PPARs of the Heart

Abstract

The peroxisome proliferator-activated receptors (PPARs) are a family of ligand-activated transcription factors within the broad nuclear receptor superfamily. The PPAR family includes three members encoded by distinct genes: α, β/δ, and γ (see reviews1,2). PPARα was originally identified as the intracellular receptor for a class of nongenotoxic rodent hepatocarcinogens, which includes the hypolipidemic drug clofibrate, a potent inducer of hepatic peroxisomal proliferation and hypolipidemic agent. The three PPARs are now distinguished by tissue- and developmental-specific patterns of expression and by the distinct, albeit overlapping, nature of ligands capable of activating each receptor. PPARα, which is abundant in tissues with high rates of mitochondrial fatty acid oxidation, such as heart, liver, and kidney, regulates a wide variety of target genes involved in cellular lipid catabolism. In contrast, PPARγ, an adipose-enriched nuclear receptor, directs the expression of genes involved in adipocyte differentiation and fat storage. The function of the ubiquitously expressed PPARβ/δ, is not well understood although some evidence suggests that it exerts actions on the epidermis and activates antiinflammatory programs. Ligand activation of PPARs leads to obligate heterodimerization with the 9- cis retinoic acid-activated receptor, RXR, promoting binding of the complex to cognate DNA response elements within PPAR target gene promoter regions (Figure). A variety of natural and synthetic compounds including fatty acids, eicosanoids, and arachidonic acid derivatives can serve as activators of the PPARs, some in a receptor-specific manner. However, the true endogenous ligands have not been identified. PPAR transcriptional regulatory complex. PPARs bind to sequence-specific target elements (PPREs) as a liganded heterodimer with the retinoid X receptor (RXR). Major functions based on known target genes and examples of relevant tissues (in parentheses) for each member of the PPAR family are shown. The question mark indicates that target genes for PPARβ/δ are largely unidentified. PPARα has been shown to …