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

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. In this study Guo et al. show that skeletal muscle IRF4-FSTL1 exerts metabolic regulation on the liver via DIP2A/CD14 in NASH. FSTL1 from skeletal muscle that enters the circulation promotes the development of NASH.

Automated summary

In this study, the researchers elucidate an endocrine pathway involving skeletal muscle interferon regulatory factor 4 (IRF4) and follistatin-like protein 1 (FSTL1), which manipulates liver pathology in the pathogenesis of nonalcoholic steatohepatitis (NASH). They demonstrate that IRF4 can transcriptionally regulate FSTL1 and that inducing FSTL1 expression in the muscles of genetically modified mice is sufficient to restore liver pathology. Co-culture experiments reveal that FSTL1 plays a distinct role in various liver cell types via different receptors. Furthermore, the study observes a positive correlation between serum FSTL1 levels and NASH progression in humans.