Effectiveness of the PPARγ agonist, GW570, in liver fibrosis.
BACKGROUND
The peroxisome proliferator-activated receptors (PPARs) are well established to be important in modulating the fibrogenic response to liver injury. PPARγ plays a role in hepatic fibrosis, presumably by virtue of its expression in hepatic stellate cells, which are key effectors of fibrosis. In this study, we evaluated whether the potent nonthiozolidinedione PPARγ agonist, GW570, had effects on isolated stellate cells and hepatic fibrosis in vivo.


METHODS
Liver fibrosis and stellate cell activation were induced in vivo by either bile duct ligation (BDL) or administration of carbon tetrachloride (CCl(4)). Primary cultures of stellate cells isolated from normal rats were exposed to GW570. The PPARγ agonist was also given to male Sprague-Dawley rats before or during injury to test its ability to ameliorate fibrosis. Fibrosis biomarkers including total collagen, hydroxyproline, collagen I α1 and smooth muscle α actin were measured.


RESULTS
GW570 had potent effects on isolated stellate cells, both simulating PPARγ mediated gene transcription, as well as inhibiting collagen I α1 mRNA and protein expression and smooth muscle α actin protein abundance, consistent with suppression of stellate cell activation. In BDL liver injury, a daily dose of 10 mg/kg per day of GW570 inhibited collagen I α1 mRNA, while concentrations of 1 also inhibited fibrosis as measured by hydroxyproline and total collagen content. Lower doses of GW570 (0.1-1.0 mg/kg per day) did not significantly abrogate whole liver collagen or hydroxyproline content in this model. In a CCl(4) model, 0.1-1.0 mg/kg per day GW570 reduced expression of smooth muscle α actin, but did not affect whole liver collagen or hydroxyproline content. Finally, we found that GW570 had anti-inflammatory effects on Kupffer cells as well as in vivo during CCl(4) injury.


CONCLUSIONS
PPARγ receptor agonism with the nonthiozolidinedione, GW570, inhibited stellate cell activation in vitro and in vivo, and abrogated the fibrogenic response to injury in a dose responsive fashion.
Yang
Liu
L
Department of Medicine, Duke University Medical Center, Durham, USA.
Stimpson
Stephen A
SA
Chen
Lihong
L
Wallace Harrington
W
W
Rockey
Don C
DC
D000199:Actins / Q000378:metabolism; D000818:Animals; D001652:Bile Ducts / Q000601:surgery; D002251:Carbon Tetrachloride / Q000494:pharmacology; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000502:physiology; D007249:Inflammation / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D047495:PPAR gamma / Q000819:agonists*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000199:Actins; D024042:Collagen Type I; D047495:PPAR gamma; D002251:Carbon Tetrachloride