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Journal of Enzymology and Metabolism

Review Article

Diverse Facets of Lipid Metabolism in Cardiac Pathology

Priyanka De*

Department of Biotechnology, St. Xavier’s College (Autonomous), Kolkata, India


Corresponding author: Priyanka De*, Department of Biotechnology, St. Xavier’s College (Autonomous), 30, Park Street(Mother Teresa Sarani), Kolkata-700016, India; E-mail: udity2002@yahoo.co.in


Citation: Priyanka De. Diverse Facets of Lipid Metabolism in Cardiac Pathology. J Enzymol Metabol. 2015;1(1): 105.


Copyright © 2014 Priyanka De. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Journal of Enzymology and Metabolism | Volume: 1, Issue: 1


Submission: 28/10/2015; Accepted: 19/12/2015; Published: 26/12/2015


Abstract


Myocardial lipid accumulation play significant role in the pathogenesis of heart failure. The disorders pertaining to diverse aspects of lipid metabolism manifest in the form of various types of cardiovascular diseases. Extensive studies are required to excavate thepossibilities of various pharmacologic modulation of lipid metabolism in a failing heart and accompanying alterations in myocardialstructure and function. The present review focuses on myriads of facets of lipid metabolism and associated myocardial pathology.


Keywords: lipid metabolism, cardiac pathology, cardiac metabolism, atherosclerosis

Abbreviations: Apo E: Apolipoprotein E; ATP: Adenosine triphosphate; AMPK:AMP activated protein kinase; ATGL: Adipose triglyceride lipase;ECM: Extracellular matrix; FA: Fatty acid; G0S2: G0/G1 switch2; Glut 4: Glucose transporter type 4; IGF-1: Insulin-like growthfactor I; LXR: Liver X receptor; MUFA: Monounsaturated fattyacid; mTOR: mechanistic target of rapamycin ; PPAR: Peroxisomeproliferator-activated receptor gamma; ROS: Reactive oxygen species;SCD: Stearoyl-CoA desaturase; SREBP-1c: Sterol regulatory elementbinding protein-1c; TGF-ß: Transforming growth factor beta.

Introduction


Various types of cardiac stressors may cause considerablechanges in myocardium in the form of tissue remodeling and cardiachypertrophy ultimately leading to heart failure. Cardiac hypertrophy,though beneficial initially, becomes decompensatory andpathological, characterised by a metabolic shift in energy substrateutilization from fatty acids (FA) to glucose. While systemic metabolicdisturbances contribute to cardiac dysfunction, chronic heart failuresyndrome, though primarily a cardiac anomaly, may affect multiple organ systems in the long run, especially in the patients with highblood pressure, diabetes, obesity and hyperlipidemia [1].


Fatty acid metabolism and cardiac remodeling


An adult heart relies chiefly on fatty acid utilization for oxidativephosphorylation and ATP generation while the foetal heart prefersglucose as energy fuel, being in a relatively hypoxic environment. Soafter birth, there is increased expression of genes involved in fattyacid metabolism. However, adult heart is subjected to extensivecardiac remodelling in response to a variety of stressors that bringsabout a reprogramming of foetal genes resulting in the reducedexpression of genes involved in fatty acid metabolism and relativeincrease in gene products involved in glucose metabolism [2]. Sincethe total number of ATP molecules generated during glycolysis is lessthan that produced during fatty acid oxidation, this altered substrateutilization during pathological remodeling results in overall reducedATP production. Even in the absence of systemic metabolic disorders,such as diabetes or hyperlipidemia, alteration of cardiomyocyte lipidhomeostasis contributes to the pathophysiological changes similar tothose in diabetic cardiomyopathy [3].


