Acta Pharmacologica Sinica 2006 June; 27 (6): 715-723; doi: 10.1111/j.1745-7254.2006.00299.x

Aim: To investigate the effect of peroxisome proliferator-activated receptor gamma (PPARγ) activation on the growth of rat hepatic stellate cells (HSC) and transforming growth factor beta (TGF-β)-induced connective tissue growth factor (CTGF) expression.

Methods: After being treated with various amounts of the PPARγ natural ligand 15-deoxy-D12,14-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 PPARγ-specific antagonist GW9662 prior to the addition of 15-d-PGJ₂ or GW7845 and were subsequently stimulated with TGFβ1. 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, PPARγ ligands significantly suppressed TGF-β1-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 PPARγ. Moreover, morphological observation revealed that PPARγ activation caused obvious changes of HSC from activated to quiescent phenotype.

Conclusion: The PPARγ ligand has a potent inhibitory effect on the growth of HSC and TGF-β1-induced CTGF expression, which makes it a potential antifibrotic candidate for the treatment and prevention of hepatic fibrosis.

Keywords: PPAR gamma; transforming growth factor beta; connective tissue growth factor; hepatic stellate cells