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Updated: Sep 13, 2025
A Mouse Model of Chronic Liver Fibrosis for the Study of Biliary Atresia
Published on: February 3, 2023
PRAG1 promotes cholangiocyte epithelial-mesenchymal transition and liver fibrosis in biliary atresia
Wei Zhu1, Zhongxian Zhu1, Jie Feng2
1Department of Pediatric Surgery, Children's Hospital of Nanjing Medical University, Nanjing 210008, China.
Insights
PEAK1-related kinase activating pseudokinase 1 (PRAG1) promotes liver fibrosis in biliary atresia by driving epithelial-mesenchymal transition. PRAG1 targets FBXO11 to stabilize SNAIL1, exacerbating fibrosis progression in this pediatric liver disease.
Area of Science:
- Hepatology
- Pediatric Gastroenterology
- Molecular Biology
Background:
- Biliary atresia (BA) is a severe pediatric liver disease characterized by progressive liver fibrosis (LF), significantly impacting patient prognosis.
- Epithelial-mesenchymal transition (EMT) is a critical cellular process implicated in the development and advancement of LF in BA.
Purpose of the Study:
- To investigate the role and underlying mechanism of PEAK1-related kinase activating pseudokinase 1 (PRAG1) in EMT-associated LF within the context of BA.
- To explore the molecular interactions of PRAG1 in promoting fibrogenesis and EMT in biliary epithelial cells.
Main Methods:
- Analysis of PRAG1 expression in BA patients and a bile duct ligation (BDL) rodent model.
- In vitro studies using human intrahepatic biliary epithelial cells (HIBECs) to assess PRAG1's effects on EMT markers, fibrosis markers, and cell proliferation.
- Investigation of PRAG1's interaction with F-box protein 11 (FBXO11) and its impact on SNAIL1 regulation.
Main Results:
- PRAG1 expression was significantly elevated in BA patients and the BDL model, correlating positively with fibrosis severity and cholangiocyte/mesenchymal markers.
- PRAG1 overexpression in HIBECs promoted mesenchymal and fibrosis markers (VIM, ACTA2, COL1A1, FN1), inhibited epithelial marker CDH1, and enhanced cell proliferation.
- PRAG1 overexpression led to increased SNAIL1 expression and delayed degradation, mediated by reversed FBXO11 inhibition.
Conclusions:
- PRAG1 plays a significant role in promoting EMT and liver fibrosis progression in biliary atresia.
- The PRAG1-FBXO11-SNAIL1 axis represents a potential therapeutic target for mitigating LF in BA.
- PRAG1's pro-fibrotic and pro-EMT activities highlight its importance in the pathogenesis of BA-associated liver disease.
Abstract:
Biliary atresia (BA) is a severe pediatric liver disease in which progressive liver fibrosis (LF) significantly affects the prognosis. Epithelial-mesenchymal transition (EMT) is considered a key factor in the development and progression of LF. This study aimed to investigate the role and mechanism of PEAK1-related kinase activating pseudokinase 1 (PRAG1) in the EMT-related LF process in BA. We found that the expression of PRAG1 was significantly elevated in both patients with BA and the bile duct ligation (BDL) model, and predominantly localized on biliary epithelial cells. Also, the expression of PRAG1 positively correlated with the cholangiocyte marker KRT19 and the mesenchymal marker ACTA2, and increased with the severity of fibrosis. In human intrahepatic biliary epithelial cells (HIBECs), PRAG1 promoted the expression of mesenchymal markers (VIM and ACTA2) and fibrosis markers (COL1A1 and FN1), inhibited the expression of the epithelial marker CDH1, and enhanced cell proliferation. The key factor of EMT-SNAIL1 presented increased expression and delayed degradation after overexpression of PRAG1. Moreover, we identified PRAG1 could bind with F-box protein 11 (FBXO11) and subsequently reversed FBXO11-mediated inhibition of SNAIL1 protein expression, cell proliferation, and the EMT phenotype. This study provides the potential role of PRAG1 in the mechanisms underlying the LF progression of BA.
