The role of cardiac lipotoxicity in the pathogenesis of diabetic cardiomyopathy

Expert Review of Cardiovascular Therapy

Volumn 12, Issue 3, 2014, Pages 345-358

  Ussher, John R ^a  

^a UNIVERSITY OF TORONTO   (Canada)

Author keywords

cardiac lipotoxicity; ceramide; diabetes; diabetic cardiomyopathy; diacylglycerol; fatty acid oxidation; fatty acid uptake; obesity; triacyglycerol

Indexed keywords

ACYL COENZYME A DEHYDROGENASE; CARNITINE PALMITOYLTRANSFERASE I; CERAMIDE; DIACYLGLYCEROL; DIOCTANOIN; GLYCOSYLPHOSPHATIDYLINOSITOL; HEART MUSCLE EXTRACT; INSULIN; INSULIN RECEPTOR; PROTEIN KINASE C; PYRUVATE DEHYDROGENASE; REACTIVE OXYGEN METABOLITE; TRANSCRIPTION FACTOR FKHR; TRANSCRIPTION FACTOR FKHRL1; TRIACYLGLYCEROL;

AEROBIC METABOLISM; CARDIAC LIPOTOXICITY; CARDIOTOXICITY; CARDIOVASCULAR RISK; CELL FUNCTION; CELL GROWTH; COMPARATIVE STUDY; CYTOTOXICITY; DIABETIC CARDIOMYOPATHY; DIABETIC PATIENT; DIASTOLIC HEART FAILURE; DISORDERS OF MITOCHONDRIAL FUNCTIONS; DYSLIPIDEMIA; ENDOPLASMIC RETICULUM; ENDOPLASMIC RETICULUM STRESS; ENERGY METABOLISM; FAT INTAKE; FATTY ACID METABOLISM; FATTY ACID OXIDATION; FATTY ACID TRANSPORT; GLUCOSE METABOLISM; GLUCOSE OXIDATION; GLUCOSE TRANSPORT; HEART LEFT VENTRICLE MASS; HEART MUSCLE CELL; HEART MUSCLE METABOLISM; HUMAN; INSULIN RESISTANCE; INSULIN SENSITIVITY; INSULIN TREATMENT; LIPID DIET; LIPID STORAGE; LIPOTOXICITY; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; OXIDATIVE PHOSPHORYLATION; OXIDATIVE STRESS; PATHOPHYSIOLOGY; PROTEIN EXPRESSION; REVIEW; SIGNAL TRANSDUCTION; UNFOLDED PROTEIN RESPONSE;

ANIMALS; CARDIOMYOPATHIES; DIABETES MELLITUS, TYPE 2; DIABETIC CARDIOMYOPATHIES; HUMANS; LIPID METABOLISM; OBESITY;

EID: 84896766392     PISSN: 14779072     EISSN: 17448344     Source Type: Journal    
DOI: 10.1586/14779072.2014.891939     Document Type: Review

References (121)

