Nuciferine alleviates non-alcoholic steatohepatitis by restoring endoplasmic reticulum stress

Abstract

Background

Nuciferine(NF) has been shown to alleviate Non-alcoholic steatohepatitis (NASH), however, the exact mechanism of action remains to be explored. In this study we evaluated the pharmacological impact of NF on NASH models in vitro and in vivo, with a particular focus on its roles in regulating lipid metabolism, mitigating endoplasmic reticulum stress(ERS), and safeguarding mitochondrial function.

Methods

In vivo, Male C57BL/6J mice were fed a methionine and choline-deficient(MCD) diet to induce NASH, and then given NF orally for four weeks. NASH indexes were evaluated by histopathological analysis and biochemical parameters. In vitro, we established a free fatty acid (FFA)-induced NASH model in HepG2 cells and evaluated NASH by detecting cellular lipids and inflammatory factors.

Results

We found that NF had the potential ability to counteract the weight loss triggered by the MCD diet and to dose-dependently ameliorate liver steatosis and inflammatory responses as observed histopathologically. It was further found that NF was able to reduce hepatic malondialdehyde (MDA) levels, and elevate superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) activities. An in vitro model of FFA-induced steatotic HepG2 cells was established, and it was found that NF was able to reduce cellular lipid accumulation, lower triglyceride (TG) levels, and reduce MDA levels and restore mitochondrial respiratory function. In vitro and in vivo studies showed that NF was able to downregulate ERS-related protein expression.

Conclusion

In conclusion, NF played a multifaceted role by reducing oxidative stress, decreasing the levels of inflammatory cytokines, and mitigating ERS, which are pivotal in the pathogenesis of NASH.