A novel bellidifolin intervention mitigates nonalcoholic fatty liver disease-like changes induced by bisphenol F

Abstract

As a potential endocrine-disrupting chemical, bisphenol F (BPF) may cause nonalcoholic fatty liver disease (NAFLD)-like changes, but the mechanisms under its pathogenesis as well as the intervention strategies remain unclear. Using the electron microscopy technology, along with LipidTOX Deep Red neutral and Bodipy 493/503 staining assays, we observed that BPF treatment elicited a striking accumulation of lipid droplets in HepG2 cells, accompanied by an increased total level of triglycerides. At the molecular level, the lipogenesis-associated mRNAs and proteins, including acetyl-CoA carboxylase, fatty acid synthase, stearoyl-CoA desaturase-1, peroxisome proliferator-activated receptor gamma, and CCAAT-enhancer-binding proteins, increased significantly via the AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) signaling regulation in both in vitro and in vivo studies. Furthermore, the immunofluorescence results also showed the robust lipogenesis induced by BPF, evident in its ability to promote the translocation of sterol regulatory element-binding protein-1c from the cytoplasm to the nuclei. To investigate the intervention strategies for BPF-induced NAFLD-like changes, we demonstrated that bellidifolin, isolated and purified from Swertia chirayita, significantly attenuated BPF-induced lipid droplet deposition in HepG2 cells and NAFLD-like changes in mice by blocking the expression of lipogenesis-associated proteins. Therefore, the present study elucidates the mechanisms underlying the BPF-induced lipid accumulation in HepG2 cells, while also highlighting the potential of bellidifolin to mitigate BPF-induced NAFLD-like changes.

Keywords

bisphenol F / lipogenesis / non-alcoholic fatty liver disease / bellidifolin

Fundings

This work was supported by the Natural Science Foundation of the Jiangsu Higher Education Institutions of China (Grant No. 21KJA330002), Natural Science Foundation of Jiangsu Province (Grant No. BK20211252), Young and Middle-aged Academic Leaders of the "Blue Project" in Jiangsu Universities (2022-2), Jiangsu Health and Family Planning Commission Medical Research Program (Grant No. Z2018035), Project of Public Health Research Center of Jiangnan University (Grant No. JUPH201842) and Natural Science Foundation of Nanjing University of Chinese Medicine (Grant No. XZR2020021).

Acknowledgments

None.

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