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

作者：Korman Benjamin^*; Marangoni Roberta Goncalves; Lord Gabriel; Olefsky Jerrold; Tourtellotte Warren; Varga John

来源：Arthritis Research and Therapy, 2018, 20(1): 145.

DOI：10.1186/s13075-018-1630-z

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

Background: A pivotal role for adipose tissue homeostasis in systemic sclerosis (SSc) skin fibrosis is increasingly recognized. The nuclear receptor PPAR-gamma is the master regulator of adipogenesis. Peroxisome proliferator activated receptor-gamma (PPAR-gamma) has antifibrotic effects by blocking transforming growth factor-beta (TGF-beta) and is dysregulated in SSc. To unravel the impact of dysregulated PPAR-gamma in SSc, we focused on nuclear corepressor (NCoR), which negatively regulates PPAR-gamma 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-gamma signaling (R = 0.919, p < 0.0001), whereas negative correlations with TGF-beta 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-gamma.
Conclusions: Our results implicate, for the first time, to our knowledge, deregulated NCoR/PPAR-gamma pathways in SSc, and they support a role of adipocyte modulation of skin fibrosis. Pharmacologic restoration of NCoR/PPAR-gamma signaling may represent a novel strategy to control skin fibrosis in SSc.

• 出版日期2018-7-11
• 单位西北大学