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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

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

Lehwald Nadja N Tao Guo-Zhong GZ Jang Kyu Yun KY Sorkin Michael M Knoefel Wolfram T WT Sylvester Karl G KG

Gastroenterology 20110504 2

<h4>Background & aims</h4>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.<h4>Methods</h4>Hepatic injury following ischemia or I/R was investigated in hepatocyte-speci ...[more]

PMID: 21679710

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Project description:BackgroundHepatic ischemia-reperfusion (IR) injury is the primary reason for complications following hepatectomy and liver transplantation (LT). Insulin-induced gene 2 (Insig2) is one of several proteins that anchor the reticulum in the cytoplasm and is essential for metabolism and inflammatory responses. However, its function in IR injury remains ambiguous.MethodsInsig2 global knock-out (KO) mice and mice with adeno-associated-virus8 (AAV8)-delivered Insig2 hepatocyte-specific overexpression were subjected to a 70% hepatic IR model. Liver injury was assessed by monitoring hepatic histology, inflammatory responses, and apoptosis. Hypoxia/reoxygenation stimulation (H/R) of primary hepatocytes and hypoxia model induced by cobalt chloride (CoCl2) were used for in vitro experiments. Multi-omics analysis of transcriptomics, proteomics, and metabolomics was used to investigate the molecular mechanisms underlying Insig2.ResultsHepatic Insig2 expression was significantly reduced in clinical samples undergoing LT and the mouse IR model. Our findings showed that Insig2 depletion significantly aggravated IR-induced hepatic inflammation, cell death and injury, whereas Insig2 overexpression caused the opposite phenotypes. The results of in vitro H/R experiments were consistent with those in vivo. Mechanistically, multi-omics analysis revealed that Insig2 is associated with increased antioxidant pentose phosphate pathway (PPP) activity. The inhibition of glucose-6-phosphate-dehydrogenase (G6PD), a rate-limiting enzyme of PPP, rescued the protective effect of Insig2 overexpression, exacerbating liver injury. Finally, our findings indicated that mouse IR injury could be attenuated by developing a nanoparticle delivery system that enables liver-targeted delivery of substrate of PPP (glucose 6-phosphate).ConclusionsInsig2 has a protective function in liver IR by upregulating the PPP activity and remodeling glucose metabolism. The supplementary glucose 6-phosphate (G6P) salt may serve as a viable therapeutic target for alleviating hepatic IR.

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

Publications

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

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