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Bmal1 inhibits phenotypic transformation of hepatic stellate cells in liver fibrosis via IDH1/α-KG-mediated glycolysis

A Correction to this article was published on 20 May 2021

This article has been updated

Abstract

Hepatic stellate cells (HSCs) play an important role in the initiation and development of liver fibrogenesis, and abnormal glucose metabolism is increasingly being considered a crucial factor controlling phenotypic transformation in HSCs. However, the role of the factors affecting glycolysis in HSCs in the experimental models of liver fibrosis has not been completely elucidated. In this study, we showed that glycolysis was significantly enhanced, while the expression of brain and muscle arnt-like protein-1 (Bmal1) was downregulated in fibrotic liver tissues of mice, primary HSCs, and transforming growth factor-β1 (TGF-β1)-induced LX2 cells. Overexpression of Bmal1 in TGF-β1-induced LX2 cells blocked glycolysis and inhibited the proliferation and phenotypic transformation of activated HSCs. We further confirmed the protective effect of Bmal1 in liver fibrosis by overexpressing Bmal1 from hepatic adeno-associated virus 8 in mice. In addition, we also showed that the regulation of glycolysis by Bmal1 is mediated by the isocitrate dehydrogenase 1/α-ketoglutarate (IDH1/α-KG) pathway. Collectively, our results indicated that a novel Bmal1-IDH1/α-KG axis may be involved in regulating glycolysis of activated HSCs and might hence be used as a therapeutic target for alleviating liver fibrosis.

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Fig. 1: Establishment of liver fibrosis model induced by CCl4 in C57 mice.
Fig. 2: Enhanced glycolysis in activated HSCs.
Fig. 3: Effect of glycolysis inhibitor 2-DG on activated LX2 cells.
Fig. 4: Downregulated expression of Bmal1 in vivo and in vitro.
Fig. 5: Overexpression of Bmal1 inhibits glycolysis.
Fig. 6: Overexpression of Bmal1 regulates the phenotypic transformation of activated HSCs.
Fig. 7: Overexpression of IDH1 promotes the production of α-KG to inhibit glycolysis.
Fig. 8: Bmal1 targets IDH1/α-KG to inhibit HSCs glycolysis.
Fig. 9: Liver-specific Bmal1 overexpression inhibits glycolysis of CCl4-induced liver fibrosis in mice.
Fig. 10: Liver-specific Bmal1 overexpression alleviates CCl4-induced liver fibrosis.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (Grant/Award Number: 82070629) and Natural Science Foundation of Anhui Province of China (Grant/Award Number: 20080852MH242).

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Contributions

LX, YWZ and MFW conceived and designed the study, performed the experiments, collected the data, analyzed and interpreted the data, and drafted the manuscript. JS and JLC contributed to data collection and some of the experiments. JQW, QXL and SYC provided a series of experimental instructions. LZ contributed to language polishing. TYY contributed to the revision of the manuscript.

Corresponding author

Correspondence to Lei Zhang.

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The authors declare no competing interests.

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Xu, L., Yang, Ty., Zhou, Yw. et al. Bmal1 inhibits phenotypic transformation of hepatic stellate cells in liver fibrosis via IDH1/α-KG-mediated glycolysis. Acta Pharmacol Sin (2021). https://doi.org/10.1038/s41401-021-00658-9

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Keywords

  • Bmal1
  • HSCs
  • glycolysis
  • IDH1
  • α-KG
  • liver fibrosis

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