PPAR? Downregulation by TGF in Fibroblast and Impaired Expression and Function in Systemic Sclerosis

A Novel Mechanism for Progressive Fibrogenesis

Jun Wei, Asish K Ghosh, Jennifer L. Sargent, Kazuhiro Komura, Minghua Wu, Qi-Quan Huang, Manu Jain, Michael L. Whitfield, Carol Feghali-Bostwick, John Varga*

*Corresponding author for this work

Research output: Contribution to journalArticle

101 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere13778
JournalPLoS One
Volume5
Issue number11
DOIs
StatePublished - Nov 22 2010

Fingerprint

Peroxisome Proliferator-Activated Receptors
Systemic Scleroderma
PPAR gamma
sclerosis
Fibroblasts
fibroblasts
Down-Regulation
transforming growth factors
Transforming Growth Factors
Biopsy
skin (animal)
biopsy
Skin
rosiglitazone
Chemical activation
peroxisome proliferator-activated receptors
Genes
Orphan Nuclear Receptors
Diffuse Scleroderma
Adipogenesis

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Wei, Jun ; Ghosh, Asish K ; Sargent, Jennifer L. ; Komura, Kazuhiro ; Wu, Minghua ; Huang, Qi-Quan ; Jain, Manu ; Whitfield, Michael L. ; Feghali-Bostwick, Carol ; Varga, John. / PPAR? Downregulation by TGF in Fibroblast and Impaired Expression and Function in Systemic Sclerosis : A Novel Mechanism for Progressive Fibrogenesis. In: PLoS One. 2010 ; Vol. 5, No. 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.",
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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, Jun; Ghosh, Asish K; Sargent, Jennifer L.; Komura, Kazuhiro; Wu, Minghua; Huang, Qi-Quan; Jain, Manu; Whitfield, Michael L.; Feghali-Bostwick, Carol; Varga, John.

In: PLoS One, Vol. 5, No. 11, e13778, 22.11.2010.

Research output: Contribution to journalArticle

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AU - Wei, Jun

AU - Ghosh, Asish K

AU - Sargent, Jennifer L.

AU - Komura, Kazuhiro

AU - Wu, Minghua

AU - Huang, Qi-Quan

AU - Jain, Manu

AU - Whitfield, Michael L.

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AU - Varga, John

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AB - 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.

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