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A20 protects mice from lethal liver ischemia/reperfusion injury by increasing peroxisome proliferator‐activated receptor‐α expression
Author(s) -
Ramsey Haley E.,
Da Silva Cleide G.,
Longo Christopher R.,
Csizmadia Eva,
Studer Peter,
Patel Virendra I.,
Damrauer Scott M.,
Siracuse Jeffrey J.,
Daniel Soizic,
Ferran Christiane
Publication year - 2009
Publication title -
liver transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.814
H-Index - 150
eISSN - 1527-6473
pISSN - 1527-6465
DOI - 10.1002/lt.21879
Subject(s) - steatosis , medicine , hepatocyte , peroxisome proliferator activated receptor , reperfusion injury , liver injury , tumor necrosis factor alpha , peroxisome proliferator activated receptor alpha , liver function , necrosis , oxidative stress , pharmacology , endocrinology , immunology , ischemia , receptor , nuclear receptor , biology , biochemistry , transcription factor , gene , in vitro
The nuclear factor‐κB 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.β 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 (PPARα), 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 PPARα inhibitor MK886. In conclusion, we demonstrate that PPARα 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. © 2009 AASLD.