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DNA damage triggers a chronic autoinflammatory response, leading to fat depletion in NER progeria.

Authors
  • Karakasilioti, Ismene1
  • Kamileri, Irene
  • Chatzinikolaou, Georgia
  • Kosteas, Theodoros
  • Vergadi, Eleni
  • Robinson, Andria Rasile
  • Tsamardinos, Iannis
  • Rozgaja, Tania A
  • Siakouli, Sandra
  • Tsatsanis, Christos
  • Niedernhofer, Laura J
  • Garinis, George A
  • 1 Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, 70013 Heraklion, Crete, Greece; Department of Biology, University of Crete, 71409 Heraklion, Crete, Greece. , (Greece)
Type
Published Article
Journal
Cell metabolism
Publication Date
Sep 03, 2013
Volume
18
Issue
3
Pages
403–415
Identifiers
DOI: 10.1016/j.cmet.2013.08.011
PMID: 24011075
Source
Medline
License
Unknown

Abstract

Lipodystrophies represent a group of heterogeneous disorders characterized by loss of fat tissue. However, the underlying mechanisms remain poorly understood. Using mice carrying an ERCC1-XPF DNA repair defect systematically or in adipocytes, we show that DNA damage signaling triggers a chronic autoinflammatory response leading to fat depletion. Ercc1-/- and aP2-Ercc1F/- fat depots show extensive gene expression similarities to lipodystrophic Pparγ(ldi/+) animals, focal areas of ruptured basement membrane, the reappearance of primary cilia, necrosis, fibrosis, and a marked decrease in adiposity. We find that persistent DNA damage in aP2-Ercc1F/- fat depots and in adipocytes ex vivo triggers the induction of proinflammatory factors by promoting transcriptionally active histone marks and the dissociation of nuclear receptor corepressor complexes from promoters; the response is cell autonomous and requires ataxia telangiectasia mutated (ATM). Thus, persistent DNA damage-driven autoinflammation plays a causative role in adipose tissue degeneration, with important ramifications for progressive lipodystrophies and natural aging.

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