Cardiac steatosis amplifies the fibrotic effects of AngiotensinII through the activation of TGF-β signaling and increased ROSproduction [4]. High fat diet-induced murine cardiac remodelinghas been shown to be prevented by successful metabolic alterationsthat include reduction of cardiac AMPK, Glut 4, hexokinase 2 andreduction of toxic lipid deposits and reactive oxygen species,therebydown regulating glucose metabolism and favoring lipid metabolism(beta oxidation pathway) [5]. The liver X receptors (LXRs) act as keycardiac transcriptional regulators of both glucose and lipid metabolismduring the pathological cardiac hypertrophy. Cardiac LXRα protectsagainst such cardiac dysfunction by augmenting glucose uptakeand utilization [6]. Tissue inhibitor of metalloproteinase 3 (TIMP3)is an extracellular matrix (ECM) protein that regulates metabolicflexibility and oxidative stress response via apelin, another regulatorof fatty acid oxidation, especially during episodes of increased cardiacstress [7]. G0/G1 switch 2 (G0S2) protein regulates cardiac lipolysisthrough direct inhibition of adipose triglyceride lipase (ATGL), theprincipal triacylglycerol hydrolase, thus modulating cardiac substrateutilization. Cardiac-specific G0S2 overexpression inhibits cardiaclipolysis leading to severe cardiac steatosis, less prone to fibroticremodeling or cardiac dysfunction than hearts with a lipolyticdefect due to ATGL-deficiency [8]. Ischemic cardiac damage causesupregulation of cardiac pro-inflammatory cytokines and lymphocyticinvasion. Experimental myocardial infarction increases the numberof regulatory T cells and adoptive transfer attenuates left ventricularremodeling [9,10].


Fatty acids and atherosclerosis


Atherosclerosis refers to a chronic inflammatory disease ofarterial wall that arises from an unbalanced lipid metabolism and amaladaptive inflammatory response and leads to the developmentof fibrotic plaques within the arterial walls, usually considered to becorrelated to the uptake of oxidized low density lipoproteins [11]. Themacrophages contribute to plaque development by internalizing bothnative and modified lipoproteins converting them into cholesterolrichfoam cells, thus disrupting normal macrophage cholesterolmetabolism [12]. The lipid crystals represent one of the causativefactors of plaque rupture as they mechanically stimulate adjacentextracellular matrix (ECM) in advanced atherosclerotic plaquescausing vessel remodeling [13].


Cardiovascular diseases are linked to the increase in omega-6 anddecrease in omega-3 fatty acid levels in blood and tissues and omega-3fatty acid supplementation lowers high blood pressure [14]. Omega-3fatty acids are known to attenuate atherosclerosis by favorablychanging monocyte subsets and preventing monocyte recruitmentto the sites of aortic lesions [15]. The enzyme lipoprotein lipase actson triglyceride-rich lipoproteins producing remnant lipoproteinparticles rich in cholesterol and apolipoprotein E (apo E). Apo E actsas the ligand for uptake of remnant lipoproteins via the LDL-receptor(remnant receptor) [16]. Dysbetalipoproteinemia or Fredricksontype III hyperlipidemia, linked to mutations in apolipoprotein E thatdisrupt the clearance of remnants of triglyceride-rich lipoproteins,is an extreme disorder of remnant metabolism and these remnantlipoproteins promote atherosclerosis [17].


The remnant-like particles, namely, Remnant Lipoprotein Cholesterol (RLP-C) and Remnant Lipoprotein Triglyceride (RLP-TG)are considered as the best risk predictor for coronary atherosclerosisand sudden cardiac death, respectively [18]. The elevated LDL-C levelis the best known risk factor for coronary atherosclerosis [16].Theanti-atherosclerosis effect of Corosolic acid, a pentacyclic triterpeneacid, has been observed in apolipoprotein E-deficient mice, throughregulation of the nuclear factor kappa B (NF-κB) signaling pathwayand inhibition of monocyte chemoattractant protein-1 expression[19]. Insulin-like growth factor I (IGF-1) exhibits anti-atheroscleroticeffects, reducing lipid oxidation and macrophage-derived foam cellformation via downregulation of 12/15-lipoxygenase [20].


