HIF is under control of nitric oxide in normoxic fatty liver graft reperfusion injury

AIM: Here we examine the relevance of hypoxia inducible factor (HIF-1) and nitric oxide (NO) on the preservation of fatty liver against cold ischemia-reperfusion injury (IRI). METHODS: We used an isolated perfused rat liver model and we evaluated HIF-1α in steatotic and non-steatotic livers preserved for 24 hours at 4ºC in UW and IGL-1 solutions and then subjected to 2 hours of normothermic reperfusion. After normoxic reperfusion, AST/ALT, bile production, bromosulfophthalein clearance, as well as HIF-1α and NO (eNOS activity and nitrites/nitrates) were also measured. Other factors associated with the higher susceptibility of steatotic livers to IRI as mitochondrial damage (GLDH) and vascular resistance were evaluated. RESULTS: A significant increase of HIF-1α was evidenced in steatotic and non-steatotic livers preserved in IGL-1 after cold storage. Livers preserved in IGL-1 showed a significant prevention of liver injury and an amelioration of liver function parameters. These benefits were enhanced by the addition of trimetazidine (an anti-ischemic drug) to IGL-1 solution which induces NO and eNOS activation. In normoxic reperfusion, the presence of NO favours the HIF-1α accumulation, promoting also the activation of other cytoprotective genes, as heme-oxygenase-1. CONCLUSION: We evidenced the relevance of the HIF-1α/NO system for fatty liver preservation, especially when IGL-1 solution is used.