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Cited by 240Liver physiology and pathologyLiver Disease Diagnosis and TreatmentDrug-Induced Hepatotoxicity and Protection

Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease

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Gentric, Géraldine, Maillet, Vanessa, Paradis, Valérie, Couton, Dominique, L’Hermitte, Antoine, Panasyuk, Ganna, Fromenty, Bernard, Celton-Morizur, Séverine +1 more·2015·Journal of Clinical Investigation
DOI 10.1172/jci73957PMC PMC4362240
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Abstract

Polyploidization is one of the most dramatic changes that can occur in the genome. In the liver, physiological polyploidization events occur during both liver development and throughout adult life. Here, we determined that a pathological polyploidization takes place in nonalcoholic fatty liver disease (NAFLD), a widespread hepatic metabolic disorder that is believed to be a risk factor for hepatocellular carcinoma (HCC). In murine models of NAFLD, the parenchyma of fatty livers displayed alterations of the polyploidization process, including the presence of a large proportion of highly polyploid mononuclear cells, which are rarely observed in normal hepatic parenchyma. Biopsies from patients with nonalcoholic steatohepatitis (NASH) revealed the presence of alterations in hepatocyte ploidy compared with tissue from control individuals. Hepatocytes from NAFLD mice revealed that progression through the S/G2 phases of the cell cycle was inefficient. This alteration was associated with activation of a G2/M DNA damage checkpoint, which prevented activation of the cyclin B1/CDK1 complex. Furthermore, we determined that oxidative stress promotes the appearance of highly polyploid cells, and antioxidant-treated NAFLD hepatocytes resumed normal cell division and returned to a physiological state of polyploidy. Collectively, these findings indicate that oxidative stress promotes pathological polyploidization and suggest that this is an early event in NAFLD that may contribute to HCC development.

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  • In injured livers, oxidative stress through induction of ATR/p53/p21 signalling has been reported to induce hepatocyte polyploidy.

    “In injured livers, oxidative stress through induction of ATR/p53/p21 signalling has been reported to induce hepatocyte polyploidy72 (further reviewed in31).”

    From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [72]

    The Results report ATR activation, p53 activation and p21 accumulation in NAFLD hepatocytes; antioxidant treatment reduced ATR activation and restored a normal ploidy profile. The Discussion links oxidative stress to an ATR/p53/p21-controlled checkpoint but says the precise mechanism connecting genomic stress to pathological polyploidy remains to be established. The claim extends this NAFLD finding to injured livers generally and states the signaling pathway more definitively than the paper does. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Highly polyploid mononucleated hepatocytes observed in mouse models of NAFLD arise via activation of the ATR-p53-p21 pathway from oxidative stress, delaying the S to G2 transition and leading to endoreplication.

    “For example, highly polyploid mononucleated hepatocytes observed in mouse models of NAFLD arise via activation of the ATR-p53-p21 pathway from oxidative stress, delaying the S to G2 transition and leading to endoreplication.72”

    From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [72]

    The Discussion reports enrichment of highly polyploid mononuclear hepatocytes in NAFLD mouse models and links oxidative stress to activation of the ATR/p53/p21 checkpoint. However, the Results locate the arrest at G2/M rather than specifically at the S-to-G2 transition, and the Discussion says the observed successive S phases suggest endoreplication, rather than establishing it as the mechanism. (LLM, conf=0.88)

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Cited by

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Authors
Gentric, G., Maillet, V., Paradis, V., Couton, D., L’Hermitte, A., Panasyuk, G., Fromenty, B., Celton-Morizur, S., & Desdouets, C.
Affiliations
  • Centre National de la Recherche Scientifique (FR)
  • Inserm (FR)
Corresponding author
Desdouets, Chantal
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2015-01-26
Volume
125
Issue
3
Pages
981-992
ISSN
0021-9738 (ISSN-L)
DOI
10.1172/jci73957
PMC
PMC4362240
OpenAlex
W2052599626
Cited by
240
References
7
Citations by year
2026: 10 · 2025: 17 · 2024: 20 · 2023: 22 · 2022: 20 · 2021: 33 · 2020: 31 · 2019: 19 · 2018: 25 · 2017: 14 · 2016: 18 · 2015: 11
FWCI
13.44
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
Funders
  • Science Foundation Ireland
  • Agence Nationale de la Recherche (ANR-10-BLAN-1123, ANR 2010 BLANC 1123 02)
  • Institut National de la Santé et de la Recherche Médicale (U1016)
  • Fondation ARC pour la Recherche sur le Cancer
  • Cilag
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Keywords
polyploidization, non-alcoholic fatty liver disease, nonalcoholic steatohepatitis, oxidative stress, hepatocyte ploidy, CDK1-cyclin B1, cell cycle arrest, hepatocellular carcinoma, antioxidant treatment
MeSH terms
Animals, DNA Damage, Carcinoma, Hepatocellular, Humans, Liver, Liver Neoplasms, Male, Mice, Inbred C57BL, Middle Aged, Polyploidy, Risk Factors, Oxidative Stress, Hepatocytes, Diet, High-Fat, Non-alcoholic Fatty Liver Disease

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