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Arthritis Research & Therapy
Published in: Arthritis Research & Therapy 1/2018

Open Access 01-12-2018 | Research article

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

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

Published in: Arthritis Research & Therapy | Issue 1/2018

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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.
Literature
1.
2.
Varga J, Trojanowska M, Kuwana M. Pathogenesis of systemic sclerosis: recent insights of molecular and cellular mechanisms and therapeutic opportunities. J Scleroderma Relat Disord. 2017;2(3):137–52.CrossRef
3.
Bhattacharyya S, Wei J, Varga J. Understanding fibrosis in systemic sclerosis: shifting paradigms, emerging opportunities. Nat Rev Rheumatol. 2011;8(1):42–54.CrossRefPubMedPubMedCentral
4.
El Agha E, Kramann R, Schneider RK, Li X, Seeger W, Humphreys BD, Bellusci S. Mesenchymal stem cells in fibrotic disease. Cell Stem Cell. 2017;21(2):166–77.CrossRefPubMed
5.
Wei J, Ghosh AK, Sargent JL, Komura K, Wu M, Huang QQ, Jain M, Whitfield ML, Feghali-Bostwick C, Varga J. PPAR γ downregulation by TGF-β in fibroblasts and impaired expression and function in systemic sclerosis: a novel mechanism for progressive fibrogenesis. PLoS One. 2010;5(11):e13778.CrossRefPubMedPubMedCentral
6.
Ahmadian M, Suh JM, Hah N, Liddle C, Atkins AR, Downes M, Evans RM. PPARγ signaling and metabolism: the good, the bad and the future. Nat Med. 2013;19(5):557–66.CrossRefPubMed
7.
Wei J, Bhattacharyya S, Varga J. Peroxisome proliferator-activated receptor γ: innate protection from excessive fibrogenesis and potential therapeutic target in systemic sclerosis. Curr Opin Rheumatol. 2010;22(6):671–6.CrossRefPubMedPubMedCentral
8.
Wei J, Ghosh AK, Sargent JL, Komura K, Wu M, Huang QQ, Jain M, Whitfield ML, Feghali-Bostwick C, Varga J. PPARγ downregulation by TGFβ in fibroblast and impaired expression and function in systemic sclerosis: a novel mechanism for progressive fibrogenesis. PLoS One. 2010;5(11):e13778.CrossRefPubMedPubMedCentral
9.
Ghosh AK, Bhattacharyya S, Lakos G, Chen SJ, Mori Y, Varga J. Disruption of transforming growth factor β signaling and profibrotic responses in normal skin fibroblasts by peroxisome proliferator-activated receptor γ. Arthritis Rheum. 2004;50(4):1305–18.CrossRefPubMed
10.
Burgess HA, Daugherty LE, Thatcher TH, Lakatos HF, Ray DM, Redonnet M, Phipps RP, Sime PJ. PPARγ agonists inhibit TGF-β induced pulmonary myofibroblast differentiation and collagen production: implications for therapy of lung fibrosis. Am J Physiol Lung Cell Mol Physiol. 2005;288(6):L1146–53.CrossRefPubMed
11.
Shi-wen X, Eastwood M, Stratton RJ, Denton CP, Leask A, Abraham DJ. Rosiglitazone alleviates the persistent fibrotic phenotype of lesional skin scleroderma fibroblasts. Rheumatology (Oxford). 2010;49(2):259–63.CrossRef
12.
Kis A, Murdoch C, Zhang M, Siva A, Rodriguez-Cuenca S, Carobbio S, Lukasik A, Blount M, O'Rahilly S, Gray SL, et al. Defective peroxisomal proliferators activated receptor γ activity due to dominant-negative mutation synergizes with hypertension to accelerate cardiac fibrosis in mice. Eur J Heart Fail. 2009;11(6):533–41.CrossRefPubMedPubMedCentral
13.
Ruzehaji N, Frantz C, Ponsoye M, Avouac J, Pezet S, Guilbert T, Luccarini JM, Broqua P, Junien JL, Allanore Y. Pan PPAR agonist IVA337 is effective in prevention and treatment of experimental skin fibrosis. Ann Rheum Dis. 2016;75(12):2175–83.CrossRefPubMedPubMedCentral
14.
