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Cited by 147Liver physiology and pathologyDrug-Induced Hepatotoxicity and ProtectionCell death mechanisms and regulation

A20 protects mice from D-galactosamine/lipopolysaccharide acute toxic lethal hepatitis

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Arvelo, Maria B., Cooper, Jeffrey T., Longo, Christopher, Daniel, Soizic, Grey, Shane T., Mahiou, Jerome, Czismadia, Eva, Abu-Jawdeh, Graziella +1 more·2002·Hepatology
DOI 10.1053/jhep.2002.31309
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Abstract

Apoptosis of hepatocytes is a seminal feature of fulminant hepatic failure. We show that the anti-apoptotic protein A20 is upregulated in hepatocytes by pro-inflammatory stimuli and functions to protect from apoptosis and limit inflammation by inhibiting NF-κB. Adenoviral mediated hepatic expression of A20 in BALB/c mice yields an 85% survival rate in the D-galactosamine (D-gal)/lipolysaccharide (LPS) model of acute toxic hepatitis compared with 15% to 20 % in control mice. Expression of A20 preserves normal liver function as assessed by prothrombin time. The protective effect of A20 is independent of tumor necrosis factor (TNF) inhibition. Maintaining high circulating TNF levels may be advantageous for liver regeneration. Our data supports this hypothesis as evidenced by increased proliferating cell nuclear antigen (PCNA) expression in the livers of mice expressing A20 compared with a dominant negative mutant of the TNF receptor (TNF-R), 6 hours following D-gal/LPS administration. In conclusion, these results qualify A20 as part of a physiologic, protective response of hepatocytes to injury and a promising gene therapy candidate for clinical applications aimed at preventing and treating viral and toxic fulminant hepatic failure.

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  • No rAd.A20 treated mice developed liver carcinomas during the 6 months monitoring period.

    “no rAd.A20 treated mice developed liver carcinomas during the 6 months monitoring period (14–16).”

    From A20 promotes liver regeneration by decreasing SOCS3 expression to enhance IL-6/STAT3 proliferative signals (2013) · cites this paper as [14]

    The section “Expression of A20 in Hepatocytes Protects from Death Associated With FHF” says surviving mice were killed 2 to 4 weeks later, contrary to the claimed six-month monitoring period. The paper does not report whether those mice developed liver carcinomas. (LLM, conf=0.85)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • Hepatocyte cultures transduced with rAd. at MOI 50-200 pfu/cell lead to transgene expression in >95% of cells without toxicity.

    “Hepatocyte cultures (60% confluent) were transduced with rAd. at a multiplicity of infection (MOI) of 50–200 plaque-forming units per cell (pfu/cell), leading to transgene expression in >95% of cells without toxicity (14, 15) (Fig. S1).”

    From A20 promotes liver regeneration by decreasing SOCS3 expression to enhance IL-6/STAT3 proliferative signals (2013) · cites this paper as [14]

    The ‘Expression of A20 in Hepatocytes Is Cytoprotective’ section reports transgene expression in >98% of cultured HepG2 cells, but at an MOI of 15, not 50–200 pfu/cell. ‘Cell Culture and Cell Lines’ likewise specifies an MOI of 15; our copy does not establish 60% confluence or absence of toxicity under the claimed culture conditions. The intravenous-injection section concerns mice, not hepatocyte cultures. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • A20 exerts multiple hepatoprotective functions through combined anti-inflammatory, anti-apoptotic, and pro-proliferative effects in hepatocytes.

    “We previously demonstrated that A20/tnfaip3, a key element of the cellular response to injury and inflammation (12, 13), exerts multiple hepatoprotective functions through combined anti-inflammatory, anti-apoptotic, and pro-proliferative effects in hepatocytes (14–16).”

    From A20 promotes liver regeneration by decreasing SOCS3 expression to enhance IL-6/STAT3 proliferative signals (2013) · cites this paper as [14]

  • A20 is a NF-κB dependent gene.

    “A20 is a NF-κB dependent gene (14) that is part of the regenerative response of the liver”

    From A20 promotes liver regeneration by decreasing SOCS3 expression to enhance IL-6/STAT3 proliferative signals (2013) · cites this paper as [14]

  • Short-term overexpression of A20 does not carry a significant carcinogenic risk.

    “Our previous studies however indicate that short-term overexpression of A20 does not carry a significant carcinogenic risk. Indeed, no rAd.A20 treated mice developed liver carcinomas during the 6 months monitoring period (14–16).”

    From A20 promotes liver regeneration by decreasing SOCS3 expression to enhance IL-6/STAT3 proliferative signals (2013) · cites this paper as [14]

    The Results examine rAd.A20-treated mice over hours and days, and the Discussion addresses liver protection and adenoviral toxicity, but neither assesses carcinogenic risk. Searches for carcinoma, tumors, and six-month monitoring found no such follow-up in our copy. (LLM, conf=0.75)

    Experimental — accuracy not yet measured

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Cites

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Authors
Arvelo, M. B., Cooper, J. T., Longo, C., Daniel, S., Grey, S. T., Mahiou, J., Czismadia, E., Abu-Jawdeh, G., & Ferran, C.
Affiliations
  • Beth Israel Deaconess Medical Center (US)
  • Tufts Medical Center (US)
Corresponding author
Ferran, Christiane
ORCID
Venue
Hepatology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2002-03
Volume
35
Issue
3
Pages
535-543
ISSN
0270-9139 (ISSN-L)
DOI
10.1053/jhep.2002.31309
OpenAlex
W2143642767
Cited by
147
References
5
Citations by year
2026: 2 · 2025: 1 · 2024: 5 · 2022: 1 · 2021: 4 · 2020: 4 · 2019: 4 · 2018: 2 · 2017: 9 · 2016: 5 · 2015: 8 · 2014: 10 · 2013: 9 · 2012: 6
FWCI
5.66
Type
journal article
Language
en
Open access
Licence
Locations
  • Hepatology (publishedVersion)
  • PubMed (publishedVersion)
Funders
NIH to CF. (RO1, RO1 Grant # HL57791-01A4)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Keywords
A20, hepatocyte apoptosis, acute toxic hepatitis, D-galactosamine/lipopolysaccharide, acute liver failure, NF-κB inhibition, TNF receptor, liver regeneration, gene therapy, adenoviral gene transfer, prothrombin time, proliferating cell nuclear antigen
MeSH terms
Tumor Necrosis Factor alpha-Induced Protein 3, Adenoviridae, Animals, Cysteine Endopeptidases, DNA-Binding Proteins, Galactosamine, Humans, Inflammation, Lipopolysaccharides, Male, Mice, Inbred BALB C, Nuclear Proteins, Proteins, Tumor Cells, Cultured, Genetic Therapy, Cytokines, NF-kappa B, Liver Failure, Apoptosis, Receptors, Tumor Necrosis Factor, Cytoprotection, Hepatocytes, Intracellular Signaling Peptides and Proteins, Mice, Chemical and Drug Induced Liver Injury

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