Lipotoxicity and cardiac pathology


The metabolism of myocardial triacylglycerol stores are vitalfor normal myocardial functioning. While triacylglycerol synthesisdetoxifies and recycles fatty acids to prevent lipotoxicity, lipolysis ortriacylglycerol hydrolysis remobilizes fatty acids from endogenousstore house. Lipotoxicity characterised by accumulation of increasedlevels of toxic metabolic intermediates is found in a failing heart,especially in diabetic and obese patients [1, 21-24]. Increasedstores of triglycerides are noticeable in the heart of animals withobesity and diabetes as well as in obese and diabetic patients withcardiac dysfunction and heart failure [25]. Many studies highlightthe significance of altered mitochondrial activity as a majorcontributor to cardiac dysfunction in diabetic cardiomyopathy.Such mitochondrial dysfunction involves altered cardiac substratemetabolism, lipotoxicity, impaired calcium handling, oxidative stressand mitochondrial uncoupling [26-28].


The ectopic myocardial lipid deposits may be an indication ofprogressive myocardial degradation during the progression of cardiacfailure [1]. The development of diabetic cardiomyopathy is associatedwith lipotoxic injury caused by increased myocardial triglyceridecontent, myocardial steatosis and impaired left ventricular diastolicfunction [29-31]. Recent studies have revealed the role of mTOR inlipid homeostasis and that mTOR dysregulation may lead to abnormallipid partitioning ie redistribution of triglycerides from adipocytes tononadipose peripheral tissues and resulting lipotoxicity [32].


Recent studies showed that stearoyl-CoA desaturase (SCD),the rate-limiting enzyme in the biosynthesis of monounsaturatedfatty acids (MUFA), can reprogram cardiac metabolism to improvecardiac function, signifying the role of SCD in the pathogenesis oflipotoxic cardiomyopathies [33]. SCD1 deficiency inhibits fatty acidbeta oxidation and increases glucose utilization in the cardiac muscleby upregulating insulin signaling and decreasing FA availabilityand expression of FA oxidation genes [34]. SCD4, a cardiac-specificisoform of SCD, is specifically regulated by leptin and other dietaryfactors [35]. Clinical studies have also revealed high levels of circulatingleptin, an adipokine in case of development of cardiac hypertrophy inobese people. Leptin plays a significant role in protecting the heartfrom cardiac lipotoxicity [36, 37]. The activation of the transcriptionfactor Sterol Regulatory Element Binding Protein-1c (SREBP-1c)as well as the transcriptional coactivator peroxisome proliferatoractivatedreceptor gamma (PPARγ) might be significant molecularswitches regulating the event of lipotoxicity [1].


Lipid metabolism based pharmacological intervention


Impaired calcium handling and intracellular calcium overloadinduced by chronic hypoxia plays a vital role in mediating myocardialinjury. Trimetazidine, a well-known drug for angina pectoris,ameliorates such calcium imbalance through enhanced metabolicshift from lipid oxidation to glucose oxidation, thereby preventinghypoxic damage [38]. The pathogenesis of calcific aortic valve stenosismay be modulated by peroxisome proliferator-activated receptor-γ(PPAR-γ). Pioglitazone, an antidiabetic drug, is a PPAR-γ ligandthat inhibits such valvular calcification and may be beneficial inpreventing or slowing stenosis of aortic valves [39]. Resveratrol, a redwine polyphenol, exhibits cardioprotective effect against high fat dietsdue to its anti-atherogenic property and is a potential compound tobe consumed for our healthy life-style [40].


Conclusion


The increased levels of toxic lipid intermediates in a failing heartis a suggestive of underlying impaired lipid metabolism. Furtherinvestigation is required to deal with the complex metabolic pathwaysand the role of huge diversity of intermediate metabolites. The areaof cardiovascular lipidomics will help us to expand the horizon ofpathophysiology of various cardiovascular diseases and provide noveltherapeutic agents as well as preventive and diagnostic biomarkers.


