Adipocyte-specific Repression of PPAR-gamma by NCoR Contributes to Scleroderma Skin Fibrosis
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 tran...
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| Format: | Article |
| Language: | English |
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BMC
2018-07-01
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| Series: | Arthritis Research & Therapy |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13075-018-1630-z |
| _version_ | 1818313966916468736 |
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| author | Benjamin Korman Roberta Goncalves Marangoni Gabriel Lord Jerrold Olefsky Warren Tourtellotte John Varga |
| author_facet | Benjamin Korman Roberta Goncalves Marangoni Gabriel Lord Jerrold Olefsky Warren Tourtellotte John Varga |
| author_sort | Benjamin Korman |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T08:42:09Z |
| format | Article |
| id | doaj.art-8a5a4e6e07f4466e8494b4eeadd3eca1 |
| institution | Directory Open Access Journal |
| issn | 1478-6362 |
| language | English |
| last_indexed | 2024-12-13T08:42:09Z |
| publishDate | 2018-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Arthritis Research & Therapy |
| spelling | doaj.art-8a5a4e6e07f4466e8494b4eeadd3eca12022-12-21T23:53:30ZengBMCArthritis Research & Therapy1478-63622018-07-0120111110.1186/s13075-018-1630-zAdipocyte-specific Repression of PPAR-gamma by NCoR Contributes to Scleroderma Skin FibrosisBenjamin Korman0Roberta Goncalves Marangoni1Gabriel Lord2Jerrold Olefsky3Warren Tourtellotte4John Varga5Northwestern Scleroderma Program, Division of Rheumatology, Northwestern University Feinberg School of MedicineNorthwestern Scleroderma Program, Division of Rheumatology, Northwestern University Feinberg School of MedicineNorthwestern Scleroderma Program, Division of Rheumatology, Northwestern University Feinberg School of MedicineDivision of Endocrinology, University of California, San DiegoDepartment of Pathology, Cedars Sinai Medical CenterNorthwestern Scleroderma Program, Division of Rheumatology, Northwestern University Feinberg School of MedicineAbstract 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.http://link.springer.com/article/10.1186/s13075-018-1630-zNCoRAdipocyteSkin fibrosisSclerodermaPPAR-γAdipogenesis |
| spellingShingle | Benjamin Korman Roberta Goncalves Marangoni Gabriel Lord Jerrold Olefsky Warren Tourtellotte John Varga Adipocyte-specific Repression of PPAR-gamma by NCoR Contributes to Scleroderma Skin Fibrosis Arthritis Research & Therapy NCoR Adipocyte Skin fibrosis Scleroderma PPAR-γ Adipogenesis |
| title | Adipocyte-specific Repression of PPAR-gamma by NCoR Contributes to Scleroderma Skin Fibrosis |
| title_full | Adipocyte-specific Repression of PPAR-gamma by NCoR Contributes to Scleroderma Skin Fibrosis |
| title_fullStr | Adipocyte-specific Repression of PPAR-gamma by NCoR Contributes to Scleroderma Skin Fibrosis |
| title_full_unstemmed | Adipocyte-specific Repression of PPAR-gamma by NCoR Contributes to Scleroderma Skin Fibrosis |
| title_short | Adipocyte-specific Repression of PPAR-gamma by NCoR Contributes to Scleroderma Skin Fibrosis |
| title_sort | adipocyte specific repression of ppar gamma by ncor contributes to scleroderma skin fibrosis |
| topic | NCoR Adipocyte Skin fibrosis Scleroderma PPAR-γ Adipogenesis |
| url | http://link.springer.com/article/10.1186/s13075-018-1630-z |
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