title: A20 protects mice from lethal liver ischemia/reperfusion injury by increasing peroxisome proliferator-activated receptor-alpha expression.
abstract: The nuclear factor-kappaB inhibitory protein A20 demonstrates hepatoprotective abilities through combined antiapoptotic, anti-inflammatory, and pro-proliferative functions. Accordingly, overexpression of A20 in the liver protects mice from toxic hepatitis and lethal radical hepatectomy, whereas A20 knockout mice die prematurely from unfettered liver inflammation. The effect of A20 on oxidative liver damage, as seen in ischemia/reperfusion injury (IRI), is unknown. In this work, we evaluated the effects of A20 upon IRI using a mouse model of total hepatic ischemia. Hepatic overexpression of A20 was achieved by recombinant adenovirus (rAd.)-mediated gene transfer. Although only 10%-25% of control mice injected with saline or the control rAd.beta galactosidase survived IRI, the survival rate reached 67% in mice treated with rAd.A20. This significant survival advantage in rAd.A20-treated mice was associated with improved liver function, pathology, and repair potential. A20-treated mice had significantly lower bilirubin and aminotransferase levels, decreased hemorrhagic necrosis and steatosis, and increased hepatocyte proliferation. A20 protected against liver IRI by increasing hepatic expression of peroxisome proliferator-activated receptor alpha (PPARalpha), a regulator of lipid homeostasis and of oxidative damage. A20-mediated protection of hepatocytes from hypoxia/reoxygenation and H(2)O(2)-mediated necrosis was reverted by pretreatment with the PPARalpha inhibitor MK886. In conclusion, we demonstrate that PPARalpha is a novel target for A20 in hepatocytes, underscoring its novel protective effect against oxidative necrosis. By combining hepatocyte protection from necrosis and promotion of proliferation, A20-based therapies are well-poised to protect livers from IRI, especially in the context of small-for-size and steatotic liver grafts. Liver Transpl 15:1613-1621, 2009. (c) 2009 AASLD.
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Haley E
authors.initials: HE
authors.lastname: Ramsey
authors.forename: Cleide G
authors.initials: CG
authors.lastname: Da Silva
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Longo
authors.forename: Eva
authors.initials: E
authors.lastname: Csizmadia
authors.forename: Peter
authors.initials: P
authors.lastname: Studer
authors.forename: Virendra I
authors.initials: VI
authors.lastname: Patel
authors.forename: Scott M
authors.initials: SM
authors.lastname: Damrauer
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Siracuse
authors.forename: Soizic
authors.initials: S
authors.lastname: Daniel
authors.forename: Christiane
authors.initials: C
authors.lastname: Ferran
mesh_terms: D000818:Animals; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D005688:Galactosamine / Q000633:toxicity; D015870:Gene Expression / Q000502:physiology; D006498:Hepatectomy; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology; D006861:Hydrogen Peroxide / Q000633:toxicity; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D017114:Liver Failure, Acute / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016031:Liver Transplantation; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009336:Necrosis; D016877:Oxidants / Q000633:toxicity; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D016877:Oxidants; D047493:PPAR alpha; D005688:Galactosamine; D006861:Hydrogen Peroxide; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse