Activation of Peroxisome Proliferator-Activated Receptor-γ During Hepatic Ischemia Is Age-Dependent

Hepatic ischemia/reperfusion injury is a complication of liver surgery, transplantation, and shock and is known to be age-dependent. Our laboratory has recently shown that peroxisome proliferator-activated receptor-gamma (PPARγ) is down-regulated during hepatic ischemia and that this exacerbates injury. Here we examined whether activation of PPARγ during ischemia was age-dependent. Male mice of different ages (young: 4–5 weeks; adult: 10–12 weeks; old: 10–12 months) were subjected to up to 90 min of hepatic ischemia. PPARγ activation occurred throughout ischemia in young mice, whereas activation in adult and old mice was lost after 30 min. No significant differences were noted in PPARγ ligand expression among the age groups. However, in young mice we observed a predominance of PPARγ1 in the nucleus, whereas in old mice this isoform remained largely in the cytoplasm. Finally, the degree of PPARγ activation was associated with autophagy in the liver, a mechanism of self-preservation. PPARγ activation is prolonged in young mice as compared to older mice. This appears to be mediated by a selective retention of PPARγ1 in the nucleus and is associated with increased autophagy. The data suggest that PPARγ activation is an important component of the age-dependent response to hepatic ischemia/reperfusion injury.