Hepatic artery malformations associated with a primary defect in intrahepatic bile duct development

Background/Aims: The portal tracts contain bile ducts associated with branches of the portal vein and of the hepatic artery. Hepatic artery malformations are found in diseases in which fetal biliary structures persist after birth (ductal plate malformations). Here we investigated how hepatic artery malformations relate to abnormal bile duct development. Methods: Hepatic artery and biliary development was analyzed in fetuses with Jeune syndrome or Meckel syndrome, which show ductal plate malformations. We also analyzed hepatic artery development in transgenic mice which exhibit biliary anomalies following inactivation of the genes for hepatocyte nuclear factor (HNF)-6 or HNF-1β, two transcription factors expressed in biliary cells, but not in arteries. Results: We show that arterial anomalies occurred in fetuses with Jeune syndrome or Meckel syndrome. We provide the first description of hepatic artery branch development in the mouse and show that inactivation of the Hnf6 or Hnf1β gene results in anomalies of the hepatic artery branches. In the transgenic mice and in the human syndromes, the biliary anomalies preceded the arterial anomalies. Conclusions: A primary defect in biliary epithelial cells is associated with hepatic artery malformations in mice. Our data provide a model to interpret and study hepatic artery anomalies in humans.