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PPAR gamma inhibits growth of rat hepatic stellate cells and TGF beta-induced connective tissue growth factor expression

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Aim: To investigate the effect of peroxisome proliferator-activated receptor gamma (PPAR) activation on the growth of rat hepatic stellate cells (HSC) and transforming growth factor beta (TGF-)-induced connective tissue growth factor (CTGF) expression. Methods: After being treated with various amounts of the PPAR natural ligand 15-deoxy-A12,14-prostaglandin J2 (15-d-PGJ2) or synthetic ligand GW7845, the status of HSC proliferation and apoptosis were detected by MTT assay and flow cytometry. Furthermore, HSC were treated with PPAR-specific antagonist GW9662 prior to the addition of 15-d-PGJ2 or GW7845 and were subsequently stimulated with TGF-1. The mRNA and protein levels of CTGF expression were detected by semi-quantitative RT-PCR and Western blotting analysis. Morphological changes in the HSC were observed by electron microscopy. Results: 15-d-PGJ2 and GW7845 markedly inhibited HSC proliferation and induced cell apoptosis in a dose-dependent manner. Furthermore, PPAR ligands significantly suppressed TGF-1-induced CTGF expression (at both transcriptional and post-transcriptional levels) in HSC, and the inhibitory effect was dramatically, if not completely, abolished by pretreatment with GW9662, suggesting that the inhibition was indeed mediated by PPAR. Moreover, morphological observation revealed that PPAR activation caused obvious changes of HSC from activated to quiescent phenotype. Conclusion: The PPAR? ligand has a potent inhibitory effect on the growth of HSC and TGF-1-induced CTGF expression, which makes it a potential antifibrotic candidate for the treatment and prevention of hepatic fibrosis.
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Keywords: PPAR gamma; connective tissue growth factor; hepatic stellate cells; transforming growth factor beta

Document Type: Research Article

Affiliations: Department of Hepatobiliary Surgery, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China

Publication date: 2006-06-01

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