title: Dearterialization of the liver causes intrahepatic cholestasis due to reduced bile transporter expression.
abstract: BACKGROUND
  Bile duct injury after hepatic artery thrombosis (HAT) in liver transplantation is believed to be caused by ischemia predominantly. We aimed to define the involvement of bile secretory dysfunction in the pathogenesis of liver injury after HAT.
  
  
  METHODS
  In a murine model, the main hepatic artery, the extrahepatic peribiliary plexus, or both arterial connections to the liver were interrupted (n=5 for each group). After 1, 14, or 28 days, hepatobiliary function was assessed by analysis of bile transporter expression, serum bile acids and bilirubin, and hepatic ATP content. In addition, cellular injury was assessed by light microscopy and biochemical markers.
  
  
  RESULTS
  There were no signs of hepatobiliary dysfunction or injury in sham-operated animals or in mice with interruption of the hepatic artery or the extrahepatic peribiliary plexus alone. However, as early as 24 hr after complete dearterialization, bile transporter expression was significantly reduced and intrahepatic cholestasis started to progress the following weeks. Histologic studies at 28 days after complete dearterialization showed severe hepatobiliary injury.
  
  
  CONCLUSIONS
  This study indicates that arterial blood supply is critical for normal bile secretion. Bile duct injury after complete arterial deprivation is preceded by a loss of bile secretory function and subsequent intrahepatic cholestasis.
authors.affiliation: Department of Visceral and Transplant Surgery, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Harm
authors.initials: H
authors.lastname: Hoekstra
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Tian
authors.forename: Wolfram
authors.initials: W
authors.lastname: Jochum
authors.forename: Bruno
authors.initials: B
authors.lastname: Stieger
authors.forename: Rolf
authors.initials: R
authors.lastname: Graf
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Porte
authors.forename: Pierre-Alain
authors.initials: PA
authors.lastname: Clavien
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001646:Bile / Q000378:metabolism*; D001692:Biological Transport; D002780:Cholestasis, Intrahepatic / Q000209:etiology*; D016207:Cytokines / Q000502:physiology; D006499:Hepatic Artery / Q000502:physiology*; D006801:Humans; D007511:Ischemia / Q000150:complications*; D008099:Liver / Q000098:blood supply*; D051379:Mice; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D027981:Symporters / Q000235:genetics; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate; D016207:Cytokines; D029363:Organic Anion Transporters, Sodium-Dependent; D012333:RNA, Messenger; D027981:Symporters; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C490549:Abcb11 protein, mouse; C071908:sodium-bile acid cotransporter