title: Wnt-β-catenin signaling protects against hepatic ischemia and reperfusion injury in mice.
abstract: OBJECTIVE
  Ischemia and reperfusion injury are common causes of oxidative tissue damage associated with many liver diseases and hepatic surgery. The Wnt-β-catenin signaling pathway is an important regulator of hepatic development, regeneration, and carcinogenesis. However, the role of Wnt signaling in the hepatocellular response to ischemia-reperfusion (I/R) injury has not been determined.
  
  
  METHODS
  Hepatic injury following ischemia or I/R was investigated in hepatocyte-specific, β-catenin-deficient mice, as well as Wnt1-overexpressing and wild-type (control) mice.
  
  
  RESULTS
  Wnt-β-catenin signaling was affected by the cellular redox balance in hepatocytes. Following ischemia or I/R, mice with β-catenin-deficient hepatocytes were significantly more susceptible to liver injury. Conversely, mice that overexpressed Wnt1 in hepatocytes were resistant to hepatic I/R injury. Hypoxia inducible factor (HIF)-1α signaling was reduced in β-catenin-deficient liver but increased in hepatocytes that overexpressed Wnt1 under hypoxia and following I/R, indicating an interaction between β-catenin and HIF-1α signaling in the liver. The mechanism by which Wnt signaling protects against liver injury involves the role of β-catenin as a transcriptional coactivator of HIF-1α signaling, which promotes hepatocyte survival under hypoxic conditions.
  
  
  CONCLUSIONS
  Cellular redox balance affects Wnt-β-catenin signaling, which protects against hypoxia and I/R injury. These findings might be used to develop strategies for protection of hepatocytes, regeneration of liver, and inhibition of carcinogenesis.
authors.affiliation: Divison of Pediatric Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, California 94305-5148, USA.
authors.forename: Nadja
authors.initials: N
authors.lastname: Lehwald
authors.forename: Guo-Zhong
authors.initials: GZ
authors.lastname: Tao
authors.forename: Kyu Yun
authors.initials: KY
authors.lastname: Jang
authors.forename: Michael
authors.initials: M
authors.lastname: Sorkin
authors.forename: Wolfram T
authors.initials: WT
authors.lastname: Knoefel
authors.forename: Karl G
authors.initials: KG
authors.lastname: Sylvester
mesh_terms: D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D002478:Cells, Cultured; D019610:Cytoprotection / Q000502:physiology*; D051538:Hepatocyte Nuclear Factor 1-alpha; D022781:Hepatocytes; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007511:Ischemia / Q000503:physiopathology*; D008107:Liver Diseases / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D009336:Necrosis; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000494:pharmacology; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051822:T Cell Transcription Factor 1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*
chemical_list: C485502:HIF-2 protein, mouse; D051538:Hepatocyte Nuclear Factor 1-alpha; C497443:Hif1a protein, mouse; C496488:Hnf1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D051822:T Cell Transcription Factor 1; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin