEPATOLOGY 2012;55:1994–2004) The aryl hydrocarbon

receptor (AhR) is a ligand-activated transcription factor belonging to the basic helix-loop-helix (bHLH)/Per ARNT Sim (PAS) family of transcription factors. Ligands for the AhR include the planar, hydrophobic halogenated aromatic hydrocarbons and polycyclic aromatic hydrocarbons, many of which are environmental contaminants. Activation of AhR by xenobiotic agonists, such as TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), a prototypic potent ligand, is known to have toxic consequences, illustrating its role as an exogenous chemical sensor. Atypical ligands include bilirubin and indirubin.1, 2 The presence of potent endogenous ligands for the human AhR exhibiting agonistic activities, such as kynurenic acid3 and 3-indoxyl sulfate,4 have been identified. Upon ligand binding, the AhR heterodimerizes with the AhR nuclear translocator protein (ARNT), another bHLH-PAS family member.5 The AhR/ARNT heterodimer represents a fully competent transcription factor capable of binding a consensus sequence known as dioxin response element (DRE) or xenobiotic response element.

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