The Pleiotropic Nature of the Vascular PPAR Gene Regulatory Pathway

The peroxisome proliferator-activated receptors (PPARs) are a family of ligand-activated transcription factors within the broad nuclear receptor superfamily. Recent evidence indicates that the PPARs play critical regulatory roles in a variety of biologic processes relevant to the heart and vasculature including lipid and energy metabolism, inflammation, and cellular differentiation (reviewed in Desvergne and Wahli1). The PPAR family includes three members encoded by distinct genes: α, β (also known as δ or Nuc1), and γ. The three PPARs are distinguished by tissue- and developmental-specific patterns of expression and by the distinct, albeit overlapping, nature of lipid and eicosanoid ligands capable of activating each receptor. For instance, the expression of PPARγ is highly adipose-enriched, whereas PPARα is expressed in tissues with high rates of mitochondrial fatty acid oxidation, such as heart and liver. Ligand activation of PPAR leads to obligate heterodimerization with members of the retinoid X receptor (RXR) subfamily and subsequent binding to cognate DNA response elements within target gene promoter regions. The true endogenous PPAR ligands have not been defined with certainty. Long-chain fatty acids activate each of the PPARs to varying degrees suggesting that lipid species serve as cell-specific PPAR ligands. A number of pharmacologically active, PPAR-specific compounds have been identified leading to a rapidly growing interest in this family of nuclear receptors as targets for drug development. For example, the PPARα activators clofibrate and gemfibrozil have been developed as hypolipidemic agents. Thiazolidinediones (eg, troglitazone, rosiglitazone) are PPARγ-specific activators with potent insulin-sensitizing action.The activity of the PPAR/RXR complex is controlled by an exquisite array of regulatory mechanisms (Figure; reviewed in Barger and Kelly2). The remarkably pleiotropic nature of this regulation allows for the dynamic modulation of PPAR target gene expression across a wide …