Abstract
Diabetes and obesity are both associated with lipotoxic cardiomyopathy exclusive of coronary artery disease and hypertension. Lipotoxicities have become a public health concern and are responsible for a significant portion of clinical cardiac disease. These abnormalities may be the result of a toxic metabolic shift to more fatty acid and less glucose oxidation with concomitant accumulation of toxic lipids. Lipids can directly alter cellular structures and activate downstream pathways leading to toxicity. Recent data have implicated fatty acids and fatty acyl coenzyme A, diacylglycerol, and ceramide in cellular lipotoxicity, which may be caused by apoptosis, defective insulin signaling, endoplasmic reticulum stress, activation of protein kinase C, MAPK activation, or modulation of PPARs.
Similar content being viewed by others
References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Augustus AS, Buchanan J, Park TS, Hirata K, Noh HL, Sun J, et al. Loss of lipoprotein lipase-derived fatty acids leads to increased cardiac glucose metabolism and heart dysfunction. J Biol Chem. 2006;281:8716–23.
Taegtmeyer H, McNulty P, Young ME. Adaptation and maladaptation of the heart in diabetes: Part i: General concepts. Circulation. 2002;105:1727–33.
Stanley WC, Lopaschuk GD, Hall JL, McCormack JG. Regulation of myocardial carbohydrate metabolism under normal and ischaemic conditions. Potential for pharmacological interventions. Cardiovasc Res. 1997;33:243–57.
Ballard FB, Danforth WH, Naegle S, Bing RJ. Myocardial metabolism of fatty acids. J Clin Invest. 1960;39:717–23.
Tamboli A, O'Looney P, Vander Maten M, Vahouny GV. Comparative metabolism of free and esterified fatty acids by the perfused rat heart and rat cardiac myocytes. Biochim Biophys Acta. 1983;750:404–10.
Zimmermann R, Strauss JG, Haemmerle G, Schoiswohl G, Birner-Gruenberger R, Riederer M, et al. Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. Science. 2004;306:1383–6.
Villena JA, Roy S, Sarkadi-Nagy E, Kim KH, Sul HS. Desnutrin, an adipocyte gene encoding a novel patatin domain-containing protein, is induced by fasting and glucocorticoids: Ectopic expression of desnutrin increases triglyceride hydrolysis. J Biol Chem. 2004;279:47066–75.
• Banke NH, Wende AR, Leone TC, O'Donnell JM, Abel ED, Kelly DP, et al. Preferential oxidation of triacylglyceride-derived fatty acids in heart is augmented by the nuclear receptor pparalpha. Circ Res. 2010;107:233–41. This is a paper that sheds light on an important aspect of cardiac metabolism, which pertains to whether fatty acids that are used for cardiac ATP production are obtained from intracellular store of triglycerides or not.
Kienesberger PC, Pulinilkunnil T, Sung MM, Nagendran J, Haemmerle G, Kershaw EE, et al. Myocardial atgl overexpression decreases the reliance on fatty acid oxidation and protects against pressure overload-induced cardiac dysfunction. Mol Cell Biol. 2012;32:740–50.
Goldberg IJ. Lipoprotein lipase and lipolysis: Central roles in lipoprotein metabolism and atherogenesis. J Lipid Res. 1996;37:693–707.
Levak-Frank S, Hofmann W, Weinstock PH, Radner H, Sattler W, Breslow JL, et al. Induced mutant mouse lines that express lipoprotein lipase in cardiac muscle, but not in skeletal muscle and adipose tissue, have normal plasma triglyceride and high-density lipoprotein-cholesterol levels. Proc Natl Acad Sci U S A. 1999;96:3165–70.
Chajek T, Stein O, Stein Y. Pre- and post-natal development of lipoprotein lipase and hepatic triglyceride hydrolase activity in rat tissues. Atherosclerosis. 1977;26:549–61.
Singh-Bist A, Komaromy MC, Kraemer FB. Transcriptional regulation of lipoprotein lipase in the heart during development in the rat. Biochem Biophys Res Commun. 1994;202:838–43.
Semenkovich CF, Chen SH, Wims M, Luo CC, Li WH, Chan L. Lipoprotein lipase and hepatic lipase mrna tissue specific expression, developmental regulation, and evolution. J Lipid Res. 1989;30:423–31.
Ruge T, Wu G, Olivecrona T, Olivecrona G. Nutritional regulation of lipoprotein lipase in mice. Int J Biochem Cell Biol. 2004;36:320–9.
Pulinilkunnil T, Abrahani A, Varghese J, Chan N, Tang I, Ghosh S, et al. Evidence for rapid "metabolic switching" through lipoprotein lipase occupation of endothelial-binding sites. J Mol Cell Cardiol. 2003;35:1093–103.
Sambandam N, Abrahani MA, Craig S, Al-Atar O, Jeon E, Rodrigues B. Metabolism of vldl is increased in streptozotocin-induced diabetic rat hearts. Am J Physiol Heart Circ Physiol. 2000;278:H1874–82.
Liu L, Severson DL. Regulation of myocardial lipoprotein lipase activity by diabetes and thyroid hormones. Can J Physiol Pharmacol. 1994;72:1259–64.
