DNA damage triggers a chronic auto-inflammatory response leading to fat depletion in NER progeria

• Published in: Cell metabolism Vol. 18; no. 3; pp. 403 - 415
• Main Authors: Karakasilioti, Ismene, 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.
• Format: Journal Article
• Language: English
• Published: 03-09-2013
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2013.08.011

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 auto-inflammatory response leading to fat depletion.
Ercc1
−/−
and aP2-
Ercc1
f
/−
fat depots show extensive gene expression similarities to lipodystrophic
Pparγ
ldi
/+
animals along with 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-
Ercc1
f
/−
fat depots and in adipocytes
ex vivo
trigger the induction of pro-inflammatory factors by promoting transcriptionally active histone marks and the dissociation of nuclear receptor co-repressor complexes from promoters; the response is cell-autonomous and requires ATM. Thus, persistent DNA damage-driven auto-inflammation plays a causative role in adipose tissue degeneration with important ramifications for progressive lipodystrophies and natural aging.