School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou 325000, China.
Department of Pharmacy, Taizhou Central Hospital, Taizhou, Zhejiang, China.
Pharmacol Res. 2022 Apr;178:106139. doi: 10.1016/j.phrs.2022.106139. Epub 2022 Feb 21.
Liver fibrosis, which is characterized by excessive accumulation of extracellular matrix (ECM) primarily produced by hepatic stellate cells (HSCs), can eventually lead to cirrhosis. Fibroblast growth factor 18 (FGF18) mediates various biological activities. However, the precise role of FGF18 in the pathological process of liver fibrosis and the underlying mechanisms have not been elucidated. In this study, we found that FGF18 was markedly upregulated in carbon tetrachloride (CCl)-induced fibrotic mouse liver tissues and transforming growth factor β (TGF-β) stimulated LX-2 cells. Furthermore, our studies demonstrated that overexpression of FGF18 in the liver significantly alleviated CCl-induced fibrosis and inhibited the activation of HSCs, while exacerbated by HSC-specific deletion of FGF18. Mechanistically, FGF18 treatment dramatically activated Hippo signaling pathway by suppressing smoothened (SMO) both in vivo and in vitro. Moreover, the interaction between SMO and LATS1 was crucial for the FGF18 induced protective effects. In conclusion, these results indicated that FGF18 attenuates liver fibrosis at least partially via the SMO-LATS1-YAP signaling pathway and therefore may be a potential therapeutic target for liver fibrosis.
肝纤维化的特征是细胞外基质（ECM）的过度积累，主要由肝星状细胞（HSCs）产生，最终可导致肝硬化。成纤维细胞生长因子 18（FGF18）介导多种生物学活性。然而，FGF18 在肝纤维化病理过程中的确切作用及其潜在机制尚未阐明。在本研究中，我们发现 FGF18 在四氯化碳（CCl）诱导的纤维化小鼠肝组织和转化生长因子β（TGF-β）刺激的 LX-2 细胞中显著上调。此外，我们的研究表明，FGF18 在肝脏中的过表达显著减轻了 CCl 诱导的纤维化，并抑制了 HSCs 的激活，而 HSCs 特异性缺失 FGF18 则加剧了纤维化。机制上，FGF18 通过体内和体外抑制 smoothened（SMO）来显著激活 Hippo 信号通路。此外，SMO 和 LATS1 之间的相互作用对于 FGF18 诱导的保护作用至关重要。总之，这些结果表明，FGF18 通过 SMO-LATS1-YAP 信号通路至少部分减轻肝纤维化，因此可能是肝纤维化的潜在治疗靶点。