Masuzaki H, Jingami H, Matsuoka N, Nakagawa O, Ogawa Y, Mizuno M, et al. Regulation of very-low-density lipoprotein receptor in hypertrophic rat heart. Circ Res. 1996;78:8–14.
Augustus A, Yagyu H, Haemmerle G, Bensadoun A, Vikramadithyan RK, Park SY, et al. Cardiac-specific knock-out of lipoprotein lipase alters plasma lipoprotein triglyceride metabolism and cardiac gene expression. J Biol Chem. 2004;279:25050–7.
Yagyu H, Chen G, Yokoyama M, Hirata K, Augustus A, Kako Y, et al. Lipoprotein lipase (lpl) on the surface of cardiomyocytes increases lipid uptake and produces a cardiomyopathy. J Clin Invest. 2003;111:419–26.
Coburn CT, Knapp Jr FF, Febbraio M, Beets AL, Silverstein RL, Abumrad NA. Defective uptake and utilization of long chain fatty acids in muscle and adipose tissues of cd36 knockout mice. J Biol Chem. 2000;275:32523–9.
Hamilton JA. Fatty acid transport: Difficult or easy? J Lipid Res. 1998;39:467–81.
Fukuchi K, Nozaki S, Yoshizumi T, Hasegawa S, Uehara T, Nakagawa T, et al. Enhanced myocardial glucose use in patients with a deficiency in long-chain fatty acid transport (cd36 deficiency). J Nucl Med. 1999;40:239–43.
Yamashita S, Hirano K, Kuwasako T, Janabi M, Toyama Y, Ishigami M, et al. Physiological and pathological roles of a multi-ligand receptor cd36 in atherogenesis; insights from cd36-deficient patients. Mol Cell Biochem. 2007;299:19–22.
Kuang M, Febbraio M, Wagg C, Lopaschuk GD, Dyck JR. Fatty acid translocase/cd36 deficiency does not energetically or functionally compromise hearts before or after ischemia. Circulation. 2004;109:1550–7.
Irie H, Krukenkamp IB, Brinkmann JF, Gaudette GR, Saltman AE, Jou W, et al. Myocardial recovery from ischemia is impaired in cd36-null mice and restored by myocyte cd36 expression or medium-chain fatty acids. Proc Natl Acad Sci U S A. 2003;100:6819–24.
Bharadwaj KG, Hiyama Y, Hu Y, Huggins LA, Ramakrishnan R, Abumrad NA, et al. Chylomicron- and vldl-derived lipids enter the heart through different pathways: In vivo evidence for receptor- and non-receptor-mediated fatty acid uptake. J Biol Chem. 2010;285:37976–86.
Yang J, Sambandam N, Han X, Gross RW, Courtois M, Kovacs A, et al. Cd36 deficiency rescues lipotoxic cardiomyopathy. Circ Res. 2007;100:1208–17.
Kim JK, Gimeno RE, Higashimori T, Kim HJ, Choi H, Punreddy S, et al. Inactivation of fatty acid transport protein 1 prevents fat-induced insulin resistance in skeletal muscle. J Clin Invest. 2004;113:756–63.
Gimeno RE, Ortegon AM, Patel S, Punreddy S, Ge P, Sun Y, et al. Characterization of a heart-specific fatty acid transport protein. J Biol Chem. 2003;278:16039–44.
Drosatos K, Bharadwaj KG, Lymperopoulos A, Ikeda S, Khan R, Hu Y, et al. Cardiomyocyte lipids impair beta-adrenergic receptor function via pkc activation. Am J Physiol Endocrinol Metab. 2011;300:E489–99.
Listenberger LL, Han X, Lewis SE, Cases S, Farese Jr RV, Ory DS, et al. Triglyceride accumulation protects against fatty acid-induced lipotoxicity. Proc Natl Acad Sci U S A. 2003;100:3077–82.
Okere IC, Chandler MP, McElfresh TA, Rennison JH, Sharov V, Sabbah HN, et al. Differential effects of saturated and unsaturated fatty acid diets on cardiomyocyte apoptosis, adipose distribution, and serum leptin. Am J Physiol Heart Circ Physiol. 2006;291:H38–44.
Park TS, Hu Y, Noh HL, Drosatos K, Okajima K, Buchanan J, et al. Ceramide is a cardiotoxin in lipotoxic cardiomyopathy. J Lipid Res. 2008;49:2101–12.
Inoguchi T, Battan R, Handler E, Sportsman JR, Heath W, King GL. Preferential elevation of protein kinase c isoform beta ii and diacylglycerol levels in the aorta and heart of diabetic rats: Differential reversibility to glycemic control by islet cell transplantation. Proc Natl Acad Sci U S A. 1992;89:11059–63.
Newton AC, Johnson JE. Protein kinase c: A paradigm for regulation of protein function by two membrane-targeting modules. Biochim Biophys Acta. 1998;1376:155–72.
Nishizuka Y. Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase c. Science. 1992;258:607–14.
Cheng D, Meegalla RL, He B, Cromley DA, Billheimer JT, Young PR. Human acyl-coa:Diacylglycerol acyltransferase is a tetrameric protein. Biochem J. 2001;359:707–14.
Cases S, Stone SJ, Zhou P, Yen E, Tow B, Lardizabal KD, et al. Cloning of dgat2, a second mammalian diacylglycerol acyltransferase, and related family members. J Biol Chem. 2001;276:38870–6.