1. Lopaschuk GD, Folmes CD, Stanley WC. Cardiac energy metabolism in obesity. Circ Res 2007;101(4):335-47
2. Garcia MJ, McNamara PM, Gordon T, Kannel WB. Morbidity and mortality in diabetics in the Framingham population. Sixteen year follow-up study. Diabetes 1974;23(2):105-11
3. Ussher JR, Drucker DJ. Cardiovascular biology of the incretin system. Endocr Rev 2012;33(2):187-215
4. Ussher JR, Sutendra G, Jaswal JS. The impact of current and novel anti-diabetic therapies on cardiovascular risk. Future Cardiol 2012;8(6):895-912
5. Campbell JE, Drucker DJ. Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metab 2013;17(6): 819-37
6. Drevinge C, Karlsson LO, Stahlman M, et al. Cholesteryl esters accumulate in the heart in a porcine model of ischemia and reperfusion. PLoS One 2013;8(4):e61942
7. Nagendran J, Pulinilkunnil T, Kienesberger PC, et al. Cardiomyocyte-specific ablation of CD36 improves post-ischemic functional recovery. J Mol Cell Cardiol 2013;63:180-8
8. Perman JC, Bostrom P, Lindbom M, et al. The VLDL receptor promotes lipotoxicity and increases mortality in mice following an acute myocardial infarction. J Clin Invest 2011;121(7):2625-40
9. Lopaschuk GD, Ussher JR, Folmes CD, et al. Myocardial fatty acid metabolism in health and disease. Physiol Rev 2010;90(1): 207-58
10. Rubler S, Dlugash J, Yuceoglu YZ, et al. New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am J Cardiol 1972;30(6):595-602
11. Battiprolu PK, Lopez-Crisosto C, Wang ZV, et al. Diabetic cardiomyopathy and metabolic remodeling of the heart. Life Sci 2013; 92(11):609-15
12. van de Weijer T, Schrauwen-Hinderling VB, Schrauwen P. Lipotoxicity in type 2 diabetic cardiomyopathy. Cardiovasc Res 2011;92(1): 10-18
13. Nielsen JM, Kristiansen SB, Norregaard R, et al. Blockage of receptor for advanced glycation end products prevents development of cardiac dysfunction in db/db type 2 diabetic mice. Eur J Heart Fail 2009;11(7):638-47
14. Katare R, Caporali A, Zentilin L, et al. Intravenous gene therapy with PIM-1 via a cardiotropic viral vector halts the progression of diabetic cardiomyopathy through promotion of prosurvival signaling. Circ Res 2011;108(10):1238-51
15. Lillioja S, Mott DM, Spraul M, et al. Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus. Prospective studies of Pima Indians. N Engl J Med 1993;329(27):1988-92
16. Warram JH, Martin BC, Krolewski AS, et al. Slow glucose removal rate and hyperinsulinemia precede the development of type II diabetes in the offspring of diabetic parents. Ann Intern Med 1990; 113(12):909-15
17. Ussher JR, Lopaschuk GD. Clinical implications of energetic problems in cardiovascular disease. Heart Metab 2006;32:9-17
18. Jagasia D, Whiting JM, Concato J, et al. Effect of non-insulin-dependent diabetes mellitus on myocardial insulin responsiveness in patients with ischemic heart disease. Circulation 2001;103(13): 1734-9
19. Utriainen T, Takala T, Luotolahti M, et al. Insulin resistance characterizes glucose uptake in skeletal muscle but not in the heart in NIDDM. Diabetologia 1998;41(5): 555-9
20. Hafstad AD, Solevag GH, Severson DL, et al. Perfused hearts from Type 2 diabetic (db/db) mice show metabolic responsiveness to insulin. Am J Physiol Heart Circ Physiol 2006;290(5):H1763-9
21. Petersen KF, Dufour S, Savage DB, et al. The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome. Proc Natl Acad Sci USA 2007; 104(31):12587-94
22. Shimizu I, Minamino T, Toko H, et al. Excessive cardiac insulin signaling exacerbates systolic dysfunction induced by pressure overload in rodents. J Clin Invest 2010;120(5):1506-14
23. Kubota T, Kubota N, Kumagai H, et al. Impaired insulin signaling in endothelial cells reduces insulin-induced glucose uptake by skeletal muscle. Cell Metab 2011;13(3): 294-307
24. Frescas D, Valenti L, Accili D. Nuclear trapping of the forkhead transcription factor FoxO1 via Sirt-dependent deacetylation promotes expression of glucogenetic genes. J Biol Chem 2005;280(21):20589-95
25. Matsumoto M, Han S, Kitamura T, Accili D. Dual role of transcription factor FoxO1 in controlling hepatic insulin sensitivity and lipid metabolism. J Clin Invest 2006;116(9):2464-72
26. Battiprolu PK, Hojayev B, Jiang N, et al. Metabolic stress-induced activation of FoxO1 triggers diabetic cardiomyopathy in mice. J Clin Invest 2012;122(3):1109-18
27. Jaswal JS, Keung W, Wang W, et al. Targeting fatty acid and carbohydrate oxidation-a novel therapeutic intervention in the ischemic and failing heart. Biochim Biophys Acta 2011;1813(7):1333-50
28. Muoio DM, Newgard CB. Mechanisms of disease: molecular and metabolic mechanisms of insulin resistance and beta-cell failure in type 2 diabetes. Nat Rev Mol Cell Biol 2008;9(3):193-205
29. Hotamisligil GS. Role of endoplasmic reticulum stress and c-Jun NH2-terminal kinase pathways in inflammation and origin of obesity and diabetes. Diabetes 2005; 54(Suppl 2):S73-8
30. Ozcan U, Cao Q, Yilmaz E, et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 2004;306(5695):457-61
31. Dong F, Ren J. Adiponectin improves cardiomyocyte contractile function in db/db diabetic obese mice. Obesity 2009;17(2): 262-8
32. Miki T, Miura T, Hotta H, et al. Endoplasmic reticulum stress in diabetic hearts abolishes erythropoietin-induced myocardial protection by impairment of phospho-glycogen synthase kinase-3beta-mediated suppression of mitochondrial permeability transition. Diabetes 2009;58(12):2863-72
33. Ceylan-Isik AF, Sreejayan N, Ren J. Endoplasmic reticulum chaperon tauroursodeoxycholic acid alleviates obesity-induced myocardial contractile dysfunction. J Mol Cell Cardiol 2011;50(1): 107-16
34. Xu J, Wang G, Wang Y, et al. Diabetes-and angiotensin II-induced cardiac endoplasmic reticulum stress and cell death: metallothionein protection. J Cell Mol Med 2009;13(8A):1499-512
35. Younce CW, Wang K, Kolattukudy PE. Hyperglycaemia-induced cardiomyocyte death is mediated via MCP-1 production and induction of a novel zinc-finger protein MCPIP. Cardiovasc Res 2010;87(4):665-74
36. Younce CW, Burmeister MA, Ayala JE. Exendin-4 attenuates high glucose-induced cardiomyocyte apoptosis via inhibition of endoplasmic reticulum stress and activation of SERCA2a. Am J Physiol Cell Physiol 2013;304(6):C508-18
37. Liu J, Liu Y, Chen L, et al. Glucagon-like peptide-1 analog liraglutide protects against diabetic cardiomyopathy by the inhibition of the endoplasmic reticulum stress pathway. J Diabetes Res 2013;2013:630537
38. Ren LP, Chan SM, Zeng XY, et al. Differing endoplasmic reticulum stress response to excess lipogenesis versus lipid oversupply in relation to hepatic steatosis and insulin resistance. PLoS One 2012;7(2): e30816
39. Ferre P, Foufelle F. Hepatic steatosis: a role for de novo lipogenesis and the transcription factor SREBP-1c. Diabetes Obes Metab 2010;12(Suppl 2):83-92
40. Ussher JR, Jaswal JS, Lopaschuk GD. Pyridine nucleotide regulation of cardiac intermediary metabolism. Circ Res 2012; 111(5):628-41
41. Scheuermann-Freestone M, Madsen PL, Manners D, et al. Abnormal cardiac and skeletal muscle energy metabolism in patients with type 2 diabetes. Circulation 2003;107(24):3040-6
42. Boudina S, Sena S, Theobald H, et al. Mitochondrial energetics in the heart in obesity-related diabetes: direct evidence for increased uncoupled respiration and activation of uncoupling proteins. Diabetes 2007;56(10):2457-66
43. Bugger H, Chen D, Riehle C, et al. Tissue-specific remodeling of the mitochondrial proteome in type 1 diabetic akita mice. Diabetes 2009;58(9):1986-97
44. Diamant M, Lamb HJ, Groeneveld Y, et al. Diastolic dysfunction is associated with altered myocardial metabolism in asymptomatic normotensive patients with well-controlled type 2 diabetes mellitus. J Am Coll Cardiol 2003;42(2):328-35
45. Anderson EJ, Kypson AP, Rodriguez E, et al. Substrate-specific derangements in mitochondrial metabolism and redox balance in the atrium of the type 2 diabetic human heart. J Am Coll Cardiol 2009; 54(20):1891-8
46. Young ME, Guthrie PH, Razeghi P, et al. Impaired long-chain fatty acid oxidation and contractile dysfunction in the obese Zucker rat heart. Diabetes 2002;51(8): 2587-95
47. Lee Y, Hirose H, Ohneda M, et al. Beta-cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats: impairment in adipocyte-beta-cell relationships. Proc Natl Acad Sci USA 1994;91(23):10878-82
48. Unger RH. Lipotoxicity in the pathogenesis of obesity-dependent NIDDM. Genetic and clinical implications. Diabetes 1995;44(8): 863-70
49. Choi CS, Savage DB, Abu-Elheiga L, et al. Continuous fat oxidation in acetyl-CoA carboxylase 2 knockout mice increases total energy expenditure, reduces fat mass, and improves insulin sensitivity. Proc Natl Acad Sci USA 2007;104(42): 16480-5
50. Holland WL, Brozinick JT, Wang LP, et al. Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell Metab 2007;5(3):167-79
51. Shimabukuro M, Higa M, Zhou YT, et al. Lipoapoptosis in beta-cells of obese prediabetic fa/fa rats. Role of serine palmitoyltransferase overexpression. J Biol Chem 1998;273(49):32487-90
52. Ussher JR, Koves TR, Cadete VJ, et al. Inhibition of de novo ceramide synthesis reverses diet-induced insulin resistance and enhances whole-body oxygen consumption. Diabetes 2010;59(10):2453-64
53. Jaswal JS, Ussher JR, Lopaschuk GD. Myocardial fatty acid utilization as a determinant of cardiac efficiency and function. Clin Lipidol 2009;4(3):379-89
54. Drosatos K, Schulze PC. Cardiac lipotoxicity: molecular pathways and therapeutic implications. Curr Heart Fail Rep 2013;10(2):109-21
55. Angin Y, Steinbusch LK, Simons PJ, et al. CD36 inhibition prevents lipid accumulation and contractile dysfunction in rat cardiomyocytes. Biochem J 2012;448(1): 43-53
56. Pulinilkunnil T, Kienesberger PC, Nagendran J, et al. Myocardial adipose triglyceride lipase overexpression protects diabetic mice from the development of lipotoxic cardiomyopathy. Diabetes 2013; 62(5):1464-77
57. Saddik M, Lopaschuk GD. Myocardial triglyceride turnover and contribution to energy substrate utilization in isolated working rat hearts. J Biol Chem 1991; 266(13):8162-70
58. Wisneski JA, Stanley WC, Neese RA, Gertz EW. Effects of acute hyperglycemia on myocardial glycolytic activity in humans. J Clin Invest 1990;85(5):1648-56
59. Paul A, Chan L, Bickel PE. The PAT family of lipid droplet proteins in heart and vascular cells. Curr Hypertens Rep 2008; 10(6):461-6
60. Banke NH, Wende AR, Leone TC, et al. Preferential oxidation of triacylglyceride-derived fatty acids in heart is augmented by the nuclear receptor PPARalpha. Circ Res 2010;107(2):233-41
