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Sulforaphane ameliorates non-alcoholic fatty liver disease in mice by promoting FGF21/FGFR1 signaling pathway

Abstract

Most studies regarding the beneficial effect of sulforaphane (SFN) on non-alcoholic fatty liver disease (NAFLD) have focused on nuclear factor E2-related factor 2 (Nrf2). But the molecular mechanisms underlying the beneficial effect of SFN in the treatment of NAFLD remain controversial. Fibroblast growth factor (FGF) 21 is a member of the FGF family expressed mainly in liver but also in adipose tissue, muscle and pancreas, which functions as an endocrine factor and has been considered as a promising therapeutic candidate for the treatment of NAFLD. In the present study we investigated whether FGF21 was involved in the therapeutic effect of SFN against NAFLD. C57BL/6J mice were fed a high-fat diet (HFD) for 12 weeks to generate NAFLD and continued on the HFD for additional 6 weeks with or without SFN treatment. We showed that administration of SFN (0.56 g/kg) significantly ameliorated hepatic steatosis and inflammation in NAFLD mice, along with the improved glucose tolerance and insulin sensitivity, through suppressing the expression of proteins responsible for hepatic lipogenesis, while enhancing proteins for hepatic lipolysis and fatty acids oxidation. SFN administration significantly increased hepatic expression of FGFR1 and fibroblast growth factor 21 (FGF21) in NAFLD mice, along with decreased phosphorylation of p38 MAPK (the downstream of FGF21). HepG2 cells were treated in vitro with FFAs (palmitic acid and oleic acid) followed by different concentrations of SFN. We showed that the effects of SFN on FGF21 and FGFR1 protein expression were replicated in FFAs-treated HepG2 cells. Moreover, the increased FGFR1 protein occurred earlier than increased FGF21 protein. Interestingly, the rapid effect of SFN on FGFR1 protein was not regulated by the FGFR1 gene transcription. Knockdown of FGFR1 and p38 genes weakened SFN-reduced lipid deposition in FFAs-treated HepG2 cells. SFN administration in combination with rmFGF21 (1.5 mg/kg, i.p., every other day) for 3 weeks further suppressed hepatic steatosis in NAFLD mice. In conclusion, SFN ameliorates lipid metabolism disorders in NAFLD mice by upregulating FGF21/FGFR1 pathway. Our results verify that SFN may become a promising intervention to treat or relieve NAFLD.

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Fig. 1: Effects of SFN on HFD-induced hepatic steatosis and inflammation.
Fig. 2: Regulation of hepatic lipogenesis, lipolysis and fatty acid oxidation by SFN.
Fig. 3: Effects of SFN on glucose tolerance and insulin sensitivity.
Fig. 4: Regulation of hepatic ER stress, FGF21-related and MAPK protein expression levels by SFN.
Fig. 5: FGF21 signaling was the target of SFN and the beneficial role of SFN was influenced by the knockdown of FGFR1 in vitro.
Fig. 6: SFN combines with exogenous FGF21 to further improve hepatic steatosis in vivo and in vitro.
Fig. 7: Schematic diagram showing the effect of SFN on NAFLD.

Data availability

The authors declare that the main data supporting the findings of this study are available within the article and its Supplementary Information files. Extra data are available from the corresponding author upon request.

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Acknowledgements

This research was supported by the National Natural Science Foundation of China (Grant No. 31871773 to QXZ, 81600664 to XLY and 31471321 to ZH).

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YKW performed experiments and analyzed data. ZNR and SLZ assisted the experiments. GW, HZ and WC critically reviewed the manuscript. YZW and XLY provided the FGF21 growth factor. YKW and QXZ designed and interpreted experiments. YKW, ZH and QXZ wrote the paper.

Corresponding authors

Correspondence to Xian-long Ye or Qi-xiao Zhai.

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The authors declare no competing interests.

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Wu, Yk., Ren, Zn., Zhu, Sl. et al. Sulforaphane ameliorates non-alcoholic fatty liver disease in mice by promoting FGF21/FGFR1 signaling pathway. Acta Pharmacol Sin (2021). https://doi.org/10.1038/s41401-021-00786-2

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Keywords

  • non-alcoholic fatty liver disease
  • sulforaphane
  • fibroblast growth factor 21
  • fibroblast growth factor receptor-1
  • p38MAPK
  • insulin sensitivity

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