ARNT has been linked to cholesterol homeostasis through its regulation of the ATP-binding cassette transporter A1, a major reverse cholesterol transporter.23 Agonist treatment leads to the formation of AhR-ARNT heterodimer formation, and the ablation of ARNT expression can assess whether this heterodimer plays a role in gene repression studied here. Unlike the AhR, partial absence of ARNT in Hep3B cells had no effect on the mRNA levels of cholesterol-synthesis Cisplatin genes, suggesting that the AhR mediates gene repression in the absence of heterodimer formation (Supporting Fig.

6). This result is consistent with the ability of the DRE-binding mutant, AhR, to repress the genes described here. Based on our findings, Wnt antagonist one might speculate that the decrease in the expression of all cholesterol-synthesis genes examined in mice and humans would result in a lowered cholesterol synthesis

and subsequent secretion. For this purpose, we treated primary human hepatocytes with BNF and used the gas chromatography/mass spectrometry (GC-MS) technique to quantify cholesterol in the media. As expected, treated cells showed a significant repression in the levels of secreted cholesterol, indicating an overall regulation of the pathway by the AhR (Fig. 7). In the current study, we established a transgenic mouse model that demonstrated the ability of the AhR to modulate the expression of a number of genes that encode for enzymes involved in the cholesterol-synthetic

pathway independent of DRE-binding, leading to a repression in cholesterol-secretion rate. There has been extensive interest in assessing the effect of TCDD exposure on serum lipid levels and, more recently, on the expression of lipid metabolism genes in rodents using microarrays,9, 10 but little progress has been made with regard to the AhR modulation of those genes in vivo in the absence of an exogenous ligand. Evolutionary conservation of the receptor coupled with the ahr-null mice phenotype suggests a role for the receptor beyond mediating xenobiotic metabolism. Differential constitutive expression of cholesterol-biosynthesis genes between CreAlbAhrflox/flox mice and AhR-silenced human cell lines and their AhR-expressing counterparts, selleck screening library as well as between Ahd and Ahb allele congenic mice, suggests a function for the AhR in cholesterol homeostasis. Although whether there is an endogeneous ligand(s) that mediates this effect is not known. Considering that cholesterol and oxysterols are involved in the feedback regulation of cholesterol homeostasis, it will be important to test whether there are sterols that can act as AhR ligands. Indeed, 7-ketocholesterol is a key oxysterol present in serum that has been shown to be an AhR antagonist.24 Clearly, there is a need to examine the ability of other endogenous metabolites to act as AhR ligands and regulate cholesterol biosynthesis.