61. Patton S, Zulak IM, Trams EG. Fatty acid metabolism via triglyceride in the salmon heart. J Mol Cell Cardiol 1975;7(11): 857-65
62. Shipp JC, Thomas JM, Crevasse L. Oxidation of carbon-14-labeled endogenous lipids by isolated perfused rat heart. Science 1964;143(3604):371-3
63. Kienesberger PC, Pulinilkunnil T, Nagendran J, Dyck JR. Myocardial triacylglycerol metabolism. J Mol Cell Cardiol 2013;55:101-10
64. Zimmermann R, Strauss JG, Haemmerle G, et al. Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. Science 2004;306(5700):1383- 6
65. Haemmerle G, Zimmermann R, Hayn M, et al. Hormone-sensitive lipase deficiency in mice causes diglyceride accumulation in adipose tissue, muscle, and testis. J Biol Chem 2002;277(7):4806-15
66. Severson DL, Hee-Cheong M. Monoacylglycerol lipase activity in cardiac myocytes. Biochem Cell Biol 1988;66(9): 1013-18
67. Atkinson LL, Kozak R, Kelly SE, et al. Potential mechanisms and consequences of cardiac triacylglycerol accumulation in insulin-resistant rats. Am J Physiol Endocrinol Metab 2003;284(5):E923-30
68. Buchanan J, Mazumder PK, Hu P, et al. 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 2005;146(12): 5341-9
69. Zhang L, Ussher JR, Oka T, et al. Cardiac diacylglycerol accumulation in high fat-fed mice is associated with impaired insulin-stimulated glucose oxidation. Cardiovasc Res 2011;89(1):148-56
70. Listenberger LL, Han X, Lewis SE, et al. Triglyceride accumulation protects against fatty acid-induced lipotoxicity. Proc Natl Acad Sci USA 2003;100(6):3077-82
71. Ussher JR, Lopaschuk GD. The malonyl CoA axis as a potential target for treating ischaemic heart disease. Cardiovasc Res 2008;79(2):259-68
72. McGarry JD, Leatherman GF, Foster DW. Carnitine palmitoyltransferase I. The site of inhibition of hepatic fatty acid oxidation by malonyl-CoA. J Biol Chem 1978;253(12): 4128-36
73. Ussher JR, Koves TR, Jaswal JS, et al. Insulin-stimulated cardiac glucose oxidation is increased in high-fat diet-induced obese mice lacking malonyl CoA decarboxylase. Diabetes 2009;58(8):1766-75
74. Liu L, Shi X, Bharadwaj KG, et al. DGAT1 expression increases heart triglyceride content but ameliorates lipotoxicity. J Biol Chem 2009;284(52): 36312-23
75. Ueno M, Suzuki J, Zenimaru Y, et al. Cardiac overexpression of hormone-sensitive lipase inhibits myocardial steatosis and fibrosis in streptozotocin diabetic mice. Am J Physiol Endocrinol Metab 2008;294(6): E1109-18
76. Haemmerle G, Moustafa T, Woelkart G, et al. ATGL-mediated fat catabolism regulates cardiac mitochondrial function via PPAR-alpha and PGC-1. Nat Med 2011; 17(9):1076-85
77. Kienesberger PC, Pulinilkunnil T, Nagendran J, et al. Early structural and metabolic cardiac remodelling in response to inducible adipose triglyceride lipase ablation. Cardiovasc Res 2013;99(3):442-51
78. Lass A, Zimmermann R, Haemmerle G, et al. Adipose triglyceride lipase-mediated lipolysis of cellular fat stores is activated by CGI-58 and defective in Chanarin-Dorfman Syndrome. Cell Metab 2006;3(5):309-19
79. Zierler KA, Jaeger D, Pollak NM, et al. Functional cardiac lipolysis in mice critically depends on comparative gene identification-58. J Biol Chem 2013; 288(14):9892-904
80. Pickersgill L, Litherland GJ, Greenberg AS, et al. Key role for ceramides in mediating insulin resistance in human muscle cells. J Biol Chem 2007;282(17):12583-9
81. Ledeen RW, Wu G. Nuclear sphingolipids: metabolism and signaling. J Lipid Res 2008; 49(6):1176-86
82. Park TS, Hu Y, Noh HL, et al. Ceramide is a cardiotoxin in lipotoxic cardiomyopathy. J Lipid Res 2008;49(10):2101-12
