FXR and AHR mediate aristolochic acid-induced liver injury: mode of action from the nuclear receptors' point of view

Abstract

Aristolochic acid (AA) is an emerging contaminant in herbal medicines or crops, which has long been recognized for causing nephropathy. Recently, the linkage between AA 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 AA-induced liver injury. Bioinformatic analysis of AA-interacting genes indicated nuclear receptor-mediated metabolizing pathways; Transcriptomic profiling of AA-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 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.