PPARgamma agonists prevent TGFbeta1/Smad3-signaling in human hepatic stellate cells.
PPARgamma agonists inhibit liver fibrosis, but the mechanisms involved are uncertain. We hypothesized that PPARgamma agonists inhibit transforming growth factor (TGF)beta1-activation of TGFbeta receptor (TGFbetaR)-1 signaling in quiescent stellate cells, thereby abrogating Smad3-dependent induction of extracellular matrix (ECM) genes, such as PAI-1 and collagen-1alphaI. To test this, human HSC were cultured to induce a quiescent phenotype, characterized by lipid accumulation and PPARgamma expression and transcriptional activity. These adipocytic HSC were then treated with TGFbeta1+/-a TGFbetaR-1 kinase inhibitor (SB431542) or a PPARgamma agonist (GW7845). TGFbeta1 caused dose- and time-dependent increases in Smad3 phosphorylation, followed by induction of collagen and PAI-1 expression. Like the TGFbetaR-1 kinase inhibitor, the PPARgamma agonist caused dose-dependent inhibition of all of these responses without effecting HSC proliferation or viability. Thus, the anti-fibrotic actions of PPARgamma agonists reflect their ability to inhibit TGFbeta1-TGFbetaR1 signaling that initiates ECM gene expression in quiescent HSC.
Zhao
Caiyan
C
Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
Chen
Wei
W
Yang
Liu
L
Chen
Lihong
L
Stimpson
Stephen A
SA
Diehl
Anna Mae
AM
D030201:Activin Receptors, Type I / Q000037:antagonists & inhibitors; D017667:Adipocytes / Q000166:cytology; D001549:Benzamides / Q000494:pharmacology; D002460:Cell Line; D003470:Culture Media; D004149:Dioxoles / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D008099:Liver / Q000166:cytology* / Q000378:metabolism; D010080:Oxazoles / Q000494:pharmacology; D047495:PPAR gamma / Q000819:agonists*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D015398:Signal Transduction; D051900:Smad3 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology
C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; D003470:Culture Media; D004149:Dioxoles; D016326:Extracellular Matrix Proteins; D010080:Oxazoles; D047495:PPAR gamma; D047428:Protein Kinase Inhibitors; D018125:Receptors, Transforming Growth Factor beta; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; C401311:GW 7845; D014443:Tyrosine; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I