[Molecular mechanism of ciglitazone inhibiting the expression of extracellular matrix in human hepatic stellate cells].
OBJECTIVE
We tested a hypothesis that PPARgamma inhibits TGFbeta1-activation of TGFbeta receptor (TGFbetaR)-1 signaling in quiescent stellate cells, thereby abrogating Smad3 phosphorylation and inhibiting PAI-1 and collagen expressions.


METHODS
Human stellate cells (HSC) were cultured in a medium containing isobutylmethylxanthine, dexamethasone and insulin (MDI) to induce a quiescent adipocytic phenotype one, and then they were treated with TGFbeta1 with or without SB431542, a TGFbetaR1 kinase inhibitor, or the PPARgamma agonist ciglitazone. Effects on Smad 3 phosphorylation, TGFbeta-responsive transcriptional activity, and expressions of collagen and PAI-1 were assessed.


RESULTS
Culturing HSC in MDI induced an adipocytic phenotype characterized by lipid accumulation and increased PPARgamma expression and transcriptional activity. TGFbeta1 treatment caused dose- and time-dependent increases in ECM gene expression, increasing collagen and PAI-1 mRNAs by 3 fold within 3 h and increasing PAI-1 protein levels by 8 fold within 6 h. Treatment with the TGFbetaR1 kinase inhibitor, SB431542, inhibited all of these responses. The PPARbeta agonist ciglitazone also caused a dose-dependent inhibition of TGFbeta1's fibrogenic actions. 1 mmol/L ciglitazone blocked TGFbeta1-transcriptional activity and abolished TGFbeta-mediated induction of collagen and PAI-1 expressions.


CONCLUSIONS
The anti-fibrotic ability of PPARgamma agonist ciglitazone may be related to its ability to inhibit TGFbeta1-TGFbetaR1 signaling and blocking pSmad3-dependent induction of PAI-1 and collagen expression.
Zhao
Cai-Yan
CY
Department of Infectious Diseases, Third Hospital of Hebei Medical University, Shijiazhuang 050051, China. zhaoyy63811@vip.sohu.com
Zhou
Jun-Ying
JY
Yang
Liu
L
Wang
Ya-Dong
YD
D001549:Benzamides / Q000494:pharmacology; D002460:Cell Line; D003094:Collagen / Q000378:metabolism; D004149:Dioxoles / Q000494:pharmacology; D015870:Gene Expression; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D010766:Phosphorylation; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; D004149:Dioxoles; D047495:PPAR gamma; D017395:Plasminogen Activator Inhibitor 1; D051900:Smad3 Protein; D045162:Thiazolidinediones; D053773:Transforming Growth Factor beta1; D003094:Collagen; C039671:ciglitazone