Geniposide alleviated bile acid-associated NLRP3 inflammasome activation by regulating SIRT1/FXR signaling in bile duct ligation-induced liver fibrosis

Abstract

Background: Geniposide (GE), the active compound derived from Gardeniae Fructus, possesses valuable bioactivity for liver diseases, but GE effects on bile duct ligation (BDL)-induced cholestasis remain unclear. This study aimed to elucidate the influence of GE on BDL-induced liver fibrosis and to investigate the underlying mechanisms.

Methods: GE (25 or 50 mg/kg) were intragastrical administered to C57BL/6 J mice for two weeks to characterize the hepatoprotective effect of GE on BDL-induced liver fibrosis. NLRP3 inflammasome activation was detected in vivo, and BMDMs were isolated to explore whether GE directly inhibited NLRP3 inflammasome activation. Serum bile acid (BA) profiles were assessed utilizing UPLC-MS/MS, and the involvement of SIRT1/FXR pathways was identified to elucidate the role of SIRT1/FXR in the hepaprotective effect of GE. The veritable impact of SIRT1/FXR signaling was further confirmed by administering the SIRT1 inhibitor EX527 (10 mg/kg) to BDL mice treated with GE.

Results: GE treatment protected mice from BDL-induced liver fibrosis, with NLRP3 inflammasome inhibition. However, development in vitro experiments revealed that GE could not directly inhibit NLRP3 activation under ATP, monosodium urate, and nigericin stimulation. Further mechanistic data showed that GE activated SIRT1, which subsequently deacetylated FXR and restored CDCA, TUDCA, and TCDCA levels, thereby contributing to the observed hepaprotective effect of GE. Notably, EX527 treatment diminished the hepaprotective effect of GE on BDL-induced liver fibrosis.

Conclusion: This study first proved the hepaprotective effect of GE on liver fibrosis in BDL mice, which was closely associated with the restoration of BA homeostasis and NLRP3 inflammasome inhibition. The activation of SIRT1 and the subsequent FXR deacetylation restored the BA profiles, especially CDCA, TUDCA, and TCDCA contents, which was the main contributor to NLRP3 inhibition and the hepaprotective effect of GE. Overall, our work provides novel insights that GE as well as Gardeniae Fructus might be the potential attractive candidate for ameliorating BDL-induced liver fibrosis.

Keywords: Bile acid homeostasis; Cholestasis; Geniposide; NLRP3 inflammasome; SIRT1/FXR signaling.