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Metabolic crosstalk between skeletal muscle cells and liver through IRF4-FSTL1 in nonalcoholic steatohepatitis

Author

Listed:
  • Shanshan Guo

    (Fudan University)

  • Yonghao Feng

    (Fudan University)

  • Xiaopeng Zhu

    (Fudan University)

  • Xinyi Zhang

    (Fudan University)

  • Hui Wang

    (Fudan University)

  • Ruwen Wang

    (Shanghai University of Sport)

  • Qiongyue Zhang

    (Fudan University)

  • Yiming Li

    (Fudan University)

  • Yan Ren

    (Shanghai University of Traditional Chinese Medicine)

  • Xin Gao

    (Fudan University)

  • Hua Bian

    (Fudan University)

  • Tiemin Liu

    (Fudan University
    Fudan University
    Fudan University
    Fudan University)

  • Huanqing Gao

    (Fudan University)

  • Xingxing Kong

    (Fudan University
    Fudan University)

Abstract

Inter-organ crosstalk has gained increasing attention in recent times; however, the underlying mechanisms remain unclear. In this study, we elucidate an endocrine pathway that is regulated by skeletal muscle interferon regulatory factor (IRF) 4, which manipulates liver pathology. Skeletal muscle specific IRF4 knockout (F4MKO) mice exhibited ameliorated hepatic steatosis, inflammation, and fibrosis, without changes in body weight, when put on a nonalcoholic steatohepatitis (NASH) diet. Proteomics analysis results suggested that follistatin-like protein 1 (FSTL1) may constitute a link between muscles and the liver. Dual luciferase assays showed that IRF4 can transcriptionally regulate FSTL1. Further, inducing FSTL1 expression in the muscles of F4MKO mice is sufficient to restore liver pathology. In addition, co-culture experiments confirmed that FSTL1 plays a distinct role in various liver cell types via different receptors. Finally, we observed that the serum FSTL1 level is positively correlated with NASH progression in humans. These data indicate a signaling pathway involving IRF4-FSTL1-DIP2A/CD14, that links skeletal muscle cells to the liver in the pathogenesis of NASH.

Suggested Citation

  • Shanshan Guo & Yonghao Feng & Xiaopeng Zhu & Xinyi Zhang & Hui Wang & Ruwen Wang & Qiongyue Zhang & Yiming Li & Yan Ren & Xin Gao & Hua Bian & Tiemin Liu & Huanqing Gao & Xingxing Kong, 2023. "Metabolic crosstalk between skeletal muscle cells and liver through IRF4-FSTL1 in nonalcoholic steatohepatitis," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41832-3
    DOI: 10.1038/s41467-023-41832-3
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    References listed on IDEAS

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    1. Nadim Aizarani & Antonio Saviano & Sagar & Laurent Mailly & Sarah Durand & Josip S. Herman & Patrick Pessaux & Thomas F. Baumert & Dominic Grün, 2019. "A human liver cell atlas reveals heterogeneity and epithelial progenitors," Nature, Nature, vol. 572(7768), pages 199-204, August.
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