PGC-1α Protects against Hepatic Ischemia Reperfusion Injury by Activating PPARα and PPARγ and Regulating ROS Production

Peroxisome proliferator-activated receptors (PPARs) alpha and gamma have been shown to be protective in hepatic ischemia/reperfusion (I/R) injury. However, the precise role of PPAR gamma coactivator-1 alpha (PGC-1 alpha), which can coactivate both of these receptors, in hepatic I/R injury, remains largely unknown. This study was designed to test our hypothesis that PGC-1 alpha is protective during hepatic I/R injury in vitro and in vivo. Our results show that endogenous PGC-1 alpha is basally expressed in normal livers and is moderately increased by I/R. Ectopic PGC-1 alpha protects against hepatic I/R and hepatocyte anoxia/reoxygenation (A/R) injuries, whereas knockdown of endogenous PGC-1 alpha aggravates such injuries, as evidenced by assessment of the levels of serum aminotransferases and inflammatory cytokines, necrosis, apoptosis, cell viability, and histological examination. The EMSA assay shows that the activation of PPAR alpha and PPAR gamma is increased or decreased by the overexpression or knockdown of PGC-1 alpha, respectively, during hepatic I/R and hepatocyte A/R injuries. In addition, the administration of specific antagonists of either PPAR alpha (MK886) or PPAR gamma (GW9662) can effectively decrease the protective effect of PGC-1 alpha against hepatic I/R and hepatocyte A/R injuries. We also demonstrate an important regulatory role of PGC-1 alpha in reactive oxygen species (ROS) metabolism during hepatic I/R, which is correlated with the induction of ROS-detoxifying enzymes and is also dependent on the activations of PPAR alpha and PPAR gamma. These data demonstrate that PGC-1 alpha protects against hepatic I/R injury, mainly by regulating the activation of PPAR alpha and PPAR gamma. Thus, PGC-1 alpha may be a promising therapeutic target for the protection of the liver against I/R injury.