Molecular mechanism of ciglitazone inhibiting the expression of extracellular matrix in human hepatic stellate cells / 中华肝脏病杂志
Chinese Journal of Hepatology
; (12): 840-844, 2007.
Article
em Zh
| WPRIM
| ID: wpr-354614
Biblioteca responsável:
WPRO
ABSTRACT
<p><b>OBJECTIVE</b>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.</p><p><b>METHODS</b>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.</p><p><b>RESULTS</b>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.</p><p><b>CONCLUSION</b>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.</p>
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Base de dados:
WPRIM
Assunto principal:
Farmacologia
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Fosforilação
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Benzamidas
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Transdução de Sinais
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Expressão Gênica
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Linhagem Celular
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Colágeno
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Inibidor 1 de Ativador de Plasminogênio
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Tiazolidinedionas
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PPAR gama
Limite:
Humans
Idioma:
Zh
Revista:
Chinese Journal of Hepatology
Ano de publicação:
2007
Tipo de documento:
Article