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).
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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Item Type: |
Article
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Status: |
Published |
Creators/Authors: |
Creators | Email | Pitt Username | ORCID  |
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Wei, J | | | | Ghosh, AK | | | | Sargent, JL | | | | Komura, K | | | | Wu, M | | | | Huang, QQ | | | | Jain, M | | | | Whitfield, ML | | | | Feghali-Bostwick, C | | | | Varga, J | | | |
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Contributors: |
Contribution | Contributors Name | Email | Pitt Username | ORCID  |
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Editor | Sturtevant, Joy | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED |
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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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