PPAR{gamma} agonists prevent TGF{beta}1/Smad3-signaling in human hepatic stellate cells
- Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710 (United States)
- GlaxoSmithKline, Inc., Research Triangle Park, NC 27709 (United States)
PPAR{gamma} agonists inhibit liver fibrosis, but the mechanisms involved are uncertain. We hypothesized that PPAR{gamma} agonists inhibit transforming growth factor (TGF){beta}1-activation of TGF{beta} receptor (TGF{beta}R)-1 signaling in quiescent stellate cells, thereby abrogating Smad3-dependent induction of extracellular matrix (ECM) genes, such as PAI-1 and collagen-1{alpha}I. To test this, human HSC were cultured to induce a quiescent phenotype, characterized by lipid accumulation and PPAR{gamma} expression and transcriptional activity. These adipocytic HSC were then treated with TGF{beta}1 {+-} a TGF{beta}R-1 kinase inhibitor (SB431542) or a PPAR{gamma} agonist (GW7845). TGF{beta}1 caused dose- and time-dependent increases in Smad3 phosphorylation, followed by induction of collagen and PAI-1 expression. Like the TGF{beta}R-1 kinase inhibitor, the PPAR{gamma} agonist caused dose-dependent inhibition of all of these responses without effecting HSC proliferation or viability. Thus, the anti-fibrotic actions of PPAR{gamma} agonists reflect their ability to inhibit TGF{beta}1-TGF{beta}R1 signaling that initiates ECM gene expression in quiescent HSC.
- OSTI ID:
- 20854572
- Journal Information:
- Biochemical and Biophysical Research Communications, Journal Name: Biochemical and Biophysical Research Communications Journal Issue: 2 Vol. 350; ISSN BBRCA9; ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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