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

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 () and Xingxing Kong ()
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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
Huanqing Gao: Fudan University
Xingxing Kong: Fudan University

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41832-3

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