EP300/YAP1-SERPINE1 Signaling Regulates Ductular Reaction and Liver Fibrosis in Biliary Atresia

Area of Science:

• Hepatology
• Molecular Biology
• Pediatric Gastroenterology

Background:

• Biliary atresia (BA) is the leading cause of infantile cholestatic liver disease.
• BA is characterized by ductular reaction (DR) and liver fibrosis (LF), but the underlying mechanisms remain unclear.
• This study investigates molecular signals in cholangiocytes contributing to LF in BA.

Purpose of the Study:

• To elucidate the role of Yes1 associated transcriptional regulator (YAP1) in biliary atresia.
• To identify molecular pathways involved in cholangiocyte-induced liver fibrosis.
• To explore EP300 as a therapeutic target for liver fibrosis in BA.

Main Methods:

• Utilized BA liver tissue and cellular models.
• Performed ATAC-seq and RNA-seq on rhesus rotavirus (RRV)-infected cholangiocyte organoids (COs).
• Investigated EP300/YAP1-SERPINE1 pathway interactions using co-IP, ChIP, and luciferase assays; validated findings in RRV mouse models.

Main Results:

• YAP1 upregulation in BA cholangiocytes promoted proliferation and activated hepatic stellate cells.
• Identified SERPINE1 as a YAP1 target, with EP300 facilitating its transcription.
• EP300 inhibition in mice reduced DR and LF, improving cholangiocyte integrity in BA and RRV models.

Conclusions:

• The EP300/YAP1-SERPINE1 pathway is crucial for DR-associated liver fibrosis in BA.
• EP300 suppression presents a potential therapeutic strategy for progressive liver fibrosis in BA patients.