Activation of Farnesoid X Receptor by Schaftoside Ameliorates Acetaminophen-Induced Hepatotoxicity by Modulating Oxidative Stress and Inflammation

Abstract

<b><i>Aims:</i></b> Acetaminophen (APAP) overdose leads to acute liver injury by inducing hepatic mitochondrial oxidative stress and inflammation. However, the molecular mechanisms involved are still unclear. Farnesoid X receptor (FXR) serves as a therapeutic target for the treatment of liver disorders, whose activation has been proved to protect APAP-induced hepatotoxicity. In this study, we examined whether FXR activation by schaftoside (SS), a naturally occurring flavonoid from <i>Desmodium styracifolium,</i> could protect mice against APAP-induced hepatotoxicity <i>via</i> regulation of oxidative stress and inflammation. <b><i>Results:</i></b> We first found that SS exhibited potent protective effects against APAP-induced hepatotoxicity in mice. The study reveals that SS is a potential agonist of FXR, which protects mice from hepatotoxicity mostly <i>via</i> regulation of oxidative stress and inflammation. Mechanistically, the hepatoprotective SS is associated with the induction of the genes of phase II detoxifying enzymes (<i>e.g.</i>, UGT1A1, GSTα1), phase III drug efflux transporters (<i>e.g.</i>, bile salt export pump, organic solvent transporter protein β), and glutathione metabolism-related enzymes (<i>e.g.</i>, glutamate-cysteine ligase modifier subunit [Gclm], glutamate-cysteine ligase catalytic subunit [Gclc]). More importantly, SS-mediated FXR activation could fine-tune the pro- and anti-inflammatory eicosanoids generation <i>via</i> altering eicosanoids metabolic pathway, thereby resulting in decrease of hepatic inflammation. In contrast, FXR deficiency can abrogate the above effects. <b><i>Innovation and Conclusion:</i></b> Our results provided the direct evidence that FXR activation by SS could attenuate APAP-induced hepatotoxicity <i>via</i> inhibition of nuclear factor kappa-B signaling and fine-tuning the generation of proinflammatory mediators' eicosanoids. Our findings indicate that strategies to activate FXR signaling in hepatocytes may provide a promising therapeutic approach to alleviate liver injury induced by APAP overdose.