Hippo-Yap信号通路在肝脏疾病中的作用及其研究进展

Role of Hippo-Yap signaling pathway in liver diseases and its research progress

河马(Hippo)信号通路最初作为一种抑制果蝇组织生长的通路被发现,主要由MST1/2、LATS1/2和Yap/TAZ三种激酶级联组成。随着研究的进展,在哺乳动物中Hippo信号通路的同源基因也得到了证实,并且在控制器官大小和其他生理功能当中也发挥着关键的作用。Hippo信号通路主要通过调控Yap的核移位发生相应的作用。当Hippo信号通路的上游激酶失活时,Yap/TAZ被去磷酸化并且能够作为转录共激活因子进入细胞核,与相应的转录因子结合发挥作用。既往Hippo-Yap信号通路研究主要集中于细胞命运、新陈代谢、肿瘤发生和免疫系统等方面。随着研究的逐步深入以及肝脏疾病的发生率逐步升高,Hippo信号通路在肝脏疾病的发生与发展过程中的相关研究取得一定的进展。笔者从多种临床常见相关肝脏疾病(胆汁淤积性肝损伤、肝缺血再灌注损伤、非酒精性脂肪性肝病、酒精性肝病、对乙酰氨基酚诱导肝损伤、肝纤维化以及肝癌)阐述Hippo-Yap信号通路在其中所发挥作用。

The Hippo signaling pathway,initially discovered as a pathway that inhibits tissue growth in Drosophila,is mainly composed of three kinase cascades:MST1/2,LATS1/2,and Yap/TAZ.As research progressed,homologous genes of the Hippo signaling pathway were also identified in mammals,and they play a critical role in controlling organ size and other physiological functions.The Hippo signaling pathway mainly exerts its effects by regulating the nuclear translocation of Yap.When the upstream kinases of the Hippo signaling pathway are inactivated,Yap/TAZ becomes dephosphorylated and can enter the cell nucleus as a transcriptional co-activator,where it interacts with specific transcription factors to exert its effects.Previous studies on the Hippo-Yap signaling pathway have mainly focused on cell fate,metabolism,tumorigenesis,and the immune system.As research continues to deepen and the incidence of liver diseases increases,significant progress has been made in understanding the role of the Hippo signaling pathway in the occurrence and development of liver diseases.In this context,the authors discuss the involvement of the Hippo-Yap signaling pathway in various clinically common liver diseases,including cholestatic liver injury,liver ischemia-reperfusion injury,non-alcoholic fatty liver disease,alcoholic liver disease,acetaminophen-induced liver injury,liver fibrosis,and liver cancer.