TY - JOUR
T1 - Transcription factor GATA6
T2 - A novel marker and putative inducer of ductal metaplasia in biliary atresia
AU - Soini, Tea
AU - Pihlajoki, Marjut
AU - Andersson, Noora
AU - Lohi, Jouko
AU - Huppert, Kari A.
AU - Rudnick, David A.
AU - Huppert, Stacey S.
AU - Wilson, David B.
AU - Pakarinen, Mikko P.
AU - Heikinheimo, Markku
N1 - Funding Information:
Ethical statement. This study was approved by the Ethical Committee of Helsinki University Hospital and by the Finnish National Authority of Medicolegal Affairs and Health.
Funding Information:
This work was supported by the Academy of Finland; Emil Aaltonen Foundation, Finland; Finnish Pediatric Research Foundation, Finland; Helsinki University Central Hospital Research Grants, Finland; Sigrid Jusélius Foundation, Finland; and Pediatric Cancer Foundation Väre, Finland. S. Huppert was supported by funding from NIH R01 DK078640, NIH R01 DK107553, and the Integrative Morphology Core P30 DK078392 (CCHMC Digestive Health Center).
Publisher Copyright:
© 2018 the American Physiological Society.
PY - 2018/5
Y1 - 2018/5
N2 - Biliary atresia (BA), a neo- natal liver disease, is characterized by obstruction of extrahepatic bile ducts with subsequent cholestasis, inflammation, and progressive liver fibrosis. To gain insights into the pathophysiology of BA, we focused attention on GATA6, a transcription factor implicated in biliary development. Early in fetal development GATA6 expression is evident in cholangiocytes and hepatocytes, but by late gestation it is extinguished in hepatocytes. Utilizing a unique set of BA liver samples collected before and after successful portoenterostomy (PE), we found that GATA6 expression is markedly upregulated in hepatocytes of patients with BA compared with healthy and cholestatic disease controls. This upregulation is recapitulated in two murine models simulating bile duct obstruction and intrahepatic bile ductule expansion. GATA6 expression in BA livers correlates with two established negative prognostic indicators (age at PE, degree of intrahepatic bile ductule expansion) and decreases after normalization of serum bilirubin by PE. GATA6 expression in BA livers correlates with expression of known regulators of cholangiocyte differentiation (JAGGED1, HNF1β, and HNF6). These same genes are upregulated after enforced expression of GATA6 in human hepatocyte cell models. In conclusion, GATA6 is a novel marker and a putative driver of hepatocyte-cholangiocyte metaplasia in BA, and its expression in hepatocytes is downregulated after successful PE. NEW & NOTEWORTHY A pathological hallmark in the liver of patients with biliary atresia is ductular reaction, an expansion of new bile ductules that are thought to arise from conversion of mature hepatocytes. Here, we show that transcription factor GATA6 is a marker and potential driver of hepatocyte ductal metaplasia in biliary atresia. Hepatocyte GATA6 expression is elevated in biliary atresia, correlates with bile duct expansion, and decreases after successful portoenterostomy.
AB - Biliary atresia (BA), a neo- natal liver disease, is characterized by obstruction of extrahepatic bile ducts with subsequent cholestasis, inflammation, and progressive liver fibrosis. To gain insights into the pathophysiology of BA, we focused attention on GATA6, a transcription factor implicated in biliary development. Early in fetal development GATA6 expression is evident in cholangiocytes and hepatocytes, but by late gestation it is extinguished in hepatocytes. Utilizing a unique set of BA liver samples collected before and after successful portoenterostomy (PE), we found that GATA6 expression is markedly upregulated in hepatocytes of patients with BA compared with healthy and cholestatic disease controls. This upregulation is recapitulated in two murine models simulating bile duct obstruction and intrahepatic bile ductule expansion. GATA6 expression in BA livers correlates with two established negative prognostic indicators (age at PE, degree of intrahepatic bile ductule expansion) and decreases after normalization of serum bilirubin by PE. GATA6 expression in BA livers correlates with expression of known regulators of cholangiocyte differentiation (JAGGED1, HNF1β, and HNF6). These same genes are upregulated after enforced expression of GATA6 in human hepatocyte cell models. In conclusion, GATA6 is a novel marker and a putative driver of hepatocyte-cholangiocyte metaplasia in BA, and its expression in hepatocytes is downregulated after successful PE. NEW & NOTEWORTHY A pathological hallmark in the liver of patients with biliary atresia is ductular reaction, an expansion of new bile ductules that are thought to arise from conversion of mature hepatocytes. Here, we show that transcription factor GATA6 is a marker and potential driver of hepatocyte ductal metaplasia in biliary atresia. Hepatocyte GATA6 expression is elevated in biliary atresia, correlates with bile duct expansion, and decreases after successful portoenterostomy.
KW - Cholestasis
KW - Ductular reaction
KW - Hepatocyte transdifferentiation
KW - Transcriptional regulation
UR - http://www.scopus.com/inward/record.url?scp=85046882316&partnerID=8YFLogxK
U2 - 10.1152/ajpgi.00362.2017
DO - 10.1152/ajpgi.00362.2017
M3 - Article
C2 - 29388792
AN - SCOPUS:85046882316
SN - 0193-1857
VL - 314
SP - G547-G558
JO - American Journal of Physiology - Gastrointestinal and Liver Physiology
JF - American Journal of Physiology - Gastrointestinal and Liver Physiology
IS - 5
ER -