Top

Published in:

01-03-2011 | Riley Symposium

Peroxisome Proliferator Activated Receptor-Alpha (PPARα) and PPAR Gamma Coactivator-1alpha (PGC-1α) Regulation of Cardiac Metabolism in Diabetes

Author: Jennifer G. Duncan

Published in: Pediatric Cardiology | Issue 3/2011

Abstract

Cardiovascular disease is a leading cause of mortality among patients with diabetes, and heart failure exists even in the absence of coronary disease. Myocardial metabolism is altered in the diabetic heart as a result of changes in substrate availability secondary to insulin resistance. The nuclear receptor peroxisome proliferator activated receptor-alpha (PPARα) and PPAR-gamma coactivator-1alpha (PGC-1α) play important roles in transcriptional regulation of myocardial metabolism and contribute significantly to the changes that occur in the diabetic heart. This review summarizes the role of PPARα and PGC-1α in myocardial metabolism in the normal heart and in the diabetic heart.

Arany Z, He H, Lin J, Hoyer K, Handschin C, Toka O, Ahmad F, Matsui T, Chin S, Wu PH, Rybkin II, Shelton JM, Manieri M, Cinti S, Schoen FJ, Bassel-Duby R, Rosenzweig A, Ingwall JS, Spiegelman BM (2005) Transcriptional coactivator PGC-1 alpha controls the energy state and contractile function of cardiac muscle. Cell Metab 1:259–271

Arany Z, Novikov M, Chin S, Ma Y, Rosenzweig A, Spiegelman BM (2006) Transverse aortic constriction leads to accelerated heart failure in mice lacking PPARγ coactivator 1α. Proc Natl Acad Sci USA 103:10086–10091PubMedCrossRef

Barger PM, Brandt JM, Leone TC, Weinheimer CJ, Kelly DP (2000) Deactivation of peroxisome proliferator-activated receptor-α during cardiac hypertrophic growth. J Clin Invest 105:1723–1730PubMedCrossRef

Belke DD, Larsen TS, Gibbs EM, Severson DL (2000) Altered metabolism causes cardiac dysfunction in perfused hearts from diabetic (db/db) mice. Am J Physiol Endocrinol Metab 279:E1104–E1113PubMed

Bernal-Mizrachi C, Weng S, Feng C, Finck BN, Knutsen RH, Leone TC, Coleman T, Mecham RP, Kelly DP, Semenkovich CF (2003) Dexamethasone induction of hypertension and diabetes is PPAR-α dependent in LDL receptor-null mice. Nat Med 9:1069–1075PubMedCrossRef

Boudina S, Abel ED (2006) Mitochondrial uncoupling: a key contributor to reduced cardiac efficiency in diabetes. Physiology 21:250–258PubMedCrossRef

Boudina S, Sena S, O’Neill BT, Tathireddy P, Young ME, Abel ED (2005) Reduced mitochondrial oxidative capacity and increased mitochondrial uncoupling impair myocardial energetics in obesity. Circulation 112:2686–2695PubMedCrossRef

Buchanan J, Mazumder PK, Hu P, Chakrabarti G, Roberts MW, Jeong Yun U, Cooksey RC, Litwin SE, Abel ED (2005) Reduced cardiac efficiency and altered substrate metabolism precedes the onset of hyperglycemia and contractile dysfunction in two mouse models of insulin resistance and obesity. Endocrinology 146:5341–5349PubMedCrossRef

Campbell FM, Kozak R, Wagner A, Altarejos JY, Dyck JR, Belke DD, Severson DL, Kelly DP, Lopaschuk GD (2002) A role for peroxisome proliferator-activated receptor alpha (PPARalpha) in the control of cardiac malonyl-CoA levels: reduced fatty acid oxidation rates and increased glucose oxidation rates in the hearts of mice lacking PPARalpha are associated with higher concentrations of malonyl-CoA and reduced expression of malonyl-CoA decarboxylase. J Biol Chem 277:4098–4103PubMedCrossRef

10.

Chakravarthy MV, Lodhi IJ, Yin L, Malapaka RR, Xu HE, Turk J, Semenkovich CF (2009) Identification of a physiologically relevant endogenous ligand for PPARalpha in liver. Cell 138:476–488PubMedCrossRef

11.

Chiu HC, Kovacs A, Ford DA, Hsu FF, Garcia R, Herrero P, Saffitz JE, Schaffer JE (2001) A novel mouse model of lipotoxic cardiomyopathy. J Clin Invest 107:813–822PubMedCrossRef

12.

Chiu HC, Kovacs A, Blanton RM, Han X, Courtois M, Weinheimer CJ, Yamada KA, Brunet S, Xu H, Nerbonne JM, Welch MJ, Fettig NM, Sharp TL, Sambandam N, Olson KM, Ory DS, Schaffer JE (2005) Transgenic expression of FATP1 in the heart causes lipotoxic cardiomyopathy. Circ Res 96:225–233PubMedCrossRef

13.

Cook WS, Yeldandi AV, Rao MS, Hashimoto T, Reddy JK (2000) Less extrahepatic induction of fatty acid beta-oxidation enzymes by PPAR alpha. Biochem Biophys Res Commun 278:250–257PubMedCrossRef

14.

Dashti N, Ontko JA (1983) Alterations in rat serum lipids and apolipoproteins following clofibrate treatment. Atherosclerosis 49:255–266PubMedCrossRef

15.

Desvergne B, Wahli W (1999) Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev 20:649–688PubMedCrossRef

16.

Djouadi F, Bastin J, Kelly DP, Merlet-Benichou C (1996) Transcriptional regulation by glucocorticoids of mitochondrial oxidative enzyme genes in the developing rat kidney. Biochem J 315:555–562PubMed

17.

Duncan JG, Fong JL, Medeiros DM, Finck BN, Kelly DP (2007) Insulin-resistant heart exhibits a mitochondrial biogenic response driven by the peroxisome proliferator-activated receptor-α/PGC-1α gene regulatory pathway. Circulation 115:909–917PubMedCrossRef

18.

Duncan JG, Bharadwaj KG, Fong JL, Mitra R, Sambandam N, Courtois MR, Lavine KJ, Goldberg IJ, Kelly DP (2010) Rescue of cardiomyopathy in peroxisome proliferator-activated receptor-alpha transgenic mice by deletion of lipoprotein lipase identifies sources of cardiac lipids and peroxisome proliferator-activated receptor-alpha activators. Circulation 121:426–435PubMedCrossRef

19.

Fein FS, Sonnenblick EH (1985) Diabetic cardiomyopathy. Prog Cardiovasc Dis 4:255–270CrossRef

20.

Finck BN, Kelly DP (2006) PGC-1 coactivators: inducible regulators of energy metabolism in health and disease. J Clin Invest 116:615–622PubMedCrossRef

21.

Finck BN, Lehman JJ, Leone TC, Welch MJ, Bennett MJ, Kovacs A, Han X, Gross RW, Kozak R, Lopaschuk GD, Kelly DP (2002) The cardiac phenotype induced by PPARα overexpression mimics that caused by diabetes mellitus. J Clin Invest 109:121–130PubMed

22.

Finck BN, Han X, Courtois M, Aimond F, Nerbonne JM, Kovacs A, Gross RW, Kelly DP (2003) A critical role for PPARalpha-mediated lipotoxicity in the pathogenesis of diabetic cardiomyopathy: modulation by dietary fat content. Proc Natl Acad Sci USA 100:1226–1231PubMedCrossRef

23.

Gamble J, Lopaschuk GD (1994) Glycolysis and glucose oxidation during reperfusion of ischemic hearts from diabetic rats. Biochim Biophys Acta 1225:191–199PubMed

24.

Gilde AJ, van der Lee KAJM, Willemsen PHM, Chinetti G, van der Leij FR, van der Vusse GJ, Staels B, van Bilsen M (2003) PPARα and PPARβ/δ, but not PPARγ, modulate the expression of genes involved in cardiac lipid metabolism. Circ Res 92:518–524PubMedCrossRef

25.

Handschin C, Spiegelman BM (2006) Peroxisome proliferator-activated receptor gamma coactivator 1 coactivators, energy homeostasis, and metabolism. Endocr Rev 27:728–735PubMed

26.

Herrero P, Peterson LR, McGill JB, Matthew S, Lesniak D, Dence C, Gropler RJ (2006) Increased myocardial fatty acid metabolism in patients with type 1 diabetes mellitus. J Am Coll Cardiol 47:598–604PubMedCrossRef

27.

Ide T, Oku H, Sugano M (1982) Reciprocal responses to clofibrate in ketogenesis and triglyceride and cholesterol secretion in isolated rat liver. Metabolism 31:1065–1072PubMedCrossRef

28.

Kannel WB, Hjortland M, Castelli WP (1974) Role of diabetes in congestive heart failure: the Framingham Study. Am J Cardiol 34:29–34PubMedCrossRef

29.

Kelly DP, Scarpulla RC (2004) Transcriptional regulatory circuits controlling mitochondrial biogenesis and function. Genes Dev 18:357–368PubMedCrossRef

30.

Lai L, Leone TC, Zechner C, Schaeffer PJ, Kelly SM, Flanagan DP, Medeiros DM, Kovacs A, Kelly DP (2008) Transcriptional coactivators PGC-1alpha and PGC-1beta control overlapping programs required for perinatal maturation of the heart. Genes Dev 22:1948–1961PubMedCrossRef

31.

