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PPAR? Downregulation by TGF in Fibroblast and Impaired Expression and Function in Systemic Sclerosis: A Novel Mechanism for Progressive Fibrogenesis

Wei, J and Ghosh, AK and Sargent, JL and Komura, K and Wu, M and Huang, QQ and Jain, M and Whitfield, ML and Feghali-Bostwick, C and Varga, J (2010) PPAR? Downregulation by TGF in Fibroblast and Impaired Expression and Function in Systemic Sclerosis: A Novel Mechanism for Progressive Fibrogenesis. PLoS ONE, 5 (11).

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Abstract

The nuclear orphan receptor peroxisome proliferator-activated receptor-gamma (PPAR-γ) is expressed in multiple cell types in addition to adipocytes. Upon its activation by natural ligands such as fatty acids and eicosanoids, or by synthetic agonists such as rosiglitazone, PPAR-γ regulates adipogenesis, glucose uptake and inflammatory responses. Recent studies establish a novel role for PPAR-γ signaling as an endogenous mechanism for regulating transforming growth factor-ß (TGF-ß)- dependent fibrogenesis. Here, we sought to characterize PPAR-γ function in the prototypic fibrosing disorder systemic sclerosis (SSc), and delineate the factors governing PPAR-γ expression. We report that PPAR-γ levels were markedly diminished in skin and lung biopsies from patients with SSc, and in fibroblasts explanted from the lesional skin. In normal fibroblasts, treatment with TGF-ß resulted in a time- and dose-dependent down-regulation of PPAR-γ expression. Inhibition occurred at the transcriptional level and was mediated via canonical Smad signal transduction. Genome-wide expression profiling of SSc skin biopsies revealed a marked attenuation of PPAR-γ levels and transcriptional activity in a subset of patients with diffuse cutaneous SSc, which was correlated with the presence of a ''TGF-ß responsive gene signature'' in these biopsies. Together, these results demonstrate that the expression and function of PPAR-γ are impaired in SSc, and reveal the existence of a reciprocal inhibitory cross-talk between TGF-ß activation and PPAR-γ signaling in the context of fibrogenesis. In light of the potent anti-fibrotic effects attributed to PPAR-γ, these observations lead us to propose that excessive TGF-ß activity in SSc accounts for impaired PPAR-γ function, which in turn contributes to unchecked fibroblast activation and progressive fibrosis. © 2010 Wei et al.

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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Wei, J
Ghosh, AK
Sargent, JL
Komura, K
Wu, M
Huang, QQ
Jain, M
Whitfield, ML
Feghali-Bostwick, C
Varga, J
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorSturtevant, JoyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 22 November 2010
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 5
Number: 11
DOI or Unique Handle: 10.1371/journal.pone.0013778
Schools and Programs: School of Medicine > Critical Care Medicine
Refereed: Yes
MeSH Headings: Adipogenesis--drug effects; Adult; Animals; Animals, Newborn; Blotting, Western; Cells, Cultured; Down-Regulation--drug effects; Female; Fibroblasts--drug effects; Fibroblasts--metabolism; Fibrosis--genetics; Fibrosis--metabolism; Gene Expression Profiling; Humans; Lung--metabolism; Lung--pathology; Male; Mice; Mice, Knockout; Middle Aged; PPAR gamma--genetics; PPAR gamma--metabolism; Reverse Transcriptase Polymerase Chain Reaction; Scleroderma, Systemic--genetics; Scleroderma, Systemic--metabolism; Skin--metabolism; Skin--pathology; Transforming Growth Factor beta--pharmacology
Other ID: NLM PMC2970611
PubMed Central ID: PMC2970611
PubMed ID: 21072170
Date Deposited: 21 Aug 2012 14:19
Last Modified: 02 Feb 2019 16:58
URI: http://d-scholarship.pitt.edu/id/eprint/13565

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