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| Blocking of fibroblast growth factor receptor improves liver fibrosis in mice via inhibiting hepatic stellate cell activation |
| ZHOU Dongyan, CHEN Shuangya, HE Ping, LI Xiaokun, WANG Cong |
| School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China |
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ZHOU Dongyan,CHEN Shuangya,HE Ping, et al. Blocking of fibroblast growth factor receptor improves liver fibrosis in mice via inhibiting hepatic stellate cell activation[J]. JOURNAL OF WEZHOU MEDICAL UNIVERSITY, 2023, 53(8): 603-612.
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Abstract Objective: To study the effect of fibroblast growth factor receptor (FGFR) inhibition on carbon tetrachloride (CCl4)-induced liver fibrosis in mice and explore its mechanism. Methods: CCl4-induced liver fibrosis mouse model was treated with FGFR inhibitor AZD4547 and the changes in liver weight, serum alanine
transaminase (ALT) and serum aspertate aminotransferase (AST) concentrations were compared between groups. Histological staining was used to analyze changes in liver collagen deposition, fibrosis, liver inflammation and activation of hepatic stellate cells (HSCs). Quantitative PCR (qPCR) was used to detect the expression of fibrosis related genes (α-SMA, Col1a1 mRNA) in liver. Tumor necrosis factor α (TNFα)-induced human hepatic stellate cell line LX-2 was used as the inflammation model to investigate the effect of AZD4547. The expression of Vimentin was observed by immunofluorescence staining and the ultrastructure were checked by transmission electron microscope. JC-1 staining was applied to detect the mitochondrial membrane potential. The expression of adiponectin mRNA and protein in cells was analyzed, and the phosphorylation levels of JNK and AMPK were detected by Western blot. Results: FGFR inhibitor significantly reduced liver fibrosis, inflammation response and hepatic stellate cell activation in CCl4-induced mouse model without affecting ALT and AST (P<0.05). Interestingly, inhibition of FGFR could increase adiponectin expression at the damaged site, which plays the role of compensatory protection (P<0.05). In addition, FGFR inhibitors not only markedly reversed morphology and ultrastructure of TNFα-induced hepatic stellate cells, but also downregulated JNK activation (P<0.05) and alleviated mitochondrial dysfunction in HSCs (P<0.05), where adiponectin and p-AMPK were increased, suggesting a negative feedback control by FGF signaling inhibition (P<0.05). Conclusion: Inhibition of FGFR signaling indicates therapeutic effect on liver fibrosis via inhibiting the inflammation and activation of HSCs.
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