title: Hypoxia inducible factor-1alpha accumulation in steatotic liver preservation: role of nitric oxide.
abstract: OBJECTIVE
  To 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-1alpha in steatotic and non-steatotic livers preserved for 24 h at 4 degrees C in University of Wisconsin and IGL-1 solutions, and then subjected to 2 h of normothermic reperfusion. After normoxic reperfusion, liver enzymes, bile production, bromosulfophthalein clearance, as well as HIF-1alpha and NO [endothelial NO synthase (eNOS) activity and nitrites/nitrates] were also measured. Other factors associated with the higher susceptibility of steatotic livers to IRI, such as mitochondrial damage and vascular resistance were evaluated.
  
  
  RESULTS
  A significant increase in HIF-1alpha was found in steatotic and non-steatotic livers preserved in IGL-1 after cold storage. Livers preserved in IGL-1 showed a significant attenuation of liver injury and improvement in liver function parameters. These benefits were enhanced by the addition of trimetazidine (an anti-ischemic drug), which induces NO and eNOS activation, to IGL-1 solution. In normoxic reperfusion, the presence of NO favors HIF-1alpha accumulation, promoting also the activation of other cytoprotective genes, such as heme-oxygenase-1.
  
  
  CONCLUSIONS
  We found evidence for the role of the HIF-1alpha/NO system in fatty liver preservation, especially when IGL-1 solution is used.
authors.affiliation: Experimental Hepatic Ischemia Reperfusion Unit, Institut of Biomedical Research of Barcelona, Spanish National Research Council, 08036, Barcelona, Spain.
authors.forename: Mohamed Amine
authors.initials: MA
authors.lastname: Zaouali
authors.forename: Ismail
authors.initials: I
authors.lastname: Ben Mosbah
authors.forename: Eleonora
authors.initials: E
authors.lastname: Boncompagni
authors.forename: Hassen
authors.initials: H
authors.lastname: Ben Abdennebi
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Mitjavila
authors.forename: Ramon
authors.initials: R
authors.lastname: Bartrons
authors.forename: Isabel
authors.initials: I
authors.lastname: Freitas
authors.forename: Antoni
authors.initials: A
authors.lastname: Rimola
authors.forename: Joan
authors.initials: J
authors.lastname: Roselló-Catafau
mesh_terms: D000818:Animals; D050377:Cold Ischemia; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000378:metabolism*; D005969:Glutamate Dehydrogenase / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008099:Liver / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism*; D016031:Liver Transplantation; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D019188:Organ Preservation Solutions / Q000494:pharmacology; D051381:Rats; D011924:Rats, Zucker; D015427:Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control
chemical_list: C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C504757:IGL-1 solution; D019188:Organ Preservation Solutions; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D051547:Heme Oxygenase-1; D005969:Glutamate Dehydrogenase