Replication stress triggered by nucleotide pool imbalance drives DNA damage and cGAS-STING pathway activation in NAFLD

被引：51

作者：

Donne, Romain ^{[1
]}

Saroul-Ainama, Maeva ^{[1
]}

Cordier, Pierre ^{[1
]}

Hammoutene, Adel ^{[2
]}

Kabore, Christelle ^{[1
]}

Stadler, Mira ^{[3
]}

Nemazanyy, Ivan ^{[5
]}

Galy-Fauroux, Isabelle ^{[1
]}

Herrag, Mounia ^{[4
]}

Riedl, Tobias ^{[3
]}

Chansel-Da Cruz, Marie ^{[4
]}

Caruso, Stefano ^{[6
]}

Bonnafous, Stephanie ^{[7
]}

Ollinger, Rupert ^{[8
]}

Rad, Roland ^{[8
]}

Unger, Kristian ^{[9
]}

Tran, Albert ^{[7
]}

Couty, Jean-Pierre ^{[1
]}

Gual, Philippe ^{[7
]}

Paradis, Valerie ^{[2
,10
]}

Celton-Morizur, Severine ^{[1
]}

Heikenwalder, Mathias ^{[3
]}

Revy, Patrick ^{[4
]}

Desdouets, Chantal ^{[1
]}

机构：

[1] Univ Paris Cite, Team Proliferat Stress & Liver Physiopathol, Ctr Rech Cordeliers, INSERM,Sorbonne Univ, F-75006 Paris, France

[2] Univ Paris Cite, Ctr Rech Sur Inflammat, INSERM, CNRS,ERL8252,U1149, F-75018 Paris, France

[3] German Canc Res Ctr, Div Chron Inflammat & Canc F180, Heidelberg, Germany

[4] Univ Paris Cite, Inst Imagine, Lab Genome Dynam Immune Syst, Labellise Ligue,INSERM,UMR 1163, Paris, France

[5] INSERM, Platform Metab Anal, Struct Federat Rech Necker, CNRS,UMS 3633, Paris, France

[6] Univ Paris 13, Funct Genom Solid Tumors Team, INSERM,Sorbonne Univ,Univ Paris Cite,Ctr Rech Cor, Labex Immunooncol,Equipe Labellisee Ligue Canc, Paris, France

[7] Univ Cote dAzur, CHU, C3M, U1065,INSERM, Nice, France

[8] Rechts Isar Univ Hosp, Inst Mol Oncol & Funct Genom, Munich, Germany

[9] Helmholtz Zentrum Munchen, Res Unit Radiat Cytogenet, Neuherberg, Germany

[10] Hop Beaujon, AP HP, Serv Anat Pathol, Clichy, France

来源：

DEVELOPMENTAL CELL | 2022年 / 57卷 / 14期

关键词：

NONALCOHOLIC FATTY LIVER; HEPATOCELLULAR-CARCINOMA; GENOMIC INSTABILITY; MATURE HEPATOCYTES; FORK PROGRESSION; SCORING SYSTEM; STEATOHEPATITIS; DISEASE; INFLAMMATION; SENESCENCE;

D O I：

10.1016/j.devcel.2022.06.003

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

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.

引用

页码：1728 / +

页数：21

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