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


METHODS
After being treated with various amounts of the PPAR gamma natural ligand 15-deoxy-delta12,14-prostaglandin J(2) (15-d-PGJ(2)) 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 gamma -specific antagonist GW9662 prior to the addition of 15-d-PG J(2) or GW7845 and were subsequently stimulated with TGF- beta1. 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-PGJ(2) and GW7845 markedly inhibited HSC proliferation and induced cell apoptosis in a dose-dependent manner. Furthermore, PPAR gamma ligands significantly suppressed TGF-beta1-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 gamma. Moreover, morphological observation revealed that PPAR gamma activation caused obvious changes of HSC from activated to quiescent phenotype.


CONCLUSIONS
The PPAR gamma ligand has a potent inhibitory effect on the growth of HSC and TGF-beta1-induced CTGF expression, which makes it a potential antifibrotic candidate for the treatment and prevention of hepatic fibrosis.
Sun
Kai
K
Department of Hepatobiliary Surgery, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China.
Wang
Qian
Q
Huang
Xiao-Hui
XH
D000813:Anilides / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism; D017874:Immediate-Early Proteins / Q000096:biosynthesis* / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D008024:Ligands; D010080:Oxazoles / Q000008:administration & dosage / Q000494:pharmacology*; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000502:physiology*; D015230:Prostaglandin D2 / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014443:Tyrosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
C097240:15-deoxy-delta(12,14)-prostaglandin J2; C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; C526316:CCN2 protein, rat; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D010080:Oxazoles; D047495:PPAR gamma; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; C401311:GW 7845; D014443:Tyrosine; D015230:Prostaglandin D2