Metabolic Crosstalk Between Skeletal Muscle Cells and Liver Through IRF4-FSTL1 in Nonalcoholic Steatohepatitis

Overview

Journal Nat Commun

Specialty Biology

Date 2023 Sep 28

PMID 37770480

Authors

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

Affiliations

Soon will be listed here.

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.

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