Inhibiting Yes-associated protein alleviates CCl4 liver fibrosis in mice by reducing epithelial mesenchymal transition
10.12122/j.issn.1673-4254.2024.10.01
- VernacularTitle:抑制Yes相关蛋白通过抑制上皮间质转化减轻CCl4诱导的小鼠肝纤维化
- Author:
Wen ZHAO
1
;
Hejing RUAN
;
Siyuan WANG
;
Yuzhe CHENG
;
Miao LEI
;
Jiufa ZHAO
;
Chuanmiao LIU
Author Information
1. 蚌埠医科大学第一附属医院传染性疾病科,安徽 蚌埠 233000
- Keywords:
liver fibrosis;
Yes-associated protein;
epithelial mesenchymal transition;
biomarkers
- From:
Journal of Southern Medical University
2024;44(10):1839-1849
- CountryChina
- Language:Chinese
-
Abstract:
Objective To explore whether Yes-associated protein(YAP)affects occurrence and progression of liver fibrosis by regulating epithelial-mesenchymal transition(EMT).Methods In a 8-week-old C57BL/6 mouse model of CCl4-induced liver fibrosis,the effect of verteporfin(a YAP inhibitor)intervention was assessed with HE staining and by detecting liver biochemistry and expressions of YAP and EMT-related genes using immunohistochemistry and Western blotting.Transcriptome and proteomic sequencing and informatics analysis were used to investigate the main downstream pathways of YAP in liver fibrosis.Serum levels of YAP,N-cadherin,vimentin and Twist were examined in 60 healthy individuals,60 patients with chronic hepatitis B(CHB),and 60 patients with HBV-related liver cirrhosis.In another 24 C57BL/6 mice,the effects of Twist inhibitor alone or in combination with harmine(a YAP activator)on CCl4-induced liver fibrosis were evaluated by histopathological examination and Western blotting.Results The mouse models of liver fibrosis showed obvious structural damages of the liver lobes with formation of pseudolobules,and verteporfin treatment significantly improved these pathologies and lowered plasma ALT and AST levels of the mice.Transcriptome and proteomic sequencing and informatics analysis suggested that N-cadherin and Twist were differentially expressed in liver fibrosis in close correlation with YAP.Inhibition of YAP obviously downregulated hepatic N-cadherin and Twist protein expressions in the mice with liver fibrosis.In patients with CHB and liver cirrhosis,serum levels of YAP elevated obviously with the severity of liver fibrosis and were significantly correlated with N-cadherin,vimentin and Twist levels.In mice with liver fibrosis,inhibiting Twist effectively improved liver inflammation and fibrosis,while the combined treatment with YAP activator worsened hepatic collagen fiber deposition and increased hepatic YAP and α-SMA expressions.Conclusion EMT is an important pathogenic mechanism of liver fibrosis,and inhibiting YAP can alleviate liver fibrosis by reducing EMT.
