Aristolochic acid-induced dyslipidemia and hepatotoxicity: The potential role of FXR and AHR receptors

Aristolochic acids (AAs) represent a class of nitrophenanthrene carboxylic acids naturally existing or accidentally mixed in herbal medicines or crops, which have long been recognized for causing nephropathy. Recently, the linkage between AAs and liver injury has become a concern; however, the current understanding of the mechanism or mode of action (MOA) is limited. In the present study, we investigated nuclear receptor-mediated MOA associated with AAs-induced liver injury including dyslipidemia and hepatotoxicity. Bioinformatic analysis of AAI-interacting genes indicated nuclear receptor-mediated metabolizing pathways; Transcriptomic profiling of AAs-exposed rats with liver injury suggested FXR-, NRF2-, and AHR- mediated pathways in the injured livers of the rats. Mechanistic investigation using HepG2 cells indicated AAI-induced hepatic lipid accumulation by elevating Triglyceride (TG) through inhibition of the FXR. In addition, AAI-induced hepatocellular damage by activating the AHR pathway, which further generated ROS and activated the NRF2 pathway. Together, these results provided new clues for researchers who are interested in chemical-induced liver injury.