Celastrol ameliorates fibrosis in Western diet/tetrachloromethane-induced nonalcoholic steatohepatitis by suppressing Notch/osteopontin signaling.

BACKGROUND

Celastrol was recently identified as a potential treatment for obesity and hepatic steatosis. However, whether Celastrol effectively suppresses the nonalcoholic fatty liver disease (NAFLD) stage remains unknown. This study aimed to evaluate the role of Celastrol in the progression from simple steatosis to nonalcoholic steatohepatitis (NASH) and fibrosis.

METHODS

C57BL/6 mice were fed a Western diet combined with a weekly low-dose injection of CCl4 (WD/CCl4) for 16 weeks to establish NASH models. The effects of Celastrol on NASH were further explored through histopathological assessments, immunoblotting, and in vitro analyses.

RESULTS

Celastrol treatment effectively attenuated hepatic steatosis and fibrosis in WD/CCl4-induced NASH models, in which Notch2 was downregulated by Celastrol in a posttranscriptional manner. In vitro experiments revealed that Notch2 suppression in Celastrol-treated hepatocytes further decreased osteopontin (OPN) levels, inhibiting hepatic stellate cells (HSCs) activation. Moreover, the protective effects of Celastrol on NASH progression were abolished in Notch2-overexpressing mice.

CONCLUSION

This study demonstrated the protective effects of Celastrol on NASH-related liver fibrosis by modulating Notch/OPN signaling, providing fresh insights into the potential application of Celastrol in NASH treatment.