Zhao Ye, Wang Huiling, He Tianhua, Ma Bo, Chen Guoguang, Tzeng Chimeng
School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, 211800, China.
School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361005, China.
J Cell Commun Signal. 2023 Dec;17(4):1335-1354. doi: 10.1007/s12079-023-00775-6. Epub 2023 Jun 20.
Liver fibrosis is an aberrant wound healing response to tissue injury characterized by excessive extracellular matrix deposition and loss of normal liver architecture. Hepatic stellate cells (HSCs) activation is regards to be the major process in liver fibrogenesis which is dynamic and reversible. Both Hippo signaling core factor Yap and Hedgehog (Hh) signaling promote HSCs transdifferentiation thereby regulating the repair process of liver injury. However, the molecular function of YAP and the regulation between Yap and Hh during fibrogenesis remain uncertain. In this study, the essential roles of Yap in liver fibrosis were investigated. Yap was detected to be increased in liver fibrotic tissue by the thioacetamide (TAA)-induced zebrafish embryonic and adult models. Inhibition of Yap by both embryonic morpholino interference and adult's inhibitor treatment was proved to alleviate TAA-induced liver lesions by and histology and gene expression examination. Transcriptomic analysis and gene expression detection showed that Yap and Hh signaling pathway have a cross talking upon TAA-induced liver fibrosis. In addition, TAA induction promoted the nuclear colocalization of YAP and Hh signaling factor GLI2α. This study demonstrates that Yap and Hh play synergistic protective roles in liver fibrotic response and provides new theoretical insight concerning the mechanisms of fibrosis progression.
肝纤维化是对组织损伤的一种异常伤口愈合反应，其特征是细胞外基质过度沉积和正常肝结构丧失。肝星状细胞（HSCs）激活被认为是肝纤维化形成中的主要过程，该过程是动态且可逆的。Hippo信号通路的核心因子Yap和Hedgehog（Hh）信号通路均促进肝星状细胞转分化，从而调节肝损伤的修复过程。然而，Yap的分子功能以及纤维化形成过程中Yap与Hh之间的调控关系仍不明确。在本研究中，我们对Yap在肝纤维化中的重要作用进行了研究。通过硫代乙酰胺（TAA）诱导的斑马鱼胚胎和成年模型，检测到肝纤维化组织中Yap表达增加。通过胚胎吗啉代干扰和成年抑制剂处理抑制Yap，经组织学和基因表达检测证明可减轻TAA诱导的肝损伤。转录组分析和基因表达检测表明，在TAA诱导的肝纤维化过程中，Yap和Hh信号通路存在相互作用。此外，TAA诱导促进了YAP与Hh信号因子GLI2α的核共定位。本研究表明，Yap和Hh在肝纤维化反应中发挥协同保护作用，并为纤维化进展机制提供了新的理论见解。