Lehman JJ, Barger PM, Kovacs A, Saffitz JE, Medeiros D, Kelly DP (2000) PPARγ coactivator-1 (PGC-1) promotes cardiac mitochondrial biogenesis. J Clin Invest 106:847–856PubMedCrossRef

32.

Leone TC, Weinheimer CJ, Kelly DP (1999) A critical role for the peroxisome proliferator-activated receptor alpha (PPARα) in the cellular fasting response: the PPARα-null mouse as a model of fatty acid oxidation disorders. Proc Natl Acad Sci USA 96:7473–7478PubMedCrossRef

33.

Leone TC, Lehman JJ, Finck BN, Schaeffer PJ, Wende AR, Boudina S, Courtois M, Wozniak DF, Sambandam N, Bernal-Mizrachi C, Chen Z, Holloszy JO, Medeiros DM, Schmidt RE, Saffitz JE, Abel ED, Semenkovich CF, Kelly DP (2005) PGC-1α-deficient mice exhibit multisystem energy metabolic derangements: muscle dysfunction, abnormal weight control, and hepatic steatosis. PLoS Biol 3:672–687CrossRef

34.

Lorch SM, Sharkey A (2007) Myocardial velocity, strain, and strain rate abnormalities in healthy obese children. J Cardiometab Syndr 2:30–34PubMedCrossRef

35.

Mokdad AH, Bowman BA, Ford ES, Vinicor F, Marks JS, Koplan JP (2001) The continuing epidemics of obesity and diabetes in the United States. JAMA 286:1195–1200PubMedCrossRef

36.

Molnar D (2004) The prevalence of the metabolic syndrome and type 2 diabetes mellitus in children and adolescents. Int J Obes Relat Metab Disord 28:70–74CrossRef

37.

Monsalve M, Wu Z, Adelmant G, Puigserver P, Fan M, Spiegelman BM (2000) Direct coupling of transcription and mRNA processing through the thermogenic coactivator PGC-1. Mol Cell 6:307–316PubMedCrossRef

38.

Murthy VK, Shipp JC (1977) Accumulation of myocardial triacylglycerols in ketotic diabetes. Diabetes 26:222–229PubMedCrossRef

39.

Neely JR, Rovetto MJ, Oram JF (1972) Myocardial utilization of carbohydrate and lipids. Prog Cardiovasc Dis 15:289–329PubMedCrossRef

40.

Panagia M, Gibbons GF, Radda GK, Clarke K (2005) PPAR-α activation required for decreased glucose uptake and increased susceptibility to injury during ischemia. Am J Physiol Heart Circ Physiol 288:H2677–H2683PubMedCrossRef

41.

Park SY, Cho YR, Finck BN, Kim HJ, Higashimori T, Hong EG, Lee MK, Danton C, Deshmukh S, Cline GW, Wu JJ, Bennett AM, Rothermel B, Kalinowski A, Russell KS, Kim YB, Kelly DP, Kim JK (2005) Cardiac-specific overexpression of peroxisome proliferator-activated receptor-alpha causes insulin resistance in heart and liver. Diabetes 54:2514–2524PubMedCrossRef

42.

Pinhas-Hamiel O, Zeitler P (2005) The global spread of type 2 diabetes mellitus in children and adolescents. J Pediatr 146:693–700PubMedCrossRef

43.

Puigserver P, Adelmant G, Wu Z, Fan M, Xu J, O’Malley B, Spiegelman BM (1999) Activation of PPARγ coactivator-1 through transcription factor docking. Science 286:1368–1371PubMedCrossRef

44.

Regan TJ (1983) Congestive heart failure in the diabetic. Ann Rev Med 34:161–168CrossRef

45.

Regan TJ, Lyons MM, Ahmed SS, Levinson GE, Oldewurtel HA, Ahmed MR, Haider B (1977) Evidence for cardiomyopathy in familial diabetes mellitus. J Clin Invest 60:885–899CrossRef

46.

Rodrigues B, Cam MC, McNeill JH (1995) Myocardial substrate metabolism: implications for diabetic cardiomyopathy. J Mol Cell Cardiol 27:169–179PubMedCrossRef

47.

Rubler S, Dlugash J, Yuceoglu YZ, Kumral T, Branwood AW, Grishman A (1972) New type of cardiomyopathy associated with glomerulosclerosis. Am J Cardiol 30:595–602PubMedCrossRef

48.

Russell LK, Mansfield CM, Lehman JJ, Kovacs A, Courtois M, Saffitz JE, Medeiros DM, Valencik ML, McDonald JA, Kelly DP (2004) Cardiac-specific induction of the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator-1α promotes mitochondrial biogenesis and reversible cardiomyopathy in a developmental stage-dependent manner. Circ Res 94:525–533PubMedCrossRef

49.