Liu L, Shi X, Bharadwaj KG, Ikeda S, Yamashita H, Yagyu H, et al. Dgat1 expression increases heart triglyceride content but ameliorates lipotoxicity. J Biol Chem. 2009;284:36312–23.
Buhman KK, Smith SJ, Stone SJ, Repa JJ, Wong JS, Knapp Jr FF, et al. Dgat1 is not essential for intestinal triacylglycerol absorption or chylomicron synthesis. J Biol Chem. 2002;277:25474–9.
Smith SJ, Cases S, Jensen DR, Chen HC, Sande E, Tow B, et al. Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking dgat. Nat Genet. 2000;25:87–90.
Alpert MA. Obesity cardiomyopathy: Pathophysiology and evolution of the clinical syndrome. Am J Med Sci. 2001;321:225–36.
Boudina S, Abel ED. Diabetic cardiomyopathy revisited. Circulation. 2007;115:3213–23.
Sharma S, Adrogue JV, Golfman L, Uray I, Lemm J, Youker K, et al. Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart. FASEB J. 2004;18:1692–700.
Herrero P, Peterson LR, McGill JB, Matthew S, Lesniak D, Dence C, et al. Increased myocardial fatty acid metabolism in patients with type 1 diabetes mellitus. J Am Coll Cardiol. 2006;47:598–604.
McGavock JM, Lingvay I, Zib I, Tillery T, Salas N, Unger R, et al. Cardiac steatosis in diabetes mellitus: A 1 h-magnetic resonance spectroscopy study. Circulation. 2007;116:1170–5.
O'Donnell JM, Fields AD, Sorokina N, Lewandowski ED. The absence of endogenous lipid oxidation in early stage heart failure exposes limits in lipid storage and turnover. J Mol Cell Cardiol. 2008;44:315–22.
• He L, Kim T, Long Q, Liu J, Wang P, Zhou Y, et al. Carnitine palmitoyltransferase-1b deficiency aggravates pressure overload-induced cardiac hypertrophy caused by lipotoxicity. Circulation. 2012;126:1705–16. This paper shows the importance of fatty acid oxidation in preventing cardiac hypertrophy driven by severe pressure overload and indicates caution that the clinical use of fatty acid oxidation inhibitors should be applied with.
• Kolwicz Jr SC, Olson DP, Marney LC, Garcia-Menendez L, Synovec RE, Tian R. Cardiac-specific deletion of acetyl coa carboxylase 2 prevents metabolic remodeling during pressure-overload hypertrophy. Circ Res. 2012;111:728–38. This paper shows that ablation of the ACC2 enzyme that regulates the formation of a fatty acid oxidation inhibitor, malonyl-CoA, improves fatty acid oxidation in pressure-overload hearts and leads to attenuation of cardiac hypertrophy with a significant reduction in fibrosis.
Essop MF, Camp HS, Choi CS, Sharma S, Fryer RM, Reinhart GA, et al. Reduced heart size and increased myocardial fuel substrate oxidation in acc2 mutant mice. Am J Physiol Heart Circ Physiol. 2008;295:H256–65.
Rupp H, Jacob R. Metabolically-modulated growth and phenotype of the rat heart. Eur Heart J. 1992;13(Suppl D):56–61.
Bristow M. Etomoxir: A new approach to treatment of chronic heart failure. Lancet. 2000;356:1621–2.
Dobbins RL, Szczepaniak LS, Bentley B, Esser V, Myhill J, McGarry JD. Prolonged inhibition of muscle carnitine palmitoyltransferase-1 promotes intramyocellular lipid accumulation and insulin resistance in rats. Diabetes. 2001;50:123–30.
Zhou YT, Grayburn P, Karim A, Shimabukuro M, Higa M, Baetens D, et al. Lipotoxic heart disease in obese rats: Implications for human obesity. Proc Natl Acad Sci U S A. 2000;97:1784–9.
Wang P, Lloyd SG, Zeng H, Bonen A, Chatham JC. Impact of altered substrate utilization on cardiac function in isolated hearts from zucker diabetic fatty rats. Am J Physiol Heart Circ Physiol. 2005;288:H2102–10.
Buchanan J, Mazumder PK, Hu P, Chakrabarti G, Roberts MW, Yun UJ, 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;146:5341–9.
Koonen DP, Febbraio M, Bonnet S, Nagendran J, Young ME, Michelakis ED, et al. Cd36 expression contributes to age-induced cardiomyopathy in mice. Circulation. 2007;116:2139–47.
Chiu HC, Kovacs A, Ford DA, Hsu FF, Garcia R, Herrero P, et al. A novel mouse model of lipotoxic cardiomyopathy. J Clin Invest. 2001;107:813–22.
Chiu HC, Kovacs A, Blanton RM, Han X, Courtois M, Weinheimer CJ, et al. Transgenic expression of fatty acid transport protein 1 in the heart causes lipotoxic cardiomyopathy. Circ Res. 2005;96:225–33.
Finck BN, Lehman JJ, Leone TC, Welch MJ, Bennett MJ, Kovacs A, et al. The cardiac phenotype induced by pparalpha overexpression mimics that caused by diabetes mellitus. J Clin Invest. 2002;109:121–30.
