AhR/PPARγ mediates hepatic lipid metabolism disorders induced by exposure to 16 priority-controlled PAHs at environment related doses.

To investigate the relationship of abnormal liver metabolism induced by PAHs, rats were chronically exposed to various concentrations of 16 priority-controlled PAHs. Results showed that PAHs exposure significantly increased AhR and CYP1A1 expression and pro-inflammatory factor levels, while significantly reducing hepatic SOD activity (p < 0.05). The expression of PPARγ and other proteins related to lipid synthesis and fatty acid transport increases, accompanied by an increase in triglyceride (TG) and total cholesterol (TC) content. In contrast, the expression of fatty acid β-oxidation-related proteins was significantly downregulated (p < 0.05). Moreover, the appearance of lipid vacuoles indicated steatosis and the dysregulation of lipid metabolism. Exposure to 10 × PAHs significantly promoted lipid accumulation in rats (p < 0.05). Interestingly, the inhibition of PPARγ activity significantly alleviated the aforementioned changes and reduced AhR expression (p < 0.05), highlighting its critical role in the pathway. The molecular interactions between PPARγ and PAHs further showed that PAHs can activate PPARγ through non-covalent bond forces, possibly with amino acid residues 260-275 as the key binding sites. Among PAHs, benzo[a]pyrene exhibited the highest binding towards PPARγ, similar to its known agonists. The benchmark dose of PAHs is 7.67 × 10-5 μg/kg/day, far lower than typical human exposure levels. Overall, these findings demonstrate that PAHs induce hepatic lipid metabolism disorders via AhR/PPARγ signaling pathway, with PPARγ playing a crucial role.