Lee R, Reese C, Carmen-Lopez G, Perry B, Bonner M, Zemskova M, Wilson CL, Helke KL, Silver RM, Hoffman S, et al. Deficient Adipogenesis of scleroderma patient and healthy African American monocytes. Front Pharmacol. 2017;8:174.PubMedPubMedCentral
15.
Kapoor M, McCann M, Liu S, Huh K, Denton CP, Abraham DJ, Leask A. Loss of peroxisome proliferator-activated receptor γ in mouse fibroblasts results in increased susceptibility to bleomycin-induced skin fibrosis. Arthritis Rheum. 2009;60(9):2822–9.CrossRefPubMed
16.
Marangoni RG, Korman BD, Allanore Y, Dieude P, Armstrong LL, Rzhetskaya M, Hinchcliff M, Carns M, Podlusky S, Shah SJ, et al. A candidate gene study reveals association between a variant of the peroxisome proliferator-activated receptor γ (PPAR-γ) gene and systemic sclerosis. Arthritis Res Ther. 2015;17:128.CrossRefPubMedPubMedCentral
17.
Lopez-Isac E, Bossini-Castillo L, Simeon CP, Egurbide MV, Alegre-Sancho JJ, Callejas JL, Roman-Ivorra JA, Freire M, Beretta L, Santaniello A, et al. A genome-wide association study follow-up suggests a possible role for PPARG in systemic sclerosis susceptibility. Arthritis Res Ther. 2014;16(1):R6.CrossRefPubMedPubMedCentral
18.
Johnson ME, Mahoney JM, Taroni J, Sargent JL, Marmarelis E, Wu MR, Varga J, Hinchcliff ME, Whitfield ML. Experimentally-derived fibroblast gene signatures identify molecular pathways associated with distinct subsets of systemic sclerosis patients in three independent cohorts. PLoS One. 2015;10(1):e0114017.CrossRefPubMedPubMedCentral
19.
Wu M, Melichian DS, Chang E, Warner-Blankenship M, Ghosh AK, Varga J. Rosiglitazone abrogates bleomycin-induced scleroderma and blocks profibrotic responses through peroxisome proliferator-activated receptor-γ. Am J Pathol. 2009;174(2):519–33.CrossRefPubMedPubMedCentral
20.
Choi JH, Banks AS, Estall JL, Kajimura S, Bostrom P, Laznik D, Ruas JL, Chalmers MJ, Kamenecka TM, Bluher M, et al. Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARγ by Cdk5. Nature. 2010;466(7305):451–6.CrossRefPubMedPubMedCentral
21.
Feinstein DL, Spagnolo A, Akar C, Weinberg G, Murphy P, Gavrilyuk V, Dello Russo C. Receptor-independent actions of PPAR thiazolidinedione agonists: is mitochondrial function the key? Biochem Pharmacol. 2005;70(2):177–88.CrossRefPubMed
22.
Mughal RS, Warburton P, O'Regan DJ, Ball SG, Turner NA, Porter KE. Peroxisome proliferator-activated receptor γ-independent effects of thiazolidinediones on human cardiac myofibroblast function. Clin Exp Pharmacol Physiol. 2009;36(5–6):478–86.CrossRefPubMed
23.
Bortolini M, Wright MB, Bopst M, Balas B. Examining the safety of PPAR agonists - current trends and future prospects. Expert Opin Drug Saf. 2013;12(1):65–79.CrossRefPubMed
24.
Huang JV, Greyson CR, Schwartz GG. PPAR-γ as a therapeutic target in cardiovascular disease: evidence and uncertainty. J Lipid Res. 2012;53(9):1738–54.CrossRefPubMedPubMedCentral
25.
Tontonoz P, Spiegelman BM. Fat and beyond: the diverse biology of PPARγ. Annu Rev Biochem. 2008;77:289–312.CrossRefPubMed
26.
