Peroxisome proliferator-activated receptor-γ protects against hepatic ischemia/reperfusion injury in mice

The function of peroxisome proliferator-activated receptor-gamma (PPAR gamma) in hepatic inflammation and injury is unclear. In this study, we sought to determine the role of PPAR gamma in hepatic ischemia/reperfusion injury in mice. Male mice were subjected to 90 minutes of partial hepatic ischemia followed by up to 8 hours of reperfusion. PPAR gamma was found to be constitutively activated in hepatocytes but not in nonparenchymal cells. Upon induction of ischemia, hepatic PPAR gamma activation rapidly decreased and remained suppressed throughout the 8-hour reperfusion period. This reduced activation was not a result of decreased protein availability as hepatic nuclear PPAR gamma, retinoid X receptor-a (RXR alpha), and PPAR gamma/RXR alpha heterodimer expression was maintained. Accompanying the decrease in PPAR gamma activation was a decrease in the expression of the natural ligand 15-deoxy-Delta(12,14)-prostaglandinJ(2). This was associated with reduced interaction of PPAR gamma and the coactivator, p300. To determine whether PPAR gamma activation is hepatoprotective during hepatic ischemia/reperfusion injury, mice were treated with the PPAR gamma agonists, rosiglitazone and connecting peptide. These treatments increased PPAR gamma activation and reduced liver injury compared to untreated mice. Furthermore, PPAR gamma-deficient mice had more liver injury after ischemia/reperfusion than their wildtype counterparts. Conclusion: These data suggest that PPAR gamma is an important endogenous regulator of, and potential therapeutic target for, ischemic liver injury.