Hypoxia inducible factor-1alpha accumulation in steatotic liver preservation: role of nitric oxide.
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.
Zaouali
Mohamed Amine
MA
Experimental Hepatic Ischemia Reperfusion Unit, Institut of Biomedical Research of Barcelona, Spanish National Research Council, 08036, Barcelona, Spain.
Ben Mosbah
Ismail
I
Boncompagni
Eleonora
E
Ben Abdennebi
Hassen
H
Mitjavila
Maria Teresa
MT
Bartrons
Ramon
R
Freitas
Isabel
I
Rimola
Antoni
A
Roselló-Catafau
Joan
J
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
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