Yu C, Markan K, Temple KA, Deplewski D, Brady MJ, Cohen RN. The nuclear receptor corepressors NCoR and SMRT decrease peroxisome proliferator-activated receptor γ transcriptional activity and repress 3T3-L1 adipogenesis. J Biol Chem. 2005;280(14):13600–5.CrossRefPubMed
27.
28.
Li P, Fan W, Xu J, Lu M, Yamamoto H, Auwerx J, Sears DD, Talukdar S, Oh D, Chen A, et al. Adipocyte NCoR knockout decreases PPARγ phosphorylation and enhances PPARγ activity and insulin sensitivity. Cell. 2011;147(4):815–26.CrossRefPubMedPubMedCentral
29.
Ghisletti S, Huang W, Jepsen K, Benner C, Hardiman G, Rosenfeld MG, Glass CK. Cooperative NCoR/SMRT interactions establish a corepressor-based strategy for integration of inflammatory and anti-inflammatory signaling pathways. Genes Dev. 2009;23(6):681–93.CrossRefPubMedPubMedCentral
30.
Zien A, Kuffner R, Zimmer R, Lengauer T. Analysis of gene expression data with pathway scores. Proc Int Conf Intell Syst Mol Biol. 2000;8:407–17.PubMed
31.
Sargent JL, Milano A, Bhattacharyya S, Varga J, Connolly MK, Chang HY, Whitfield ML, TGFβ-responsive A. gene signature is associated with a subset of diffuse scleroderma with increased disease severity. J Invest Dermatol. 2010;130(3):694–705.CrossRefPubMed
32.
Marangoni RG, Korman B, Wei J, Wood TA, Graham L, Whitfield ML, Scherer PE, Tourtellotte WG, Varga J. Myofibroblasts in cutaneous fibrosis originate from adiponectin-positive intradermal progenitors. Arthritis Rheumatol. 2015;67(4):1062–73.CrossRefPubMedPubMedCentral
33.
Bhattacharyya S, Wang W, Morales-Nebreda L, Feng G, Wu M, Zhou X, Lafyatis R, Lee J, Hinchcliff M, Feghali-Bostwick C, et al. Tenascin-C drives persistence of organ fibrosis. Nat Commun. 2016;7:11703.CrossRefPubMedPubMedCentral
34.
Bhattacharyya S, Tamaki Z, Wang W, Hinchcliff M, Hoover P, Getsios S, White ES, Varga J. FibronectinEDA promotes chronic cutaneous fibrosis through Toll-like receptor signaling. Sci Transl Med. 2014;6(232):232ra250.CrossRef
35.
Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, Preibisch S, Rueden C, Saalfeld S, Schmid B, et al. Fiji: an open-source platform for biological-image analysis. Nat Methods. 2012;9(7):676–82.CrossRefPubMed
36.
Bhattacharyya S, Kelley K, Melichian DS, Tamaki Z, Fang F, Su Y, Feng G, Pope RM, Budinger GR, Mutlu GM, et al. Toll-like receptor 4 signaling augments transforming growth factor-β responses: a novel mechanism for maintaining and amplifying fibrosis in scleroderma. Am J Pathol. 2013;182(1):192–205.CrossRefPubMedPubMedCentral
37.
Rice LM, Padilla CM, McLaughlin SR, Mathes A, Ziemek J, Goummih S, Nakerakanti S, York M, Farina G, Whitfield ML, et al. Fresolimumab treatment decreases biomarkers and improves clinical symptoms in systemic sclerosis patients. J Clin Invest. 2015;125(7):2795–807.CrossRefPubMedPubMedCentral
38.
Furst DE, Clements PJ, Steen VD, Medsger TA Jr, Masi AT, D'Angelo WA, Lachenbruch PA, Grau RG, Seibold JR. The modified Rodnan skin score is an accurate reflection of skin biopsy thickness in systemic sclerosis. J Rheumatol. 1998;25(1):84–8.PubMed
39.
Verrecchia F, Laboureau J, Verola O, Roos N, Porcher R, Bruneval P, Ertault M, Tiev K, Michel L, Mauviel A, et al. Skin involvement in scleroderma--where histological and clinical scores meet. Rheumatology (Oxford). 2007;46(5):833–41.CrossRef
40.
