Transcription Factor GATA6: A Novel Marker and Putative Inducer of Ductal Metaplasia in Biliary Atresia.

Tea Soini, Marjut Pihlajoki, Noora Andersson, Jouko Lohi, Kari A. Huppert, David A. Rudnick, Stacey S. Huppert, David B. Wilson, Mikko P. Pakarinen, Markku Heikinheimo

Forskningsoutput: TidskriftsbidragArtikelVetenskapligPeer review

Sammanfattning

Biliary atresia (BA), a neonatal 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, HNF1 beta, 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. lepatocyte GATA6 expression is elevated in biliary atresia, correlates with bile duct expansion, and decreases after successful portoenterostomy.

Originalspråkengelska
TidskriftAmerican Journal of Physiology: Gastrointestinal and Liver Physiology
Volym314
Utgåva5
Sidor (från-till)G547–G558
Antal sidor12
ISSN0193-1857
DOI
StatusPublicerad - maj 2018
MoE-publikationstypA1 Tidskriftsartikel-refererad

Vetenskapsgrenar

  • 3121 Inre medicin
  • 1184 Genetik, utvecklingsbiologi, fysiologi
  • 3111 Biomedicinska vetenskaper

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title = "Transcription Factor GATA6: A Novel Marker and Putative Inducer of Ductal Metaplasia in Biliary Atresia.",
abstract = "Biliary atresia (BA), a neonatal 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, HNF1 beta, 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. lepatocyte GATA6 expression is elevated in biliary atresia, correlates with bile duct expansion, and decreases after successful portoenterostomy.",
keywords = "cholestasis, ductular reaction, hepatocyte transdifferentiation, transcriptional regulation, NOTCH SIGNALING PATHWAY, HUMAN LIVER-DISEASE, ALAGILLE-SYNDROME, RAT HEPATOCYTES, EXPRESSION, DIFFERENTIATION, TRANSDIFFERENTIATION, MUTATIONS, LIGATION, BIOPSIES, 3121 Internal medicine, 1184 Genetics, developmental biology, physiology, 3111 Biomedicine",
author = "Tea Soini and Marjut Pihlajoki and Noora Andersson and Jouko Lohi and Huppert, {Kari A.} and Rudnick, {David A.} and Huppert, {Stacey S.} and Wilson, {David B.} and Pakarinen, {Mikko P.} and Markku Heikinheimo",
year = "2018",
month = "5",
doi = "10.1152/ajpgi.00362.2017",
language = "English",
volume = "314",
pages = "G547–G558",
journal = "American Journal of Physiology: Gastrointestinal and Liver Physiology",
issn = "0193-1857",
publisher = "American Physiological Society",
number = "5",

}

Transcription Factor GATA6: A Novel Marker and Putative Inducer of Ductal Metaplasia in Biliary Atresia. / Soini, Tea; Pihlajoki, Marjut; Andersson, Noora; Lohi, Jouko; Huppert, Kari A.; Rudnick, David A.; Huppert, Stacey S.; Wilson, David B.; Pakarinen, Mikko P.; Heikinheimo, Markku .

I: American Journal of Physiology: Gastrointestinal and Liver Physiology, Vol. 314, Nr. 5, 05.2018, s. G547–G558.

Forskningsoutput: TidskriftsbidragArtikelVetenskapligPeer review

TY - JOUR

T1 - Transcription Factor GATA6: 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

PY - 2018/5

Y1 - 2018/5

N2 - Biliary atresia (BA), a neonatal 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, HNF1 beta, 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. lepatocyte GATA6 expression is elevated in biliary atresia, correlates with bile duct expansion, and decreases after successful portoenterostomy.

AB - Biliary atresia (BA), a neonatal 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, HNF1 beta, 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. lepatocyte 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

KW - NOTCH SIGNALING PATHWAY

KW - HUMAN LIVER-DISEASE

KW - ALAGILLE-SYNDROME

KW - RAT HEPATOCYTES

KW - EXPRESSION

KW - DIFFERENTIATION

KW - TRANSDIFFERENTIATION

KW - MUTATIONS

KW - LIGATION

KW - BIOPSIES

KW - 3121 Internal medicine

KW - 1184 Genetics, developmental biology, physiology

KW - 3111 Biomedicine

U2 - 10.1152/ajpgi.00362.2017

DO - 10.1152/ajpgi.00362.2017

M3 - Article

VL - 314

SP - G547–G558

JO - American Journal of Physiology: Gastrointestinal and Liver Physiology

JF - American Journal of Physiology: Gastrointestinal and Liver Physiology

SN - 0193-1857

IS - 5

ER -