Importance of peroxisome proliferator-activated receptor-gamma in hepatic ischemia/reperfusion injury in mice.

BACKGROUND/AIMS: Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a transcriptional factor belonging to the nuclear receptor superfamily. Recent studies have suggested that PPARgamma regulates inflammatory responses and PPARgamma specific agonists have beneficial effects on several disease conditions in the various organs. However, the precise role of PPARgamma in acute liver injury remains unknown.

METHODS: We investigated the pathophysiological role of PPARgamma and the effect of the selective PPARgamma agonist, pioglitazone, on the hepatic ischemia/reperfusion (I/R) injury.

RESULTS: PPARgamma expression in the liver was upregulated after reperfusion following ischemia. Pioglitazone treatment significantly inhibited hepatic I/R injury as determined by serological and histological analyses. The protective effect was associated with downregulation of the local expression of several potent proinflammatory cytokines, chemokines and adhesion molecules after reperfusion. The neutrophil accumulation was also inhibited by the treatment. Furthermore, the treatment inhibited the induction of apoptosis on hepatocytes. Finally, pioglitazone significantly improved the mouse survival in a lethal model of hepatic I/R injury.

CONCLUSIONS: PPARgamma plays an inhibitory role in hepatic I/R injury and the stimulation by selective agonist has a significant beneficial effect. Thus, PPARgamma may be a new therapeutic target for the protection of the liver against acute injury.