Inhibiting Yes-associated protein alleviates CCl4 liver fibrosis in mice by reducing epithelial mesenchymal transition
Objective: To investigate the role of Yes-associated protein (YAP) in the onset and progression of liver fibrosis through the regulation of epithelial-mesenchymal transition (EMT).
Methods: In an 8-week-old C57BL/6 mouse model of CCl4-induced liver fibrosis, the effects of verteporfin (a YAP inhibitor) were evaluated using hematoxylin and eosin (HE) staining, liver biochemistry, and the expression levels of YAP and EMT-related genes through immunohistochemistry and Western blotting. Transcriptomic and proteomic analyses were performed to identify the primary downstream pathways of YAP in liver fibrosis. Serum levels of YAP, N-cadherin, vimentin, and Twist were measured in 60 healthy individuals, 60 chronic hepatitis B (CHB) patients, and 60 patients with HBV-related liver cirrhosis. Additionally, the effects of Twist inhibition, alone or combined with harmine (a YAP activator), on CCl4-induced liver fibrosis were assessed in another cohort of 24 C57BL/6 mice via histopathological analysis and Western blotting.
Results: Liver fibrosis in the mouse models exhibited significant structural damage, including pseudolobule formation. Verteporfin treatment notably ameliorated these pathological changes and reduced plasma ALT and AST levels. Transcriptomic and proteomic data revealed differential expression of N-cadherin and Twist, both of which were closely associated with YAP in the context of liver fibrosis. YAP inhibition significantly decreased the expression of N-cadherin and Twist in the liver tissue. In patients with CHB and liver cirrhosis, serum levels of YAP were elevated in line with the severity of liver fibrosis and showed a significant correlation with N-cadherin, vimentin, and Twist. In mice, Twist inhibition led to improvements in liver inflammation and fibrosis, while combined treatment with a YAP activator exacerbated collagen deposition and increased hepatic YAP and α-SMA expression.
Conclusion: EMT plays a crucial role in the pathogenesis of liver fibrosis, and inhibiting YAP can reduce liver fibrosis by diminishing EMT processes.