PPARs of the heart: three is a crowd.

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: , / , and (see reviews1,2). PPAR 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 tissueand developmentalspecific patterns of expression and by the distinct, albeit overlapping, nature of ligands capable of activating each receptor. PPAR , 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, PPAR , an adiposeenriched nuclear receptor, directs the expression of genes involved in adipocyte differentiation and fat storage. The function of the ubiquitously expressed PPAR / , 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 has been shown to fulfill a critical role in the regulation of myocardial lipid and energy metabolism.2 PPAR activates the transcription of genes involved in every step of the cardiac myocyte fatty acid utilization pathway from uptake to mitochondrial fatty acid oxidation leading to ATP production. Accordingly, the activity of PPAR is an important determinant of myocardial energy production. As a fatty acid–activated transcription factor, PPAR also serves to match cardiac lipid delivery to oxidative capacity, a “lipostat” function. The activity of the PPAR gene regulatory pathway is altered in a variety of common myocardial diseases. In the pathologically hypertrophied heart, PPAR expression and activity are diminished, leading to a reduction in the capacity for fatty acid oxidation and increased rates of glucose utilization.3 The functional consequences of this metabolic switch are unknown, but some evidence indicates that it serves to preserve ventricular function in the context of chronic pressure overload.4 Similarly, the expression and activity of both RXR and PPAR are reduced in the hypoxic cardiac myocyte.5,6 Conversely, the activity of PPAR and its downstream targets are abnormally activated in the diabetic heart, leading to a marked increase in the uptake and oxidation of fatty acids. Recent evidence indicates that chronic activation of the cardiac PPAR pathway, such as occurs in the diabetic heart, may lead to myocardial lipid accumulation and features of diabetic cardiomyopathy.7 In contrast to the explosion of new information about the cardiac PPAR gene regulatory pathway, little is known about the relative expression and functions of PPAR or PPAR / in heart. The role of PPAR as a critical regulator of adipose development and metabolism has been extensively characterized.1 PPAR agonists, several of which have been developed as therapeutic agents, improve insulin sensitivity in the diabetic patient.1 Recent studies have suggested that PPAR agonists are cardioprotective against ischemic insult8,9 and may modulate the cardiac hypertrophic growth response.10,11 However, the exact mechanisms whereby PPAR exerts its effects on cardiac metabolism and function are unclear. Given that the main target for PPAR is adipose tissue, it is possible that cardiac effects are due to indirect mechanisms. Essentially nothing is known about the activity and function of PPAR / in heart. However, previous studies have shown that the expression of PPAR / is expressed at levels similar to PPAR , suggesting that it likely controls the expression of cardiac genes.1,2 Notably, most studies describing the cardiac expression of PPAR and PPAR / were performed with whole tissue extracts so that the relative expression in the myocyte versus nonmyocyte fraction, including pericardial adipocytes, has not been delineated. The study by Gilde et al in this issue of Circulation Research12 provides important new information about the expression and function of PPAR and PPAR / in heart. The authors performed a careful analysis of the relative expression levels and activities of PPAR , / , and in isolated neonatal and adult rat cardiac myocytes. They found that both PPAR and PPAR / were expressed in comparably abundant levels. In contrast, PPAR was barely detectable. Exposure of cardiac myocytes to PPAR-specific ligands resulted in the activation of known endogenous PPAR target The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Center for Cardiovascular Research, Departments of Medicine, Molecular Biology & Pharmacology, and Pediatrics, Washington University School of Medicine, St. Louis, Mo. Correspondence to Daniel P. Kelly, MD, Center for Cardiovascular Research, Washington University School of Medicine, 660 S Euclid Ave, Campus Box 8086, St. Louis, MO 63110. E-mail [email protected] (Circ Res. 2003;92:482-484.) © 2003 American Heart Association, Inc.