gms | German Medical Science

Introduction: Hypoxia is a common cause of cellular stress that accompanies numerous liver diseases and hepatic surgery. The Wnt/β-catenin signaling pathway is a critical molecular regulator of hepatic development, regeneration and carcinogenesis. However, the role of β-catenin during the hepatocellular response to hypoxia remains unclear. In this study, genetic manipulation of β-catenin or Wnt1 in mouse liver was utilized to investigate the role of Wnt/β-catenin signaling in liver hypoxia.

Materials and methods: Hepatic ischemia-reperfusion-injury (IRI) was performed on two conditional hepatocyte-specific mouse models: a β-catenin knockdown and a Wnt1 over-expression mouse. Liver damage was assessed by transaminases and tissue histology. Intracellular oxygen radicals were detected by DHE staining. Hepatocyte cell lines with β-catenin stabilization were used to determine the cellular response at a molecular level. Reactive-oxygen-species production was measured by DCF-DA staining and FACS analysis. Cell survival and apoptosis was measured by MTT assay and Western blot. β-catenin/TCF or β-catenin/HIF-1 signaling was determined by reporter assay and qRT-PCR for corresponding changes in signal activity and target gene expression.

Results: In response to IRI, Wnt1 over-expression afforded significantly increased protection from cellular injury compared to control mice. Conversely, β-catenin knockdown mice were significantly more susceptible to IRI compared to wild-type mice resulting in severe necrosis and apoptosis. Accordingly, in vitro β-catenin stabilized cells demonstrated death resistance and proliferation despite hypoxic stress. Our data demonstrates that HIF-1 signaling is impaired in β-catenin deficient livers and augmented in Wnt1 stabilized hepatocytes under IRI suggesting a close link between β-catenin and HIF-1 signaling in liver.

Conclusion: Wnt stabilized β-catenin signaling augments hepatocyte injury protection to hypoxia. We conclude that β-catenin is required for effective liver protection against IRI via effective HIF-1 signaling. These findings may suggest future clinical application of Wnt1 manipulation or other activators of Wnt/β−catenin signaling for hepatic injury protection and regeneration.