[HTML][HTML] Adipocyte-specific repression of PPAR-gamma by NCoR contributes to scleroderma skin fibrosis

B Korman, RG Marangoni, G Lord, J Olefsky… - Arthritis Research & …, 2018 - Springer
Arthritis Research & Therapy, 2018Springer
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 …
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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