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Published on: September 14, 2021

Peroxisome proliferator-activated receptor-gamma abrogates Smad-dependent collagen stimulation by targeting the p300

Asish K Ghosh1, Swati Bhattacharyya, Jun Wei

  • 1Feinberg Cardiovascular Research Institute, Chicago, IL 60611, USA. a-ghosh2@northwestern.edu

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|April 28, 2009
PubMed

Insights

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands inhibit collagen gene transcription stimulated by transforming growth factor-beta (TGF-beta). This occurs by blocking p300 recruitment and histone acetylation, offering a potential therapeutic strategy for fibrotic diseases.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Biochemistry

Background:

  • Transforming growth factor-beta (TGF-beta) stimulates collagen gene transcription, a key process in connective tissue homeostasis.
  • Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands have shown potential in modulating TGF-beta signaling pathways.
  • Understanding the precise mechanisms of PPAR-gamma's regulation of TGF-beta is crucial for therapeutic applications in fibrotic conditions.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which PPAR-gamma ligands abrogate TGF-beta-induced collagen gene transcription.
  • To investigate the role of cellular PPAR-gamma in this antagonistic regulation.
  • To determine the impact of PPAR-gamma on Smad-dependent signaling and coactivator recruitment.

Main Methods:

  • Utilized primary cultures of PPAR-gamma-null murine embryonic fibroblasts and RNAi-mediated knockdown of PPAR-gamma in human fibroblasts.
  • Assessed TGF-beta-induced responses, Smad2/3 activation, and Smad2/3-p300 interaction.
  • Examined p300 accumulation at the COL1A2 locus, histone H4 hyperacetylation, and the effect of a dominant-negative p300 mutant.

Main Results:

  • PPAR-gamma-null cells and PPAR-gamma knockdown cells showed no blockade of TGF-beta-induced responses by PPAR-gamma ligands.
  • PPAR-gamma blocked Smad-dependent transcriptional responses without preventing Smad2/3 activation.
  • PPAR-gamma inhibited the interaction between Smad2/3 and p300, p300 accumulation at the COL1A2 locus, and histone H4 hyperacetylation.

Conclusions:

  • PPAR-gamma inhibits TGF-beta-induced collagen gene expression by preventing p300 recruitment and histone H4 hyperacetylation.
  • This mechanism highlights a novel physiological role for PPAR-gamma in maintaining connective tissue homeostasis.
  • Pharmacological activation of PPAR-gamma presents a potential therapeutic strategy for targeting profibrotic responses mediated by p300 and TGF-beta.

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