doi: 10.1161/01.RES.0000064382.46274.95
© 2003 American Heart Association, Inc.
Editorials |
PPARs of the Heart
Three Is a Crowd
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 dkelly{at}im.wustl.edu
Key Words: nuclear receptors • cardiac metabolism • hormones • fatty acids
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: 
, ß/
, 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 tissue- and developmental-specific 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 adipose-enriched nuclear receptor, directs the expression of genes involved in adipocyte differentiation and fat storage. The function of the ubiquitously expressed PPARß/, 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.
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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 PPARß/ 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 PPARß/ in heart. However, previous studies have shown that the expression of PPARß/ 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 PPARß/ 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 PPARß/ in heart. The authors performed a careful analysis of the relative expression levels and activities of PPAR, ß/, and in isolated neonatal and adult rat cardiac myocytes. They found that both PPAR and PPARß/ 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 genes in a pattern that paralleled PPAR isotype-specific expression levels. Specifically, exposure of myocytes to PPAR- or ß/-specific agonists or long-chain fatty acids led to a significant induction of known PPAR target genes involved in fatty acid uptake and oxidation whereas a PPAR agonist had no effect. These results contribute two new and significant findings to our understanding of cardiac PPAR biology. First, PPAR levels and activity are low to absent in isolated rat cardiac myocytes. Second, PPARß/ is relatively abundant, fatty acid inducible, and activates the expression of known PPAR target genes involved in fatty acid utilization in cardiac myocytes.
The results of the study by Gilde et al12 suggest that most of the cardiac effects of PPAR may be mediated by indirect mechanisms. Previous studies have generally shown low levels of PPAR in heart and myocytes.1,2 However, several recent studies have indicated that PPAR exerts cardiac effects. For example, studies using PPAR-specific agonists have shown that activation of PPAR inhibits the cardiac hypertrophic response to pressure overload.10 Others have reported that PPAR agonists promote cardiac hypertrophy.11 The use of PPAR agonists has been shown to reduce myocardial injury and dysfunction caused by ischemia/reperfusion.8,9 The mechanisms responsible for the cardiac effects of PPAR are unknown but effects on lipid and glucose metabolism or antiinflammatory responses have been suggested. The results of the study by Gilde et al indicate that some or all of the cardiac effects following activation of the PPAR pathway occur via indirect mechanisms. Potential indirect mechanisms could include changes in the delivery of glucose and fatty acids to the heart via actions on adipose metabolism. Alternatively, the cardiac response to PPAR could be secondary to the effects of an extracardiac-derived circulating factor. It is important to note that the present results of Gilde et al do not exclude the possibility that expression and activity of PPAR may be induced in the heart under certain physiological or pathophysiological conditions.
In contrast to the wealth of information regarding the biologic functions of PPAR and , relatively little is known about PPARß/. Recent evidence has implicated PPARß/ in the modulation of cellular differentiation and inflammatory responses of the epidermis.13 PPARß/-specific agonists have been shown to increase the expression of noncardiac cellular lipid metabolic pathways including fatty acid thioesterification and cholesterol efflux.14 The study by Gilde et al12 provides important new information about the role of PPARß/ in cardiac myocytes. The authors show that PPARß/ is expressed at levels similar to PPAR in myocytes, stimulates the expression of known PPAR targets involved in cellular fatty acid utilization, and is activated by fatty acids in this cellular context. This latter finding is particularly interesting in view of the results of a recent study demonstrating that PPARß/ is activated in macrophages by the triglyceride-rich, very-low-density particle.15 Future studies aimed at further characterizing PPARß/ targets and delineating relevant upstream regulatory pathways will be necessary to fully assign cell-specific biologic roles to the cardiac PPARß/ pathway.
The Gilde study12 underscores an important enigma relevant to the field of nuclear receptor biology. Why is it necessary to have two functional PPARs in a single cell type such as the cardiac myocyte? The answer to this question is unknown, but the following possibilities should be considered. First, PPAR and PPARß/ may activate overlapping but distinct downstream target metabolic pathways. Although the results of the present study by Gilde et al indicate that PPARß/ is capable of activating PPAR gene targets, a more complete analysis is necessary to define the full repertoire of genes downstream of these nuclear receptors. Second, although fatty acids activate both receptors, the bona fide endogenous ligands may be distinct for PPAR and PPARß/. Ligand specificity could provide a mechanism whereby a distinct cellular metabolic response may be elicited by specific upstream lipid signaling pathways. Third, the expression of each PPAR could be regulated independently at the transcriptional or posttranscriptional levels by unique physiological stimuli. Finally, it is possible that PPAR and PPARß/ interact with a customized set of coactivators (Figure), providing an additional level of regulatory diversity.
As ligand-activated transcription factors, the PPARs represent an attractive target for the development of therapeutic agents. The results of the study by Gilde et al12 add PPARß/ to the list of candidate nuclear receptor targets for pharmacologic modulation of cardiac metabolism. However, it will first be necessary to precisely define the biologic and physiological roles and regulatory features of PPARß/ in heart and other tissues. The current identification of specific PPARs that reside in heart is an important first step.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
References
1. Desvergne B, Wahli W. Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev. 1999; 20: 649–688.
2. Barger PM, Kelly DP. PPAR signaling in the control of cardiac energy metabolism. Trends Cardiovasc Med. 2000; 10: 238–245.[CrossRef][Medline] [Order article via Infotrieve]
3. Barger PM, Brandt JM, Leone TC, Weinheimer CJ, Kelly DP. Deactivation of peroxisome proliferator-activated receptor- during cardiac hypertrophic growth. J Clin Invest. 2000; 105: 1723–1730.[Medline]
[Order article via Infotrieve]
4. Young ME, Laws FA, Goodwin GW, Taegtmeyer H. Reactivation of peroxisome proliferator-activated receptor is associated with contractile dysfunction in hypertrophied rat heart. J Biol Chem. 2001; 276: 44390–44395.
5. Huss JM, Levy FH, Kelly DP. Hypoxia inhibits the PPAR/RXR gene regulatory pathway in cardiac myocytes. J Biol Chem. 2001; 276: 27605–27612.
6. Razeghi P, Young ME, Abbasi S, Taegtmeyer H. Hypoxia in vivo decreases peroxisome proliferator-activated receptor -regulated gene expression in rat heart. Biochem Biophys Res Commun. 2001; 287: 5–10.[CrossRef][Medline]
[Order article via Infotrieve]
7. Finck B, Lehman JJ, Leone TC, Welch MJ, Bennett MJ, Kovacs A, Han X, Gross RW, Kozak R, Lopaschuk GD, Kelly DP. The cardiac phenotype induced by PPAR overexpression mimics that caused by diabetes mellitus. J Clin Invest. 2002; 109: 121–130.[CrossRef][Medline]
[Order article via Infotrieve]
8. Zhu P, Lu L, Xu Y, Schwartz G. Troglitazone improves recovery of left ventricular function after regional ischemia in pigs. Circulation. 2000; 101: 1165–1171.
9. Yue T, Chen J, Bao W, Narayanan PK, Bril A, Jiang W, Lysko PG, Gu J-L, Boyce R, Zimmerman DM, Hart TK, Buckingham RE, Ohlstein EH. In vivo myocardial protection from ischemia/reperfusion injury by the peroxisome proliferator-activated receptor- agonist rosiglitazone. Circulation. 2001; 104: 2588–2594.
10. Yamamoto K, Ohki R, Lee RT, Ikeda U, Shimada K. Peroxisome proliferator-activated receptor activators inhibit cardiac hypertrophy in cardiac myocytes. Circulation. 2001; 104: 1670–1675.
11. Actos/Pioglitazone NDA.Sub 021073, 7/15/1999.http://www.fda.gov/cder/foi/nda/99/021073A_Actos_medr_P3.pdf. Med Rev (pt 3:36–40).
12. Gilde AJ, van der Lee KAJM, Willemsen PHM, Chinetti G, van der Leij FR, van der Vusse GJ, Staels B, van Bilsen M. Peroxisome proliferator-activated receptor (PPAR) and PPARß/, but not PPAR, modulate the expression of genes involved in cardiac lipid metabolism. Circ Res. 2003; 92: 518–524.
13. Peters JM, Lee SST, Li W, Ward JM, Gavrilova O, Everett C, Reitman ML, Hudson LD, Gonzalez FJ. Growth, adipose, brain, and skin alterations resulting from targeted disruption of the mouse peroxisome proliferator-activated receptor ß(). Mol Cell Biol. 2000; 20: 5119–5128.
14. Oliver WR Jr, Shenk JL, Snaith MR, Russell CS, Plunket KD, Bodkin NL, Lewis MC, Winegar DA, Sznaidman ML, Lambert MH, Xu HE, Sternbach DD, Kliewer SA, Hansen BC, Willson TM. A selective peroxisome proliferator-activated receptor agonist promotes reverse cholesterol transport. Proc Natl Acad Sci U S A. 2001; 98: 5306–5311.
15. Chawla A, Lee C-H, Barak Y, He W, Rosenfeld J, Liao D, Han J, Kang H, Evans RM. PPAR is a very low-density lipoprotein sensor in macrophages. Proc Natl Acad Sci U S A. 2003; 100: 1268–1273.
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