Aryl hydrocarbon receptor regulates the cholesterol biosynthetic pathway in a dioxin response element-independent manner

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 / Ahrflox/flox background. These mice displayed a similar repression of cholesterol biosynthetic genes, compared to Ahrflox/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 - 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 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.