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Cited by 46Organ Transplantation Techniques and OutcomesLiver physiology and pathologyDrug-Induced Hepatotoxicity and Protection

A20 protects mice from lethal liver ischemia/reperfusion injury by increasing peroxisome proliferator-activated receptor-α expression

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Ramsey, Haley E., Da Silva, Cleide G., Longo, Christopher R., Csizmadia, Eva, Studer, Peter, Patel, Virendra I., Damrauer, Scott M., Siracuse, Jeffrey J. +2 more·2009·Liver Transplantation
DOI 10.1002/lt.21879PMC PMC2976064
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Abstract

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.

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Cited by

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Authors
Ramsey, H. E., Da Silva, C. G., Longo, C. R., Csizmadia, E., Studer, P., Patel, V. I., Damrauer, S. M., Siracuse, J. J., Daniel, S., & Ferran, C.
Affiliations
Beth Israel Deaconess Medical Center (US)
Corresponding author
Ferran, Christiane
ORCID
Venue
Liver Transplantation
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2009-11
Volume
15
Issue
11
Pages
1613-1621
ISSN
1527-6465 (ISSN-L)
DOI
10.1002/lt.21879
PMC
PMC2976064
OpenAlex
W2025649687
Cited by
46
References
2
Citations by year
2026: 2 · 2025: 1 · 2024: 2 · 2023: 1 · 2021: 3 · 2020: 2 · 2019: 2 · 2018: 2 · 2017: 5 · 2016: 4 · 2015: 4 · 2014: 5 · 2013: 4 · 2012: 4
FWCI
3.04
Type
journal article
Language
en
Open access
Licence
Locations
  • Liver Transplantation (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (NIH) RO1 (DK063275, HL080130, T32 HL07734)
  • July Henry Fund
Topics
  • Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Keywords
A20, ischemia-reperfusion injury, PPARα, hepatoprotection, hepatocyte proliferation, hepatic ischemia, adenoviral gene transfer, MK-886, small-for-size graft
MeSH terms
Tumor Necrosis Factor alpha-Induced Protein 3, Animals, Cell Division, Cells, Cultured, Cysteine Endopeptidases, Fatty Liver, Galactosamine, Hepatectomy, Hydrogen Peroxide, Lipopolysaccharides, Mice, Inbred BALB C, Necrosis, Reperfusion Injury, Gene Expression, Liver Transplantation, Oxidants, Liver Failure, Acute, Mice, Knockout, Hepatocytes, PPAR alpha, Intracellular Signaling Peptides and Proteins, Mice, Chemical and Drug Induced Liver Injury

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