Finck BN, Han X, Courtois M, Aimond F, Nerbonne JM, Kovacs A, et al. A critical role for pparalpha-mediated lipotoxicity in the pathogenesis of diabetic cardiomyopathy: Modulation by dietary fat content. Proc Natl Acad Sci U S A. 2003;100:1226–31.
Duncan JG, Bharadwaj KG, Fong JL, Mitra R, Sambandam N, Courtois MR, et al. 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. 2010;121:426–35.
Son NH, Park TS, Yamashita H, Yokoyama M, Huggins LA, Okajima K, et al. Cardiomyocyte expression of ppargamma leads to cardiac dysfunction in mice. J Clin Invest. 2007;117:2791–801.
Son NH, Yu S, Tuinei J, Arai K, Hamai H, Homma S, et al. Ppargamma-induced cardiolipotoxicity in mice is ameliorated by pparalpha deficiency despite increases in fatty acid oxidation. J Clin Invest. 2010;120:3443–54.
Kantor PF, Dyck JR, Lopaschuk GD. Fatty acid oxidation in the reperfused ischemic heart. Am J Med Sci. 1999;318:3–14.
Nohammer C, Brunner F, Wolkart G, Staber PB, Steyrer E, Gonzalez FJ, et al. Myocardial dysfunction and male mortality in peroxisome proliferator-activated receptor alpha knockout mice overexpressing lipoprotein lipase in muscle. Lab Invest. 2003;83:259–69.
Cheng L, Ding G, Qin Q, Huang Y, Lewis W, He N, et al. Cardiomyocyte-restricted peroxisome proliferator-activated receptor-delta deletion perturbs myocardial fatty acid oxidation and leads to cardiomyopathy. Nat Med. 2004;10:1245–50.
Burkart EM, Sambandam N, Han X, Gross RW, Courtois M, Gierasch CM, et al. Nuclear receptors pparbeta/delta and pparalpha direct distinct metabolic regulatory programs in the mouse heart. J Clin Invest. 2007;117:3930–9.
Georgiadi A, Lichtenstein L, Degenhardt T, Boekschoten MV, van Bilsen M, Desvergne B, et al. Induction of cardiac angptl4 by dietary fatty acids is mediated by peroxisome proliferator-activated receptor beta/delta and protects against fatty acid-induced oxidative stress. Circ Res. 2010;106:1712–21.
•• Haemmerle G, Moustafa T, Woelkart G, Buttner S, Schmidt A, van de Weijer T, et al. Atgl-mediated fat catabolism regulates cardiac mitochondrial function via ppar-alpha and pgc-1. Nat Med. 2011;17:1076–85. This paper shows that fatty acids that are released via ATGL-mediated lipolysis of cardiac triglycerides are essential for PPARα activation and fatty acid oxidation.
Osuga J, Ishibashi S, Oka T, Yagyu H, Tozawa R, Fujimoto A, et al. Targeted disruption of hormone-sensitive lipase results in male sterility and adipocyte hypertrophy, but not in obesity. Proc Natl Acad Sci U S A. 2000;97:787–92.
Konstantinidis K, Whelan RS, Kitsis RN. Mechanisms of cell death in heart disease. Arterioscler Thromb Vasc Biol. 2012;32:1552–62.
Hickson-Bick DL, Buja ML, McMillin JB. Palmitate-mediated alterations in the fatty acid metabolism of rat neonatal cardiac myocytes. J Mol Cell Cardiol. 2000;32:511–9.
Sparagna GC, Hickson-Bick DL, Buja LM, McMillin JB. A metabolic role for mitochondria in palmitate-induced cardiac myocyte apoptosis. Am J Physiol Heart Circ Physiol. 2000;279:H2124–32.
Weiss B, Stoffel W. Human and murine serine-palmitoyl-coa transferase–cloning, expression and characterization of the key enzyme in sphingolipid synthesis. Eur J Biochem. 1997;249:239–47.
Shimabukuro M, Higa M, Zhou YT, Wang MY, Newgard CB, Unger RH. Lipoapoptosis in beta-cells of obese prediabetic fa/fa rats. Role of serine palmitoyltransferase overexpression. J Biol Chem. 1998;273:32487–90.
Merrill Jr AH. De novo sphingolipid biosynthesis: A necessary, but dangerous, pathway. J Biol Chem. 2002;277:25843–6.
Haimovitz-Friedman A, Kan CC, Ehleiter D, Persaud RS, McLoughlin M, Fuks Z, et al. Ionizing radiation acts on cellular membranes to generate ceramide and initiate apoptosis. J Exp Med. 1994;180:525–35.
Hardie DG, Carling D, Carlson M. The amp-activated/snf1 protein kinase subfamily: Metabolic sensors of the eukaryotic cell? Annu Rev Biochem. 1998;67:821–55.
Chabowski A, Momken I, Coort SL, Calles-Escandon J, Tandon NN, Glatz JF, et al. Prolonged ampk activation increases the expression of fatty acid transporters in cardiac myocytes and perfused hearts. Mol Cell Biochem. 2006;288:201–12.
Habets DD, Coumans WA, Voshol PJ, den Boer MA, Febbraio M, Bonen A, et al. Ampk-mediated increase in myocardial long-chain fatty acid uptake critically depends on sarcolemmal cd36. Biochem Biophys Res Commun. 2007;355:204–10.