Sano M, Izumi Y, Helenius K, Asakura M, Rossi DJ, Xie M, Taffet G, Hu L, Pautler RG, Wilson CR, Boudina S, Abel ED, Taegtmeyer H, Scaglia F, Graham BH, Kralli A, Shimizu N, Tanaka H, MÑkelÑ TP, Schneider MD (2007) MÇnage-Ö-Trois 1 is critical for the transcriptional function of PPARγ coactivator 1. Cell Metab 5:129–142PubMedCrossRef

50.

Sharma S, Adrogue JV, Golfman L, Uray I, Lemm J, Youker K, Noon GP, Frazier OH, Taegtmeyer H (2004) Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart. FASEB J 18:1692–1700PubMedCrossRef

51.

Shen X, Zheng S, Thongboonkerd V, Xu M, Pierce WM Jr, Klein JB, Epstein PN (2004) Cardiac mitochondrial damage and biogenesis in a chronic model of type I diabetes. Am J Physiol Endocrinol Metab 287:E896–E905PubMedCrossRef

52.

Spiegelman BM, Heinrich R (2004) Biological control through regulated transcriptional coactivators. Cell 119:157–167PubMedCrossRef

53.

Stanley WC, Lopaschuk GD, McCormack JG (1997) Regulation of energy substrate metabolism in the diabetic heart. Cardiovasc Res 34:25–33PubMedCrossRef

54.

Szczepaniak LS, Victor RG, Orci L, Unger RH (2007) Forgotten but not gone: the rediscovery of fatty heart, the most common unrecognized disease in America. Circ Res 101:759–767PubMedCrossRef

55.

van Bilsen M, Smeets PJH, Gilde AJ, van der Vusse GJ (2004) Metabolic remodelling of the failing heart: the cardiac burnout syndrome? Cardiovasc Res 61:218–226PubMedCrossRef

56.

Vega RB, Huss JM, Kelly DP (2000) The coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor α in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes. Mol Cell Biol 20:1868–1876PubMedCrossRef

57.

Wallberg AE, Yamamura S, Malik S, Spiegelman BM, Roeder RG (2003) Coordination of p300-mediated chromatin remodeling and TRAP/mediator function through coactivator PGC-1α. Mol Cell 12:1137–1149PubMedCrossRef

58.

Watanabe K, Fujii H, Takahashi T, Kodama M, Aizawa Y, Ohta Y, Ono T, Hasegawa G, Naito M, Nakajima T, Kamijo Y, Gonzalez FJ, Aoyama T (2000) Constitutive regulation of cardiac fatty acid metabolism through peroxisome proliferator-activated receptor α associated with age-dependent cardiac toxicity. J Biol Chem 275:22293–22299PubMedCrossRef

59.

Yagyu H, Chen G, Yokoyama M, Hirata K, Augustus A, Kako Y, Seo T, Hu Y, Lutz EP, Merkel M, Bensadoun A, Homma S, Goldberg IJ (2003) Lipoprotein lipase (LpL) on the surface of cardiomyocytes increases lipid uptake and produces a cardiomyopathy. J Clin Invest 111:419–426PubMed

60.

Yang J, Sambandam N, Han X, Gross RW, Courtois M, Kovacs A, Febbraio M, Finck BN, Kelly DP (2007) CD36 deficiency rescues lipotoxic cardiomyopathy. Circ Res 100:1208–1217PubMedCrossRef

61.

Zhou YT, Grayburn P, Karim A, Shimabukuro M, Higa M, Baetens D, Orci L, Unger RH (2000) Lipotoxic heart disease in obese rats: implications for human disease. Proc Natl Acad Sci USA 97:1784–1789PubMedCrossRef

Title: Peroxisome Proliferator Activated Receptor-Alpha (PPARα) and PPAR Gamma Coactivator-1alpha (PGC-1α) Regulation of Cardiac Metabolism in Diabetes
Author: Jennifer G. Duncan
Publication date: 01-03-2011
Publisher: Springer-Verlag
Published in: Pediatric Cardiology / Issue 3/2011
Print ISSN: 0172-0643
Electronic ISSN: 1432-1971
DOI: https://doi.org/10.1007/s00246-011-9889-8

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Peroxisome Proliferator Activated Receptor-Alpha (PPARα) and PPAR Gamma Coactivator-1alpha (PGC-1α) Regulation of Cardiac Metabolism in Diabetes

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2011

Cardioprotective MicroRNAs

Epigenetic Regulation of E2F-1-Dependent Bnip3 Transcription and Cell Death by Nuclear Factor-κB and Histone Deacetylase-1

Akt2: A Critical Regulator of Cardiomyocyte Survival and Metabolism

Mechanism of Cardioprotection: What Can We Learn from Females?

The Mitochondrial Permeability Transition Pore and the Cardiac Necrotic Program

Bnip3 as a Dual Regulator of Mitochondrial Turnover and Cell Death in the Myocardium