Fisetin mitigates hepatic ischemia-reperfusion injury by regulating GSK3β/AMPK/NLRP3 inflammasome pathway

• Published in: Hepatobiliary & pancreatic diseases international 2021-08, Vol.20 (4), p.352-360
• Main Authors: Pu, Jun-Liang, Huang, Zuo-Tian, Luo, Yun-Hai, Mou, Tong, Li, Ting-Ting, Li, Zhong-Tang, Wei, Xu-Fu, Wu, Zhong-Jun
• Format: Article
• Language: English
• Subjects: AMP-Activated Protein Kinases; AMPK; Animals; Anti-Inflammatory Agents; Fisetin; Flavonols; Glycogen Synthase Kinase 3 beta; GSK3β; Hepatic ischemia-reperfusion injury; Inflammasomes; Interleukin-18; Interleukin-1beta; Liver; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; NLRP3; Reperfusion Injury - prevention & control; Transaminases; Tumor Necrosis Factor-alpha
• ISSN: 1499-3872
• DOI: 10.1016/j.hbpd.2021.04.013

Hepatic ischemia-reperfusion (I/R) injury (IRI) represents a crucial challenge in liver transplantation. Fisetin has anti-inflammatory, anti-aging and anti-oxidative properties. This study aimed to examine whether fisetin mitigates hepatic IRI and examine its underlying mechanisms. Sham or warm hepatic I/R operated mice were pretreated with fisetin (5, 10 or 20 mg/kg). Hepatic histological assessments, TUNEL assays and serum aminotransferase measurements were performed. An in vitro hypoxia/reoxygenation (H/R) model using RAW264.7 macrophages pretreated with fisetin (2.5, 5 or 10 µmol/L) was also used. Serum and cell supernatant concentrations of interleukin-1β (IL-1β), IL-18 and tumor necrosis factor-α (TNF-α) were determined by enzyme-linked immunosorbent assay (ELISA). Protein levels of p-GSK3β, p-AMPK and NLR family pyrin domain-containing 3 (NLRP3)-associated proteins were detected by Western blotting. Compared with the I/R group, fisetin pretreatment reduced pathological liver damage, serum aminotransferase levels, serum concentrations of IL-1β, IL-18 and TNF-α in the murine IRI model. Fisetin also reduced the expression of NLRP3 inflammasome-associated proteins (NLRP3, cleaved caspase-1, IL-1β and IL-18) in I/R-operated liver. The experiments in vitro showed that fisetin decreased the release of IL-1β, IL-18 and TNF-α, and reduced the expression of NLRP3 inflammasome-associated proteins in H/R-treated RAW264.7 cells. Moreover, fisetin increased the expressions of p-GSK3β and p-AMPK in both models, indicating that its anti-inflammatory effects were dependent on GSK3β/AMPK signaling. The anti-inflammatory effects of fisetin were partially inhibited by the AMPK specific inhibitor compound C. Fisetin showed protective effects against hepatic IRI, countering inflammatory responses through mediating the GSK3β/AMPK/NLRP3 inflammasome pathway.