Hojjati MR, Li Z, Zhou H, Tang S, Huan C, Ooi E, et al. Effect of myriocin on plasma sphingolipid metabolism and atherosclerosis in apoe-deficient mice. J Biol Chem. 2005;280:10284–9.
Listenberger LL, Ory DS, Schaffer JE. Palmitate-induced apoptosis can occur through a ceramide-independent pathway. J Biol Chem. 2001;276:14890–5.
Hickson-Bick DL, Sparagna GC, Buja LM, McMillin JB. Palmitate-induced apoptosis in neonatal cardiomyocytes is not dependent on the generation of ros. Am J Physiol Heart Circ Physiol. 2002;282:H656–64.
Du X, Edelstein D, Obici S, Higham N, Zou MH, Brownlee M. Insulin resistance reduces arterial prostacyclin synthase and enos activities by increasing endothelial fatty acid oxidation. J Clin Invest. 2006;116:1071–80.
Park SY, Cho YR, Kim HJ, Higashimori T, Danton C, Lee MK, et al. Unraveling the temporal pattern of diet-induced insulin resistance in individual organs and cardiac dysfunction in c57bl/6 mice. Diabetes. 2005;54:3530–40.
Iozzo P, Chareonthaitawee P, Dutka D, Betteridge DJ, Ferrannini E, Camici PG. Independent association of type 2 diabetes and coronary artery disease with myocardial insulin resistance. Diabetes. 2002;51:3020–4.
Mazumder PK, O'Neill BT, Roberts MW, Buchanan J, Yun UJ, Cooksey RC, et al. Impaired cardiac efficiency and increased fatty acid oxidation in insulin-resistant ob/ob mouse hearts. Diabetes. 2004;53:2366–74.
Young ME, Guthrie PH, Razeghi P, Leighton B, Abbasi S, Patil S, et al. Impaired long-chain fatty acid oxidation and contractile dysfunction in the obese zucker rat heart. Diabetes. 2002;51:2587–95.
How OJ, Aasum E, Severson DL, Chan WY, Essop MF, Larsen TS. Increased myocardial oxygen consumption reduces cardiac efficiency in diabetic mice. Diabetes. 2006;55:466–73.
Belke DD, Larsen TS, Gibbs EM, Severson DL. Altered metabolism causes cardiac dysfunction in perfused hearts from diabetic (db/db) mice. Am J Physiol Endocrinol Metab. 2000;279:E1104–13.
Belke DD, Betuing S, Tuttle MJ, Graveleau C, Young ME, Pham M, et al. Insulin signaling coordinately regulates cardiac size, metabolism, and contractile protein isoform expression. J Clin Invest. 2002;109:629–39.
Houstis N, Rosen ED, Lander ES. Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature. 2006;440:944–8.
Holland WL, Brozinick JT, Wang LP, Hawkins ED, Sargent KM, Liu Y, et al. Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell Metab. 2007;5:167–79.
Summers SA, Garza LA, Zhou H, Birnbaum MJ. Regulation of insulin-stimulated glucose transporter glut4 translocation and akt kinase activity by ceramide. Mol Cell Biol. 1998;18:5457–64.
Hajduch E, Balendran A, Batty IH, Litherland GJ, Blair AS, Downes CP, et al. Ceramide impairs the insulin-dependent membrane recruitment of protein kinase b leading to a loss in downstream signalling in l6 skeletal muscle cells. Diabetologia. 2001;44:173–83.
Teruel T, Hernandez R, Lorenzo M. Ceramide mediates insulin resistance by tumor necrosis factor-alpha in brown adipocytes by maintaining akt in an inactive dephosphorylated state. Diabetes. 2001;50:2563–71.
Stratford S, Hoehn KL, Liu F, Summers SA. Regulation of insulin action by ceramide: Dual mechanisms linking ceramide accumulation to the inhibition of akt/protein kinase b. J Biol Chem. 2004;279:36608–15.
Chavez JA, Holland WL, Bar J, Sandhoff K, Summers SA. Acid ceramidase overexpression prevents the inhibitory effects of saturated fatty acids on insulin signaling. J Biol Chem. 2005;280:20148–53.
Kellerer M, Mushack J, Seffer E, Mischak H, Ullrich A, Haring HU. Protein kinase c isoforms alpha, delta and theta require insulin receptor substrate-1 to inhibit the tyrosine kinase activity of the insulin receptor in human kidney embryonic cells (hek 293 cells). Diabetologia. 1998;41:833–8.
Cortright RN, Azevedo Jr JL, Zhou Q, Sinha M, Pories WJ, Itani SI, et al. Protein kinase c modulates insulin action in human skeletal muscle. Am J Physiol Endocrinol Metab. 2000;278:E553–62.
Motley ED, Kabir SM, Eguchi K, Hicks AL, Gardner CD, Reynolds CM, et al. Protein kinase c inhibits insulin-induced akt activation in vascular smooth muscle cells. Cell Mol Biol (Noisy-le-grand). 2001;47:1059–62.
Yu C, Chen Y, Cline GW, Zhang D, Zong H, Wang Y, et al. Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (irs-1)-associated phosphatidylinositol 3-kinase activity in muscle. J Biol Chem. 2002;277:50230–6.
Farese RV, Sajan MP, Yang H, Li P, Mastorides S, Gower Jr WR, et al. Muscle-specific knockout of pkc-lambda impairs glucose transport and induces metabolic and diabetic syndromes. J Clin Invest. 2007;117:2289–301.
Chokshi A, Drosatos K, Cheema FH, Ji R, Khawaja T, Yu S, et al. Ventricular assist device implantation corrects myocardial lipotoxicity, reverses insulin resistance, and normalizes cardiac metabolism in patients with advanced heart failure. Circulation. 2012;125:2844–53.
Luiken JJ, Koonen DP, Willems J, Zorzano A, Becker C, Fischer Y, et al. Insulin stimulates long-chain fatty acid utilization by rat cardiac myocytes through cellular redistribution of fat/cd36. Diabetes. 2002;51:3113–9.
Bastie CC, Nahle Z, McLoughlin T, Esser K, Zhang W, Unterman T, et al. Foxo1 stimulates fatty acid uptake and oxidation in muscle cells through cd36-dependent and -independent mechanisms. J Biol Chem. 2005;280:14222–9.
Nishizuka Y. Protein kinase c and lipid signaling for sustained cellular responses. FASEB J. 1995;9:484–96.
Aschrafi A, Franzen R, Shabahang S, Fabbro D, Pfeilschifter J, Huwiler A. Ceramide induces translocation of protein kinase c-alpha to the golgi compartment of human embryonic kidney cells by interacting with the c2 domain. Biochim Biophys Acta. 2003;1634:30–9.
Bourbon NA, Yun J, Kester M. Ceramide directly activates protein kinase c zeta to regulate a stress-activated protein kinase signaling complex. J Biol Chem. 2000;275:35617–23.
Fox TE, Houck KL, O'Neill SM, Nagarajan M, Stover TC, Pomianowski PT, et al. Ceramide recruits and activates protein kinase c zeta (pkc zeta) within structured membrane microdomains. J Biol Chem. 2007;282:12450–7.
Galve-Roperh I, Haro A, Diaz-Laviada I. Ceramide-induced translocation of protein kinase c zeta in primary cultures of astrocytes. FEBS Lett. 1997;415:271–4.
Huang HW, Goldberg EM, Zidovetzki R. Ceramides modulate protein kinase c activity and perturb the structure of phosphatidylcholine/phosphatidylserine bilayers. Biophys J. 1999;77:1489–97.
Huwiler A, Fabbro D, Pfeilschifter J. Selective ceramide binding to protein kinase c-alpha and -delta isoenzymes in renal mesangial cells. Biochemistry. 1998;37:14556–62.
Kajimoto T, Ohmori S, Shirai Y, Sakai N, Saito N. Subtype-specific translocation of the delta subtype of protein kinase c and its activation by tyrosine phosphorylation induced by ceramide in hela cells. Mol Cell Biol. 2001;21:1769–83.
Kajimoto T, Shirai Y, Sakai N, Yamamoto T, Matsuzaki H, Kikkawa U, et al. Ceramide-induced apoptosis by translocation, phosphorylation, and activation of protein kinase cdelta in the golgi complex. J Biol Chem. 2004;279:12668–76.
Powell DJ, Hajduch E, Kular G, Hundal HS. Ceramide disables 3-phosphoinositide binding to the pleckstrin homology domain of protein kinase b (pkb)/akt by a pkczeta-dependent mechanism. Mol Cell Biol. 2003;23:7794–808.
Wang G, Krishnamurthy K, Umapathy NS, Verin AD, Bieberich E. The carboxyl-terminal domain of atypical protein kinase czeta binds to ceramide and regulates junction formation in epithelial cells. J Biol Chem. 2009;284:14469–75.
Wang G, Silva J, Krishnamurthy K, Tran E, Condie BG, Bieberich E. Direct binding to ceramide activates protein kinase czeta before the formation of a pro-apoptotic complex with par-4 in differentiating stem cells. J Biol Chem. 2005;280:26415–24.
Wakasaki H, Koya D, Schoen FJ, Jirousek MR, Ways DK, Hoit BD, et al. Targeted overexpression of protein kinase c beta2 isoform in myocardium causes cardiomyopathy. Proc Natl Acad Sci U S A. 1997;94:9320–5.
Jalili T, Manning J, Kim S. Increased translocation of cardiac protein kinase c beta2 accompanies mild cardiac hypertrophy in rats fed saturated fat. J Nutr. 2003;133:358–61.
Wang J, Liu X, Sentex E, Takeda N, Dhalla NS. Increased expression of protein kinase c isoforms in heart failure due to myocardial infarction. Am J Physiol Heart Circ Physiol. 2003;284:H2277–87.
Belin RJ, Sumandea MP, Allen EJ, Schoenfelt K, Wang H, Solaro RJ, et al. Augmented protein kinase c-alpha-induced myofilament protein phosphorylation contributes to myofilament dysfunction in experimental congestive heart failure. Circ Res. 2007;101:195–204.
Narayan P, Valdivia HH, Mentzer Jr RM, Lasley RD. Adenosine a1 receptor stimulation antagonizes the negative inotropic effects of the pkc activator dioctanoylglycerol. J Mol Cell Cardiol. 1998;30:913–21.
Connelly KA, Kelly DJ, Zhang Y, Prior DL, Advani A, Cox AJ, et al. Inhibition of protein kinase c-beta by ruboxistaurin preserves cardiac function and reduces extracellular matrix production in diabetic cardiomyopathy. Circ Heart Fail. 2009;2:129–37.
Liu Q, Chen X, Macdonnell SM, Kranias EG, Lorenz JN, Leitges M, et al. Protein kinase c{alpha}, but not pkc{beta} or pkc{gamma}, regulates contractility and heart failure susceptibility: Implications for ruboxistaurin as a novel therapeutic approach. Circ Res. 2009;105:194–200.
Braz JC, Gregory K, Pathak A, Zhao W, Sahin B, Klevitsky R, et al. Pkc-alpha regulates cardiac contractility and propensity toward heart failure. Nat Med. 2004;10:248–54.
Hambleton M, Hahn H, Pleger ST, Kuhn MC, Klevitsky R, Carr AN, et al. Pharmacological- and gene therapy-based inhibition of protein kinase calpha/beta enhances cardiac contractility and attenuates heart failure. Circulation. 2006;114:574–82.
Boyle AJ, Kelly DJ, Zhang Y, Cox AJ, Gow RM, Way K, et al. Inhibition of protein kinase c reduces left ventricular fibrosis and dysfunction following myocardial infarction. J Mol Cell Cardiol. 2005;39:213–21.
Kolter T, Uphues I, Eckel J. Molecular analysis of insulin resistance in isolated ventricular cardiomyocytes of obese zucker rats. Am J Physiol. 1997;273:E59–67.
Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science. 2004;306:457–61.
Wu W, Muchir A, Shan J, Bonne G, Worman HJ. Mitogen-activated protein kinase inhibitors improve heart function and prevent fibrosis in cardiomyopathy caused by mutation in lamin a/c gene. Circulation. 2011;123:53–61.
Remondino A, Kwon SH, Communal C, Pimentel DR, Sawyer DB, Singh K, et al. Beta-adrenergic receptor-stimulated apoptosis in cardiac myocytes is mediated by reactive oxygen species/c-jun nh2-terminal kinase-dependent activation of the mitochondrial pathway. Circ Res. 2003;92:136–8.
Aoki H, Kang PM, Hampe J, Yoshimura K, Noma T, Matsuzaki M, et al. Direct activation of mitochondrial apoptosis machinery by c-jun n-terminal kinase in adult cardiac myocytes. J Biol Chem. 2002;277:10244–50.
Miller TA, LeBrasseur NK, Cote GM, Trucillo MP, Pimentel DR, Ido Y, et al. Oleate prevents palmitate-induced cytotoxic stress in cardiac myocytes. Biochem Biophys Res Commun. 2005;336:309–15.
Hreniuk D, Garay M, Gaarde W, Monia BP, McKay RA, Cioffi CL. Inhibition of c-jun n-terminal kinase 1, but not c-jun n-terminal kinase 2, suppresses apoptosis induced by ischemia/reoxygenation in rat cardiac myocytes. Mol Pharmacol. 2001;59:867–74.
Drosatos K, Drosatos-Tampakaki Z, Khan R, Homma S, Schulze PC, Zannis VI, et al. Inhibition of c-jun-n-terminal kinase increases cardiac ppar{alpha} expression and fatty acid oxidation and prevents lps-induced heart dysfunction. J Biol Chem. 2011;286:36331–9.
Yu XX, Murray SF, Watts L, Booten SL, Tokorcheck J, Monia BP, et al. Reduction of jnk1 expression with antisense oligonucleotide improves adiposity in obese mice. Am J Physiol Endocrinol Metab. 2008;295:E436–45.
Borradaile NM, Buhman KK, Listenberger LL, Magee CJ, Morimoto ET, Ory DS, et al. A critical role for eukaryotic elongation factor 1a-1 in lipotoxic cell death. Mol Biol Cell. 2006;17:770–8.
Borradaile NM, Han X, Harp JD, Gale SE, Ory DS, Schaffer JE. Disruption of endoplasmic reticulum structure and integrity in lipotoxic cell death. J Lipid Res. 2006;47:2726–37.
Turner MD. Fatty acyl coa-mediated inhibition of endoplasmic reticulum assembly. Biochim Biophys Acta. 2004;1693:1–4.
Song XJ, Yang CY, Liu B, Wei Q, Korkor MT, Liu JY, et al. Atorvastatin inhibits myocardial cell apoptosis in a rat model with post-myocardial infarction heart failure by downregulating er stress response. Int J Med Sci. 2011;8:564–72.
Finck BN, Bernal-Mizrachi C, Han DH, Coleman T, Sambandam N, LaRiviere LL, et al. A potential link between muscle peroxisome proliferator- activated receptor-alpha signaling and obesity-related diabetes. Cell Metab. 2005;1:133–44.
Cheng L, Ding G, Qin Q, Xiao Y, Woods D, Chen YE, et al. Peroxisome proliferator-activated receptor delta activates fatty acid oxidation in cultured neonatal and adult cardiomyocytes. Biochem Biophys Res Commun. 2004;313:277–86.
Tontonoz P, Hu E, Spiegelman BM. Stimulation of adipogenesis in fibroblasts by ppar gamma 2, a lipid-activated transcription factor. Cell. 1994;79:1147–56.
Cha BS, Ciaraldi TP, Park KS, Carter L, Mudaliar SR, Henry RR. Impaired fatty acid metabolism in type 2 diabetic skeletal muscle cells is reversed by ppargamma agonists. Am J Physiol Endocrinol Metab. 2005;289:E151–9.
Vega RB, Huss JM, Kelly DP. The coactivator pgc-1 cooperates with peroxisome proliferator-activated receptor alpha in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes. Mol Cell Biol. 2000;20:1868–76.
Karbowska J, Kochan Z, Smolenski RT. Peroxisome proliferator-activated receptor alpha is downregulated in the failing human heart. Cell Mol Biol Lett. 2003;8:49–53.
Masamura K, Tanaka N, Yoshida M, Kato M, Kawai Y, Oida K, et al. Myocardial metabolic regulation through peroxisome proliferator-activated receptor alpha after myocardial infarction. Exp Clin Cardiol. 2003;8:61–6.
Narravula S, Colgan SP. Hypoxia-inducible factor 1-mediated inhibition of peroxisome proliferator-activated receptor alpha expression during hypoxia. J Immunol. 2001;166:7543–8.
Razeghi P, Young ME, Abbasi S, Taegtmeyer H. Hypoxia in vivo decreases peroxisome proliferator-activated receptor alpha-regulated gene expression in rat heart. Biochem Biophys Res Commun. 2001;287:5–10.
Parmentier JH, Schohn H, Bronner M, Ferrari L, Batt AM, Dauca M, et al. Regulation of cyp4a1 and peroxisome proliferator-activated receptor alpha expression by interleukin-1beta, interleukin-6, and dexamethasone in cultured fetal rat hepatocytes. Biochem Pharmacol. 1997;54:889–98.
Cabrero A, Alegret M, Sanchez RM, Adzet T, Laguna JC, Carrera MV. Increased reactive oxygen species production down-regulates peroxisome proliferator-activated alpha pathway in c2c12 skeletal muscle cells. J Biol Chem. 2002;277:10100–7.
Huss JM, Torra IP, Staels B, Giguere V, Kelly DP. Estrogen-related receptor alpha directs peroxisome proliferator-activated receptor alpha signaling in the transcriptional control of energy metabolism in cardiac and skeletal muscle. Mol Cell Biol. 2004;24:9079–91.
Schreiber SN, Knutti D, Brogli K, Uhlmann T, Kralli A. The transcriptional coactivator pgc-1 regulates the expression and activity of the orphan nuclear receptor estrogen-related receptor alpha (erralpha). J Biol Chem. 2003;278:9013–8.
Lee WJ, Kim M, Park HS, Kim HS, Jeon MJ, Oh KS, et al. Ampk activation increases fatty acid oxidation in skeletal muscle by activating pparalpha and pgc-1. Biochem Biophys Res Commun. 2006;340:291–5.
Meng RS, Pei ZH, Yin R, Zhang CX, Chen BL, Zhang Y, et al. Adenosine monophosphate-activated protein kinase inhibits cardiac hypertrophy through reactivating peroxisome proliferator-activated receptor-alpha signaling pathway. Eur J Pharmacol. 2009;620:63–70.
Ravnskjaer K, Boergesen M, Dalgaard LT, Mandrup S. Glucose-induced repression of pparalpha gene expression in pancreatic beta-cells involves pp 2a activation and ampk inactivation. J Mol Endocrinol. 2006;36:289–99.
Makinde AO, Gamble J, Lopaschuk GD. Upregulation of 5'-amp-activated protein kinase is responsible for the increase in myocardial fatty acid oxidation rates following birth in the newborn rabbit. Circ Res. 1997;80:482–9.
Zong H, Ren JM, Young LH, Pypaert M, Mu J, Birnbaum MJ, et al. Amp kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation. Proc Natl Acad Sci U S A. 2002;99:15983–7.
Long YC, Barnes BR, Mahlapuu M, Steiler TL, Martinsson S, Leng Y, et al. Role of amp-activated protein kinase in the coordinated expression of genes controlling glucose and lipid metabolism in mouse white skeletal muscle. Diabetologia. 2005;48:2354–64.
Barnes BR, Long YC, Steiler TL, Leng Y, Galuska D, Wojtaszewski JF, et al. Changes in exercise-induced gene expression in 5'-amp-activated protein kinase gamma3-null and gamma3 r225q transgenic mice. Diabetes. 2005;54:3484–9.
Garcia-Roves PM, Osler ME, Holmstrom MH, Zierath JR. Gain-of-function r225q mutation in amp-activated protein kinase gamma3 subunit increases mitochondrial biogenesis in glycolytic skeletal muscle. J Biol Chem. 2008;283:35724–34.
Funding
Dr. Konstantinos Drosatos is supported by a National Heart, Lung, and Blood Institute (NHLBI) K99/R00 award (1K99HL112853-01). Dr. P. Christian Schulze is supported by a NHLBI K23 award (K23HL24534).
Conflict of Interest
Konstantinos Drosatos declares that he has no conflict of interest.
P. Christian Schulze declares that he has no conflict of interest.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Drosatos, K., Schulze, P.C. Cardiac Lipotoxicity: Molecular Pathways and Therapeutic Implications. Curr Heart Fail Rep 10, 109–121 (2013). https://doi.org/10.1007/s11897-013-0133-0
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11897-013-0133-0