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.

近年来，器官间串扰受到越来越多的关注。然而，其根本机制仍不清楚。在这项研究中，我们阐明了受骨骼肌干扰素调节因子 (IRF) 4 调节的内分泌途径，该因子可控制肝脏病理。当采用非酒精性脂肪性肝炎 (NASH) 饮食时，骨骼肌特异性 IRF4 敲除 (F4MKO) 小鼠的肝脏脂肪变性、炎症和纤维化得到改善，且体重没有变化。蛋白质组学分析结果表明，卵泡抑素样蛋白1（FSTL1）可能构成肌肉和肝脏之间的联系。双荧光素酶测定表明 IRF4 可以转录调节 FSTL1。此外，诱导 F4MKO 小鼠肌肉中 FSTL1 表达足以恢复肝脏病理。此外，共培养实验证实，FSTL1通过不同受体在各种肝细胞类型中发挥独特的作用。最后，我们观察到血清 FSTL1 水平与人类 NASH 进展呈正相关。这些数据表明，涉及 IRF4-FSTL1-DIP2A/CD14 的信号通路在 NASH 发病机制中将骨骼肌细胞与肝脏联系起来。