Bicyclol alleviates high-fat diet-induced hepatic ER stress- and autophagy-associated non-alcoholic fatty liver disease/non-alcoholic steatohepatitis in mice

Abstract

Background and objective

Non-alcoholic fatty liver disease (NAFLD) is a manifestation of the metabolic syndrome in the liver, and non-alcoholic steatohepatitis (NASH) represents its advanced stage. Bicyclol has protective activity against NAFLD in mice; however, the effect of bicyclol on high-fat diet (HFD)-induced NASH and its underlying molecular mechanism remains unknown particularly anti-endoplasmic reticulum (ER) stress and autophagic machinery potentials. Therefore, the present study was performed to investigate the protective effect and underlying mechanisms of bicyclol action on NAFLD/NASH.

Methods

Mice were fed an HFD to induce NAFLD/NASH, and bicyclol was administered as a treatment. Biochemistry and histopathological assays were performed to evaluate the effects of bicyclol on NAFLD/NASH. Moreover, the levels of hepatic ER stress- and autophagy-related markers were determined by western blotting.

Results

The present results revealed that bicyclol exerted significant protective effects against HFD-induced NAFLD/NASH. This activity was evidenced by the decrease in elevated serum transaminase and hepatic triglyceride levels, and the attenuation of negative histopathological changes. Bicyclol considerably alleviated hepatic inflammation and apoptosis. The protein expression of ER stress-related markers, including C/EBP homologous protein (CHOP) and glucose-regulated protein 78 (GRP78), was downregulated by the bicyclol treatment in HFD-induced mice. However, the protein expression of autophagy-related markers (LC3 and Beclin 1) was upregulated by the treatment with bicyclol.

Conclusion

Bicyclol protected HFD-induced NASH, and partly due to its ability of reducing ER stress and promoting autophagy.

Keywords:

• Bicyclol
• NASH
• ER stress
• autophagy
• apoptosis

Acknowledgements

We thank Zhejiang Academy of Medical Sciences (Hangzhou, China) for their valuable help.

Disclosure statement

The authors report no conflict of interest.

Data availability statement

The data that supported the study's findings is accessible from the first author, and included within the article.

Additional information

Funding

This work was supported by the Ningbo Natural Science Foundation (Grant No. 202003N4336, 2019A610223, 2019A610211, 2019A610350, 2018A610235, and 2016A610240), the Zhejiang Provincial Medicine and Health Technology Project (Grant No. 2020RC106), Basic Public Welfare Project of Zhejiang Province (Grant No. LGF22H310003), the Ningbo Science and Technology Program Public Welfare Project (Grant No. 2019C50066 and 2021S098), and the Zhejiang University Student Science and Technology Innovation Activity Plan (Grant No. 2018R458002 and 2021R460001).