| First Author | Karakasilioti I | Year | 2013 |
| Journal | Cell Metab | Volume | 18 |
| Issue | 3 | Pages | 403-15 |
| PubMed ID | 24011075 | Mgi Jnum | J:203815 |
| Mgi Id | MGI:5528774 | Doi | 10.1016/j.cmet.2013.08.011 |
| Citation | Karakasilioti I, et al. (2013) DNA damage triggers a chronic autoinflammatory response, leading to fat depletion in NER progeria. Cell Metab 18(3):403-15 |
| abstractText | 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 Ppargamma(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. |