Rice LM, Ziemek J, Stratton EA, McLaughlin SR, Padilla CM, Mathes AL, Christmann RB, Stifano G, Browning JL, Whitfield ML, et al. A longitudinal biomarker for the extent of skin disease in patients with diffuse cutaneous systemic sclerosis. Arthritis Rheumatol. 2015;67(11):3004–15.CrossRefPubMedPubMedCentral
41.
Rice LM, Stifano G, Ziemek J, Lafyatis R. Local skin gene expression reflects both local and systemic skin disease in patients with systemic sclerosis. Rheumatology (Oxford). 2016;55(2):377–9.CrossRef
42.
Hinchcliff M, Huang CC, Wood TA, Matthew Mahoney J, Martyanov V, Bhattacharyya S, Tamaki Z, Lee J, Carns M, Podlusky S, et al. Molecular signatures in skin associated with clinical improvement during mycophenolate treatment in systemic sclerosis. J Invest Dermatol. 2013;133(8):1979–89.CrossRefPubMedPubMedCentral
43.
44.
Inoue M, Maehata E, Yano M, Taniyama M, Suzuki S. Correlation between the adiponectin-leptin ratio and parameters of insulin resistance in patients with type 2 diabetes. Metab Clin Exp. 2005;54(3):281–6.CrossRefPubMed
45.
Marangoni RG, Lu TT. the roles of dermal white adipose tissue loss in scleroderma skin fibrosis. Curr Opin Rheumatol. 2017;29(6):585–90.PubMed
46.
Leesnitzer LM, Parks DJ, Bledsoe RK, Cobb JE, Collins JL, Consler TG, Davis RG, Hull-Ryde EA, Lenhard JM, Patel L, et al. Functional consequences of cysteine modification in the ligand binding sites of peroxisome proliferator activated receptors by GW9662. Biochemistry. 2002;41(21):6640–50.CrossRefPubMed
47.
Wei J, Fang F, Lam AP, Sargent JL, Hamburg E, Hinchcliff ME, Gottardi CJ, Atit R, Whitfield ML, Varga J. Wnt/β-catenin signaling is hyperactivated in systemic sclerosis and induces Smad-dependent fibrotic responses in mesenchymal cells. Arthritis Rheum. 2012;64(8):2734–45.CrossRefPubMedPubMedCentral
48.
Krogsdam AM, Nielsen CA, Neve S, Holst D, Helledie T, Thomsen B, Bendixen C, Mandrup S, Kristiansen K. Nuclear receptor corepressor-dependent repression of peroxisome-proliferator-activated receptor δ-mediated transactivation. Biochem J. 2002;363(Pt 1):157–65.CrossRefPubMedPubMedCentral
49.
Yamamoto H, Williams EG, Mouchiroud L, Canto C, Fan W, Downes M, Heligon C, Barish GD, Desvergne B, Evans RM, et al. NCoR1 is a conserved physiological modulator of muscle mass and oxidative function. Cell. 2011;147(4):827–39.CrossRefPubMedPubMedCentral
50.
Li P, Spann NJ, Kaikkonen MU, Lu M, Oh DY, Fox JN, Bandyopadhyay G, Talukdar S, Xu J, Lagakos WS, et al. NCoR repression of LXRs restricts macrophage biosynthesis of insulin-sensitizing omega 3 fatty acids. Cell. 2013;155(1):200–14.CrossRefPubMedPubMedCentral
51.
Phelps MP, Bailey JN, Vleeshouwer-Neumann T, Chen EY. CRISPR screen identifies the NCOR/HDAC3 complex as a major suppressor of differentiation in rhabdomyosarcoma. Proc Natl Acad Sci U S A. 2016;113(52):15090–5.CrossRefPubMedPubMedCentral
Metadata
Title
Adipocyte-specific Repression of PPAR-gamma by NCoR Contributes to Scleroderma Skin Fibrosis
Authors
Benjamin Korman
Roberta Goncalves Marangoni
Gabriel Lord
Jerrold Olefsky
Warren Tourtellotte
John Varga
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 1/2018
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/s13075-018-1630-z

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