Effectiveness of the PPARγ agonist, GW570, in liver fibrosis

The peroxisome proliferator-activated receptors (PPARs) are well established to be important in modulating the fibrogenic response to liver injury. PPAR gamma 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 PPAR gamma agonist, GW570, had effects on isolated stellate cells and hepatic fibrosis in vivo. Liver fibrosis and stellate cell activation were induced in vivo by either bile duct ligation (BDL) or administration of carbon tetrachloride (CCl4). Primary cultures of stellate cells isolated from normal rats were exposed to GW570. The PPAR gamma 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 alpha 1 and smooth muscle alpha actin were measured. GW570 had potent effects on isolated stellate cells, both simulating PPAR gamma mediated gene transcription, as well as inhibiting collagen I alpha 1 mRNA and protein expression and smooth muscle alpha 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 alpha 1 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 CCl4 model, 0.1-1.0 mg/kg per day GW570 reduced expression of smooth muscle alpha 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 CCl4 injury. PPAR gamma 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.