Abstract
Background and Aim: Biliary atresia (BA), an inflammatory destruction of the bile ducts, leads to liver fibrosis in infants and accounts for half of cases undergoing pediatric liver transplantation. Yes-associated protein (YAP), an effector of the Hippo signaling pathway, is critical in maintaining identities of bile ductal cells. Here, we evaluated the expression of YAP and YAP target genes in BA livers and a rhesus rotavirus (RRV)-induced BA mice model.Methods: Liver specimens collected from 200 BA patients were compared with those of 30 non-BA patients. Model mice liver tissues were also collected. The expression of YAP and YAP target genes were measured by transfection, RNA-seq, immunohistochemistry, immunoblot, and quantitative PCR. Masson's trichrome staining and the Biliary Atresia Research Consortium (BARC) system were utilized to score liver fibrosis status.Results: The expression of YAP is elevated and positively correlated with fibrosis in BA livers. Moreover, ANKRD1, which is identified as the target gene of YAP, is also highly expressed in BA livers. Consistent with clinical data, YAP and ANKRD1 are significantly upregulated in RRV-induced BA mouse model.Conclusions: YAP expression is closely correlated with the bile duct hyperplasia and liver fibrosis, and may serve as an indicator for liver fibrosis and BA progression. This study indicates an involvement of the Hippo signaling pathway in the development of BA, and the YAP induced ANKRD1 expression may also be related to bile duct hyperplasia in BA. This provides a new direction for more in-depth exploration of the etiology and pathogenesis of biliary atresia.
Highlights
Biliary atresia (BA) is a rare condition in which progressive fibrosis affecting both intra- and extrahepatic biliary ducts in the newborn leads to persistent neonatal obstructive cholestasis
The hyperplastic bile ducts presented irregular morphology, usually with larger lumens (Figure 1A). These results indicate a phenotype of bile duct hyperplasia in BA livers
Liver fibrosis is an important indicator of BA; we measured the degree of liver fibrosis using Masson’s trichrome staining, and scored fibrosis status according to the BARC system [17] (Figure 1C)
Summary
Biliary atresia (BA) is a rare condition in which progressive fibrosis affecting both intra- and extrahepatic biliary ducts in the newborn leads to persistent neonatal obstructive cholestasis. New Biomarker in Biliary Atresia contribute to pathogenesis of BA are embryonic dysplasia, abnormal prenatal circulation, genetic factors, environmental toxins, viral infection, and abnormal immune response. Kasai portoenterostomy aims to reconstruct extrahepatic bile draining structure. Though Kasai portoenterostomy at younger age has a better short-term native liver survival rate [6], most BA patients require liver transplantation on account of low survival with the native liver after portoenterostomy only [7]. Biliary atresia (BA), an inflammatory destruction of the bile ducts, leads to liver fibrosis in infants and accounts for half of cases undergoing pediatric liver transplantation. We evaluated the expression of YAP and YAP target genes in BA livers and a rhesus rotavirus (RRV)-induced BA mice model
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