TY - JOUR
T1 - Adipocyte-specific Repression of PPAR-gamma by NCoR Contributes to Scleroderma Skin Fibrosis
AU - Korman, Benjamin
AU - Marangoni, Roberta Goncalves
AU - Lord, Gabriel
AU - Olefsky, Jerrold
AU - Tourtellotte, Warren
AU - Varga, John
N1 - Funding Information:
This study was supported by (NIAMS) grant K08-AR070285-01 (to BK), Eunice Kennedy Shriver National Institute of Child Health and Human Development grant K12 HD055884 (to BK), NIAMS grant 5R03AR066343–02 (to RGM), and NIAMS grant R01 AR42309 (to JV).
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/7/11
Y1 - 2018/7/11
N2 - 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.
AB - 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.
KW - Adipocyte
KW - Adipogenesis
KW - Fibrogenesis
KW - NCoR
KW - PPAR-γ
KW - Scleroderma
KW - Skin fibrosis
UR - http://www.scopus.com/inward/record.url?scp=85050038129&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85050038129&partnerID=8YFLogxK
U2 - 10.1186/s13075-018-1630-z
DO - 10.1186/s13075-018-1630-z
M3 - Article
C2 - 29996896
AN - SCOPUS:85050038129
VL - 20
JO - Arthritis Research and Therapy
JF - Arthritis Research and Therapy
SN - 1478-6354
IS - 1
M1 - 145
ER -