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

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.

• Authors: Ismene Karakasilioti, Irene Kamileri, Georgia Chatzinikolaou, Theodoros Kosteas, Eleni Vergadi, Andria Rasile Robinson, Iannis Tsamardinos, Tania A Rozgaja, Sandra Siakouli, Christos Tsatsanis, Laura J Niedernhofer, George A Garinis
• Journal: Cell metabolism (Cell Metab) Vol. 18 Issue 3 Pg. 403-15 (Sep 03 2013) ISSN: 1932-7420 [Electronic] United States
• PMID: 24011075 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Cytokines
• DNA-Binding Proteins
• FANCI protein, mouse
• Fabp4 protein, mouse
• Fanconi Anemia Complementation Group Proteins
• Fatty Acid-Binding Proteins
• Histones
• PPAR gamma
• Ataxia Telangiectasia Mutated Proteins
• Rad51 Recombinase
• Endonucleases
• Ercc1 protein, mouse

Topics

• Adipocytes (cytology, metabolism)
• Adipose Tissue (metabolism)
• Animals
• Ataxia Telangiectasia Mutated Proteins (metabolism)
• Cells, Cultured
• Cytokines (metabolism)
• DNA Damage
• DNA Repair
• DNA-Binding Proteins (deficiency, genetics, metabolism)
• Endonucleases (deficiency, genetics, metabolism)
• Fanconi Anemia Complementation Group Proteins (metabolism)
• Fatty Acid-Binding Proteins (genetics, metabolism)
• Histones (metabolism)
• Mice
• Mice, Knockout
• PPAR gamma (genetics, metabolism)
• Progeria (metabolism, pathology)
• Rad51 Recombinase (metabolism)
• Transcriptome