• Nadja Lehwald, Guo-Zhong Tao, Kyu Yun Jang, Michael Sorkin, Wolfram T Knoefel, and Karl G Sylvester.
• Divison of Pediatric Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, California 94305-5148, USA.
• Gastroenterology. 2011 Aug 1;141(2):707-18, 718.e1-5.

Background & AimsIschemia 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.MethodsHepatic 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.ResultsWnt-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.ConclusionsCellular 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.Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

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