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

Arthritis Research & Therapy
Benjamin KormanJohn Varga

Abstract

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. An NCoR-regulated gene signature was measured in the SSc skin transcriptome. Experimental skin fibrosis was examined in mice with adipocyte-specific NCoR ablation. 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. Our results implicate, for the first time, to our kno...Continue Reading

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Citations

Nov 27, 2019·Experimental Dermatology·Yuval RamotRalf Paus
Sep 23, 2020·Current Rheumatology Reports·Hanlin YinQingran Yan
Aug 14, 2020·International Journal of Molecular Sciences·Elena BargagliClaudia Landi
Nov 23, 2020·Journal of Orthopaedic Research : Official Publication of the Orthopaedic Research Society·Jinfu ChenWeimin Zhu
Apr 3, 2021·Expert Opinion on Biological Therapy·Parnia JabbariNima Rezaei
May 1, 2021·International Journal of Molecular Sciences·Neža BrezovecKatja Lakota

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Datasets Mentioned

BETA
GSE76886

Methods Mentioned

BETA
biopsies
biopsy
ELISA

Software Mentioned

Prism
GraphPad
Fiji

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