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Adipocyte-specific Repression of PPAR-gamma by NCoR Contributes to Scleroderma Skin Fibrosis
Benjamin Korman1,2, Roberta Goncalves Marangoni3, Gabriel Lord3
1Northwestern Scleroderma Program, Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. benjamin_korman@urmc.rochester.edu.
Background:
A pivotal role for adipose tissue homeostasis in systemic sclerosis (SSc) skin fibrosis is increasingly recognized. The nuclear receptor PPAR-γ is the master regulator of adipogenesis. Peroxisome proliferator activated receptor-γ (PPAR-γ) has antifibrotic effects by blocking transforming growth factor-β (TGF-β) and is dysregulated in SSc. To unravel the impact of dysregulated PPAR-γ in SSc, we focused on nuclear corepressor (NCoR), which negatively regulates PPAR-γ activity and suppresses adipogenesis.
Methods:
An NCoR-regulated gene signature was measured in the SSc skin transcriptome. Experimental skin fibrosis was examined in mice with adipocyte-specific NCoR ablation.
Results:
SSc skin biopsies demonstrated deregulated NCoR signaling. A 43-gene NCoR gene signature showed strong positive correlation with PPAR-γ signaling (R = 0.919, p < 0.0001), whereas negative correlations with TGF-β signaling (R = - 0.796, p < 0.0001) and the modified Rodnan skin score (R = - 0.49, p = 0.004) were found. Mice with adipocyte-specific NCoR ablation demonstrated significant protection from experimental skin fibrosis and inflammation. The protective effects were mediated primarily through endogenous PPAR-γ.
Conclusions:
Our results implicate, for the first time, to our knowledge, deregulated NCoR/PPAR-γ pathways in SSc, and they support a role of adipocyte modulation of skin fibrosis. Pharmacologic restoration of NCoR/PPAR-γ signaling may represent a novel strategy to control skin fibrosis in SSc.
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