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

• Published in: Arthritis research & therapy Vol. 20; no. 1; pp. 145 - 11
• Main Authors: Korman, Benjamin, Marangoni, Roberta Goncalves, Lord, Gabriel, Olefsky, Jerrold, Tourtellotte, Warren, Varga, John
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 11.07.2018; BioMed Central; BMC
• Subjects: Ablation; Adipocyte; Adipocytes; Adipocytes - metabolism; Adipocytes - pathology; Adipogenesis; Adult; Aged; Animals; Arthritis; Biopsy; Cell receptors; Development and progression; Female; Fibroblasts; Fibrosis; Gene expression; Health aspects; Homeostasis; Humans; Laboratory animals; Ligands; Male; Mice; Mice, Inbred C57BL; Middle Aged; NCoR; Nuclear Receptor Co-Repressor 1 - metabolism; PPAR gamma - metabolism; PPAR-γ; Rheumatology; Scleroderma; Scleroderma (Disease); Scleroderma, Systemic - metabolism; Scleroderma, Systemic - pathology; Skin - pathology; Skin diseases; Skin fibrosis; Adipocyte; Skin fibrosis; NCoR; Scleroderma; Fibrogenesis; PPAR-γ; Adipogenesis
• ISSN: 1478-6362; 1478-6354; 1478-6362
• DOI: 10.1186/s13075-018-1630-z

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 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.