The PPARs were first cloned as the nuclear receptors that mediate the effects of synthetic compounds called peroxisome proliferators on gene transcription. . At the molecular level, PPARs act in a similar manner to other nuclear hormone receptors. First, they bind a specifc element in the promoter region of target genes. PPAR and some other nuclear hormone receptors bind the promoter only as a heterodimer with the receptor for 9-cis retinoic acid, RXR (retinoid X receptor). Second, they activate transcription in response to binding of the hormone (ligand).
Three PPAR isotypes have been identified: a, b (also called d and NUC1) and g. PPARa is expressed most in brown adipose tissue and liver, then kidney, heart and skeletal muscle. PPARa has mostly been studied in the context of liver parenchymal cells, where it is highly expressed. The target genes of PPARa are a relatively homogenous group of genes that participate in aspects of lipid catabolism such as fatty acid uptake through membranes, fatty acid binding in cells, fatty acid oxidation (in microsomes, peroxisomes and mitochondria) and lipoprotein assembly and transport.
Decreased peroxisome proliferator-activated receptors (PPARs) activity is closely associated with increased levels of inflammatory mediators during the agingprocess. The anti-inflammatory action of PPARs is substantiated by both in vitro and in vivo studies that signify the importance of PPARs as major players in the pathogenesis of many inflammatory diseases. The hepatocarcinogenic effect of PPARalpha agonists is enhanced by aging. Exposure to these chemicals produces a five- to seven-fold higher yield of grossly visible hepatic tumors in old relative to young animals.