83. Ussher JR, Folmes CD, Keung W, et al. Inhibition of serine palmitoyl transferase I reduces cardiac ceramide levels and increases glycolysis rates following diet-induced insulin resistance. PLoS One 2012;7(5): e37703
84. Russo SB, Baicu CF, Van Laer A, et al. Ceramide synthase 5 mediates lipid-induced autophagy and hypertrophy in cardiomyocytes. J Clin Invest 2012;122(11): 3919-30
85. Zhang QJ, Holland WL, Wilson L, et al. Ceramide mediates vascular dysfunction in diet-induced obesity by PP2A-mediated dephosphorylation of the eNOS-Akt complex. Diabetes 2012;61(7):1848-59
86. Lee SY, Kim JR, Hu Y, et al. Cardiomyocyte specific deficiency of serine palmitoyltransferase subunit 2 reduces ceramide but leads to cardiac dysfunction. J Biol Chem 2012;287(22):18429-39
87. Koitabashi N, Bedja D, Zaiman AL, et al. Avoidance of transient cardiomyopathy in cardiomyocyte-targeted tamoxifen-induced MerCreMer gene deletion models. Circ Res 2009;105(1):12-15
88. Baranowski M, Blachnio-Zabielska A, Hirnle T, et al. Myocardium of type 2 diabetic and obese patients is characterized by alterations in sphingolipid metabolic enzymes but not by accumulation of ceramide. J Lipid Res 2010;51(1):74-80
89. Jornayvaz FR, Shulman GI. Diacylglycerol activation of protein kinase Cepsilon and hepatic insulin resistance. Cell Metab 2012; 15(5):574-84
90. Savage DB, Petersen KF, Shulman GI. Disordered lipid metabolism and the pathogenesis of insulin resistance. Physiol Rev 2007;87(2):507-20
91. Drosatos K, Bharadwaj KG, Lymperopoulos A, et al. Cardiomyocyte lipids impair beta-adrenergic receptor function via PKC activation. Am J Physiol Endocrinol Metab 2011;300(3):E489-99
92. Park M, Wu D, Park T, et al. APPL1 transgenic mice are protected from high-fat diet-induced cardiac dysfunction. Am J Physiol Endocrinol Metab 2013; 305(7):E795-804
93. Zeidan YH, Hannun YA. Activation of acid sphingomyelinase by protein kinase Cdelta-mediated phosphorylation. J Biol Chem 2007;282(15):11549-61
94. Chokshi A, Drosatos K, Cheema FH, et al. Ventricular assist device implantation corrects myocardial lipotoxicity, reverses insulin resistance, and normalizes cardiac metabolism in patients with advanced heart failure. Circulation 2012;125(23):2844-53
95. Keung W, Ussher JR, Jaswal JS, et al. Inhibition of carnitine palmitoyltransferase-1 activity alleviates insulin resistance in diet-induced obese mice. Diabetes 2013;62(3):711-20
96. Cheng L, Ding G, Qin Q, et al. Cardiomyocyte-restricted peroxisome proliferator-activated receptor-delta deletion perturbs myocardial fatty acid oxidation and leads to cardiomyopathy. Nat Med 2004; 10(11):1245-50
97. Aasum E, Khalid AM, Gudbrandsen OA, et al. Fenofibrate modulates cardiac and hepatic metabolism and increases ischemic tolerance in diet-induced obese mice. J Mol Cell Cardiol 2008;44(1):201-9
98. Finck BN, Lehman JJ, Leone TC, et al. The cardiac phenotype induced by PPARalpha overexpression mimics that caused by diabetes mellitus. J Clin Invest 2002;109(1):121-30
99. Finck BN, Han X, Courtois M, et al. A critical role for PPARalpha-mediated lipotoxicity in the pathogenesis of diabetic cardiomyopathy: modulation by dietary fat content. Proc Natl Acad Sci USA 2003; 100(3):1226-31
100. Peterson LR, Herrero P, Schechtman KB, et al. Effect of obesity and insulin resistance on myocardial substrate metabolism and efficiency in young women. Circulation 2004;109(18):2191-6
101. Peterson LR, Soto PF, Herrero P, et al. Impact of gender on the myocardial metabolic response to obesity. JACC Cardiovasc Imaging 2008;1(4):424-33
102. Herrero P, Peterson LR, McGill JB, et al. Increased myocardial fatty acid metabolism in patients with type 1 diabetes mellitus. J Am Coll Cardiol 2006;47(3):598-604
103. Rijzewijk LJ, van der Meer RW, Lamb HJ, et al. Altered myocardial substrate metabolism and decreased diastolic function in nonischemic human diabetic cardiomyopathy: studies with cardiac positron emission tomography and magnetic resonance imaging. J Am Coll Cardiol 2009;54(16):1524-32
104. Crawford PA, Schaffer JE. Metabolic stress in the myocardium: adaptations of gene expression. J Mol Cell Cardiol 2013;55: 130-8
105. Boudina S, Abel ED. Mitochondrial uncoupling: a key contributor to reduced cardiac efficiency in diabetes. Physiology 2006;21:250-8
106. How OJ, Aasum E, Severson DL, et al. Increased myocardial oxygen consumption reduces cardiac efficiency in diabetic mice. Diabetes 2006;55(2):466-73
107. How OJ, Larsen TS, Hafstad AD, et al. Rosiglitazone treatment improves cardiac efficiency in hearts from diabetic mice. Arch Physiol Biochem 2007;113(4-5):211-20
108. Kuramoto K, Okamura T, Yamaguchi T, et al. Perilipin 5, a lipid droplet-binding protein, protects heart from oxidative burden by sequestering fatty acid from excessive oxidation. J Biol Chem 2012; 287(28):23852-63
109. Kuang M, Febbraio M, Wagg C, et al. Fatty acid translocase/CD36 deficiency does not energetically or functionally compromise hearts before or after ischemia. Circulation 2004;109(12):1550-7
110. Coort SL, Hasselbaink DM, Koonen DP, et al. Enhanced sarcolemmal FAT/CD36 content and triacylglycerol storage in cardiac myocytes from obese zucker rats. Diabetes 2004;53(7):1655-63
111. Sung MM, Koonen DP, Soltys CL, et al. Increased CD36 expression in middle-aged mice contributes to obesity-related cardiac hypertrophy in the absence of cardiac dysfunction. J Mol Med 2011;89(5):459-69
112. Koonen DP, Febbraio M, Bonnet S, et al. CD36 expression contributes to age-induced cardiomyopathy in mice. Circulation 2007; 116(19):2139-47
113. Yang J, Sambandam N, Han X, et al. CD36 deficiency rescues lipotoxic cardiomyopathy. Circ Res 2007;100(8): 1208-17
114. Chiu HC, Kovacs A, Blanton RM, et al. Transgenic expression of fatty acid transport protein 1 in the heart causes lipotoxic cardiomyopathy. Circ Res 2005;96(2): 225-33
115. Sharma S, Adrogue JV, Golfman L, et al. Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart. FASEB J 2004;18(14):1692-700
116. Futter JE, Cleland JG, Clark AL. Body mass indices and outcome in patients with chronic heart failure. Eur J Heart Fail 2011; 13(2):207-13
117. Romero-Corral A, Montori VM, Somers VK, et al. Association of bodyweight with total mortality and with cardiovascular events in coronary artery disease: a systematic review of cohort studies. Lancet 2006;368(9536):666-78
118. Horwich TB, Fonarow GC, Hamilton MA, et al. The relationship between obesity and mortality in patients with heart failure. J Am Coll Cardiol 2001;38(3):789-95
119. Jaswal JS, Ussher JR. Differentiating diastolic dysfunction from classic heart failure. Heart Metab 2012;57:4-7
120. Ussher JR, Jaswal JS. Inhibition of fatty acid oxidation as an approach to treat diastolic heart failure. Heart Metab 2013;61:20-4
121. Basu R, Oudit GY, Wang X, et al. Type 1 diabetic cardiomyopathy in the Akita (Ins2WT/C96Y) mouse model is characterized by lipotoxicity and diastolic dysfunction with preserved systolic function. Am J Physiol Heart Circ Physiol 2009; 297(6):H2096-108