Senescence-associated decline in hepatic peroxisomal enzyme activities corresponds with diminished levels of retinoid X receptor alpha, but not peroxisome proliferator-activated receptor alpha

Abstract

Aging is associated with alterations in hepatic peroxisomal metabolism and susceptibility to hepatocarcinogenicity produced by agonists of peroxisome proliferator-activated receptor alpha (PPARα). Mechanisms involved in these effects are not well understood. However, as a heterodimer with retinoid X receptor alpha (RXRα), PPARα regulates transcription of genes involved in oxidative stress, cell proliferation and apoptosis. Modulating these important cell functions as a result of aging may be responsible for altered hepatic peroxisomal responses in the senescent liver. Therefore, we investigated hepatic apoptosis, and peroxisomal β-oxidation activity, a major source of H 2O 2, as well as the activity of the peroxisomal anti-oxidant enzyme catalase, in male Fischer-344 rats of four age groups (4, 10, 50 and 100 week old). We further quantified protein levels of both PPARα and RXRα in these animals. Data show that peroxisomal β-oxidation and catalase activities were significantly lower in livers of the 100 week old animals compared with other age groups, while percentage of apoptotic hepatocytes were identical in all animal age groups. However, aging had no effect on hepatic PPARα protein levels. In the senescent group, the level of decline in both peroxisomal enzyme activities of 30% was surprisingly similar to the decline observed in the hepatic expression of the RXRα protein. Results from this study suggest that alterations in peroxisomal metabolism observed in the senescent liver may be a result of the decline in the availability of RXRα receptor, and not the primary PPARα receptor. On the other hand, PPARα-independent mechanisms appear to play a role in controlling apoptosis in the senescent liver.