期刊
DEVELOPMENTAL CELL
卷 57, 期 14, 页码 1728-+出版社
CELL PRESS
DOI: 10.1016/j.devcel.2022.06.003
关键词
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资金
- French grants from the Institut National de la Sante et de la Recherche Medicale (INSERM), la Fondation pour la Recherche Medicale [EQU201903007824]
- Institut National du Cancer [PLBIO18-107, PRTK-2017]
- Agence Nationale de Recherche ANR [ANR-16-CE14, ANR-19-CE14-0044-01]
- Fondation ARC (Association de Recherche sur le Cancer)
- Ligue Contre le Cancer (comite de Paris)
- Canceropole Ile-de-France
- Association Francaise pour l'Etude du Foie [AFEF-SUBV 2017, AFEF-SUBV 2019]
- EVA-Plan Cancer INSERM HTE
- SIRIC CARPEM
- Ministere de la Recherche
- Fondation pour la Recherche Medicale
- EUR G.E.N.E. [ANR-17-EURE-0013]
- Universite Paris-Cite IdEx - French Government through its Investments for the Future'' program [ANR-18-IDEX-0001]
- Plan Cancer INSERM (program Soutien pour la formation a la recherche fondamentale et translationnelle en cance rologie)
- Agence Nationale de la Recherche (ANR) [ANR-19-CE14-0044] Funding Source: Agence Nationale de la Recherche (ANR)
This study investigated the mechanisms of DNA damage response during NAFLD and found that nucleotide pool imbalance is the key driver of replication stress (RS), and DNA damage also activates the cGAS/STING pathway, promoting disease progression.
Non-alcoholic steatotic liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. NAFLD has a major effect on the intrinsic proliferative properties of hepatocytes. Here, we investigated the mechanisms underlying the activation of DNA damage response during NAFLD. Proliferating mouse NAFLD hepatocytes harbor replication stress (RS) with an alteration of the replication fork's speed and acti-vation of ATR pathway, which is sufficient to cause DNA breaks. Nucleotide pool imbalance occurring during NAFLD is the key driver of RS. Remarkably, DNA lesions drive cGAS/STING pathway activation, a major component of cells' intrinsic immune response. The translational significance of this study was reiterated by showing that lipid overload in proliferating HepaRG was sufficient to induce RS and nucleotide pool imbal-ance. Moreover, livers from NAFLD patients displayed nucleotide pathway deregulation and cGAS/STING gene alteration. Altogether, our findings shed light on the mechanisms by which damaged NAFLD hepato-cytes might promote disease progression.
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