Wnt-?-catenin signaling protects against hepatic ischemia and reperfusion injury in mice.

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

SUBMITTER: Lehwald N 

PROVIDER: S-EPMC4084974 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature