Wnt-β-catenin Signaling Protects Against Hepatic Ischemia and Reperfusion Injury in Mice

BACKGROUND & AIMS: Ischemia and reperfusion injury are common causes of oxidative tissue damage associated with many liver diseases and hepatic surgery. The Wnt-beta-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, beta-catenin-deficient mice, as well as Wnt1-overexpressing and wild-type (control) mice. RESULTS: Wnt-beta-catenin signaling was affected by the cellular redox balance in hepatocytes. Following ischemia or I/R, mice with beta-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)-1 alpha signaling was reduced in beta-catenin-deficient liver but increased in hepatocytes that overexpressed Wnt1 under hypoxia and following I/R, indicating an interaction between beta-catenin and HIF-1 alpha signaling in the liver. The mechanism by which Wnt signaling protects against liver injury involves the role of beta-catenin as a transcriptional coactivator of HIF-1 alpha signaling, which promotes hepatocyte survival under hypoxic conditions. CONCLUSIONS: Cellular redox balance affects Wnt-beta-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.