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Forkhead box A3 attenuated the progression of fibrosis in a rat model of biliary atresia
Rui Dong1, Yifan Yang1, Zhen Shen1
1Department of Pediatric Surgery, Children's Hospital of Fudan University, and Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China.
Insights
Forkhead box A3 (Foxa3) is decreased in biliary atresia, a rare infant liver disease. Increasing Foxa3 may protect against liver fibrosis and improve survival in affected infants.
Area of Science:
- Pediatric Gastroenterology
- Hepatology
- Molecular Biology
Background:
- Biliary atresia is a fatal infant liver disease characterized by bile duct destruction and fibrosis.
- The underlying causes and mechanisms of biliary atresia remain largely unknown.
- Forkhead box A3 (Foxa3) is investigated for its potential role in liver disease treatment.
Purpose of the Study:
- To investigate factors involved in biliary atresia, focusing on the role of Foxa3.
- To explore Foxa3's function in the context of biliary atresia pathogenesis and liver fibrosis.
Main Methods:
- RNA sequencing of liver tissues from biliary atresia and choledochal cyst patients.
- Utilized a rat bile duct ligation (BDL) model with adenovirus transduction to study Foxa3 function.
- Analyzed gene expression, protein deposition, and fibrosis markers.
Main Results:
- Biliary atresia livers showed enrichment in pathways related to cell junctions, cell cycle, apoptosis, and signaling.
- Foxa3 expression was significantly decreased in biliary atresia patients, correlating with poorer survival.
- Foxa3 expression in BDL rats reduced collagen deposition and profibrotic markers, indicating a protective effect against fibrosis.
Conclusions:
- Foxa3 expression is reduced in biliary atresia and its lower levels predict worse patient outcomes.
- Foxa3 demonstrates a protective role against liver fibrosis progression in biliary atresia.
- Augmenting Foxa3 levels presents a potential targeted therapeutic strategy for biliary atresia.
Abstract:
Biliary atresia is a rare, devastating disease of infants where a fibroinflammatory process destroys the bile ducts, leading to fibrosis and biliary cirrhosis, and death if untreated. The cause and pathogenesis remain largely unknown. We tried to investigate factors involved in biliary atresia, especially forkhead box A3 (Foxa3), which might exert a role in the treatment of liver disease. We used RNA sequencing to sequence the whole transcriptomes of livers from six biliary atresia and six choledochal cysts patients. Then, we employed a rat disease model by bile duct ligation (BDL) and adenovirus transduction to address the function of Foxa3 in biliary atresia. We found that tight junction, adherence junction, cell cycle, apoptosis, chemokine singling, VEGF and MAPK signaling pathways were enriched in biliary atresia livers. We showed that Foxa3 expression was notably decreased in liver samples from biliary atresia patients. More importantly, we found that its lower expression predicted a poorer overall survival of biliary atresia patients. Rats that received BDL surgery and Foxa3 expression adenovirus resulted in a significant decrease in the deposition of collagen, and expression of profibrotic cytokines (transforming growth factor-β and connective tissue growth factor) and fibrosis markers (α-smooth muscle actin, collagen I and collagen III), as compared with rats that received BDL surgery and control adenovirus. Our data suggested a protection role for Foxa3 during the progression of liver fibrosis in biliary atresia, and thereby supported increasing Foxa3 as a targeted treatment strategy.