BACKGROUND & AIMS: 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.
BACKGROUND & AIMS: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: Marieke A G Essers; Lydia M M de Vries-Smits; Nick Barker; Paulien E Polderman; Boudewijn M T Burgering; Hendrik C Korswagen Journal: Science Date: 2005-05-20 Impact factor: 47.728
Authors: Xinping Tan; Jaideep Behari; Benjamin Cieply; George K Michalopoulos; Satdarshan P S Monga Journal: Gastroenterology Date: 2006-11 Impact factor: 22.682
Authors: R H Giles; M P Lolkema; C M Snijckers; M Belderbos; P van der Groep; D A Mans; M van Beest; M van Noort; R Goldschmeding; P J van Diest; H Clevers; E E Voest Journal: Oncogene Date: 2006-05-18 Impact factor: 9.867
Authors: A de La Coste; B Romagnolo; P Billuart; C A Renard; M A Buendia; O Soubrane; M Fabre; J Chelly; C Beldjord; A Kahn; C Perret Journal: Proc Natl Acad Sci U S A Date: 1998-07-21 Impact factor: 11.205