Peroxisome proliferator-activated receptor-α regulates postischemic liver injury

Abstract

Peroxisome proliferator-activated receptor-α (PPARα) is a transcription factor that in some in vitro systems has been linked with downregulation of proinflammatory mediators, thus implicating a potential role for PPARα in the regulation of inflammatory processes. Hepatic ischemia-reperfusion injury is characterized by an intense acute inflammatory response that is dependent on a number of proinflammatory mediators. PPARα is abundantly expressed in hepatic parenchymal cells but not in Kupffer cells. This study examined whether PPARα is involved in regulation of the hepatic inflammatory response to ischemia-reperfusion. Mice nullizygous for PPARα had significantly greater liver injury than did their wild-type counterparts. Consistent with these findings, C57BL/6 mice treated with the PPARα agonist, WY-14643, had significantly less liver injury than mice receiving vehicle. PPARα-knockout mice also had greatly augmented liver neutrophil accumulation and modest increases in activation of the transcription factors NF-κB and activator protein-1. However, these effects were not associated with increased expression of proinflammatory cytokines or chemokines. In addition, PPARα-knockout mice expressed far less inducible nitric oxide synthase in liver than did wild-type mice after ischemia-reperfusion. Finally, treatment of cultured murine hepatocytes with WY-14643, a specific agonist of PPARα, protected cells against oxidant-induced injury. The data suggest that PPARα is an important regulator of the hepatic inflammatory response to ischemia-reperfusion in a manner that is independent of proinflammatory cytokines.