Adipocyte-specific Repression of PPAR-gamma by NCoR Contributes to Scleroderma Skin Fibrosis

Benjamin Korman*, Roberta Goncalves Marangoni, Gabriel Lord, Jerrold Olefsky, Warren Tourtellotte, John Varga

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number145
JournalArthritis Research and Therapy
Volume20
Issue number1
DOIs
StatePublished - Jul 11 2018

Keywords

  • Adipocyte
  • Adipogenesis
  • Fibrogenesis
  • NCoR
  • PPAR-γ
  • Scleroderma
  • Skin fibrosis

ASJC Scopus subject areas

  • Rheumatology
  • Immunology and Allergy
  • Immunology

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