FXR overexpression promotes liver regeneration through inducing FGF2 activation in APAP-induced acute liver injury

Background and purpose: Acetaminophen (APAP)-induced hepatotoxicity represents a critical medical emergency due to the rapid progression. To date, practical and feasible early interventions are limited. This study aimed to explore whether farnesoid X receptor (FXR, NR1H4) alleviates APAP-induced acute liver injury and whether this effect is mediated by Fibroblast Growth Factor 2 (FGF2) activation to promote liver regeneration.

Methods: The difference in FXR expression between healthy subjects and patients with APAP-induced acute liver injury was analyzed through the Gene Expression Omnibus (GEO) database. The adeno-associated virus-8-mediated FXR (AAV-FXR) was injected through the tail vein into mice to establish the mouse FXR-overexpressed model. pcDNA-FXR, siFXR or siFGF2 plasmids were transfected into AML-12 cells. H&E staining, quantitative Real-Time PCR, Western blotting, immunofluorescence staining, DCFH-DA staining, and TUNEL staining were applied to determine the effects of FXR and FGF2.

Results: FXR was significantly reduced in hepatic tissues of patients with APAP-induced acute liver injury compared to normal hepatic tissues. FXR overexpression attenuated APAP-induced liver injury by inhibiting inflammation, oxidative stress and Apoptosis, while promoting liver regeneration. Furthermore, FXR overexpression upregulated FGF2 expression, and its pro-regenerative effect against APAP-induced acute liver injury is dependent on FGF2. In contrast, FXR or FGF2 knockdown resulted in opposite effects.

Conclusions: FXR alleviated APAP-induced acute liver injury by mitigating inflammation, oxidative stress and Apoptosis, as well as promoting liver regeneration. This pro-regenerative effect of FXR is dependent on FGF2 activation.