References

  1. Schulze PC (2009) Myocardial lipid accumulation and lipotoxicity in heart failure. J Lipid Res 50: 2137-2138.
  2. Rajabi M, Kassiotis C, Razeghi P, Taegtmeyer H (2007) Return to the fetal gene program protects the stressed heart: a strong hypothesis. Heart Fail Rev 12: 331-343.
  3. Chiu HC, Kovacs A, Blanton RM, Han X, Courtois M, et al. (2005) Transgenic expression of fatty acid transport protein 1 in the heart causes lipotoxic cardiomyopathy. Circ Res 96: 225-233.
  4. Glenn DJ, Cardema MC, Ni W, Zhang Y, Yeghiazarians Y, et al. (2015) Cardiac steatosis potentiates angiotensin II effects in the heart. Am J Physiol Heart Circ Physiol 308: H339-H350.
  5. Roberts NW, González-Vega M, Berhanu TK, Mull A, García J, et al. (2015) Successful metabolic adaptations leading to the prevention of high fat diet-induced murine cardiac remodeling. Cardiovasc Diabetol 14: 127.
  6. Cannon MV, Silljé HH, Sijbesma JW, Vreeswijk-Baudoin I, Ciapaite J, et al. (2015) Cardiac LXRα protects against pathological cardiac hypertrophy and dysfunction by enhancing glucose uptake and utilization. EMBO Mol Med 7: 1229-1243.
  7. Stöhr R, Kappel BA, Carnevale D, Cavalera M, Mavilio M, et al. (2015) TIMP3 interplays with apelin to regulate cardiovascular metabolism in hypercholesterolemic mice. Mol Metab 4: 741-752.
  8. Heier C, Radner FP, Moustafa T, Schreiber R, Grond S, et al. (2015) G0/G1 switch gene-2 regulates cardiac lipolysis. J Biol Chem 290: 26141-50.
  9. Saxena A, Dobaczewski M, Rai V, Haque Z, Chen W, et al. (2014) Regulatory T cells are recruited in the infarcted mouse myocardium and may modulate fibroblast phenotype and function. Am J Physiol Heart Circ Physiol 307: H1233-H1242.
  10. Sharir R, Semo J, Shimoni S, Ben-Mordechai T, Landa-Rouben N, et al. (2014) Experimental myocardial infarction induces altered regulatory T cell hemostasis, and adoptive transfer attenuates subsequent remodeling.PLoS One 9: e113653.
  11. Persson J, Nilsson J, Lindholm MW (2006) Cytokine response to lipoprotein lipid loading in human monocyte-derived macrophages. Lipids Health Dis 5: 17.
  12. McLaren JE, Michael DR, Ashlin TG, Ramji DP (2011) Cytokines, macrophage lipid metabolism and foam cells: implications for cardiovascular disease therapy. Prog Lipid Res 50: 331-347.
  13. Lee ES, Park JH, Lee SW, Hahn J, Lee H, et al. (2014) Lipid crystals mechanically stimulate adjacent extracellular matrix in advanced atherosclerotic plaques. Atherosclerosis 237: 769-776.
  14. Morin C, Rousseau E, Blier PU, Fortin S (2015) Effect of docosahexaenoic acid monoacylglyceride on systemic hypertension and cardiovascular dysfunction. Am J Physiol Heart Circ Physiol 309: H93-H102.
  15. Brown AL, Zhu X, Rong S, Shewale S, Seo J, et al. (2012) Omega-3 fatty acids ameliorate atherosclerosis by favorably altering monocyte subsets and limiting monocyte recruitment to aortic lesions. Arterioscler Thromb Vasc Biol 32: 2122-2130.
  16. Takeichi S, Yukawa N, Nakajima Y, Osawa M, Saito T, et al. (1999) Association of plasma triglyceride-rich lipoprotein remnants with coronary atherosclerosis in cases of sudden cardiac death. Atherosclerosis 142: 309-315.
  17. Marais D (2015) Dysbetalipoproteinemia: an extreme disorder of remnant metabolism. Curr Opin Lipidol 26: 292-297.
  18. Takeichi S, Nakajima Y, Osawa M, Yukawa N, Saito T, et al. (1997) The possible role of remnant-like particles as a risk factor for sudden cardiac death. Int J Legal Med 110: 213-219.
  19. Chen H, Yang J, Zhang Q, Chen LH, Wang Q (2012) Corosolic acid ameliorates atherosclerosis in apolipoprotein E-deficient mice by regulating the nuclear factor-κB signaling pathway and inhibiting monocyte chemoattractant protein-1 expression. Circ J 76: 995-1003.
  20. Sukhanov S, Snarski P, Vaughn C, Lobelle-Rich P, Kim C, et al. (2015) Insulin-like growth factor I reduces lipid oxidation and foam cell formation via downregulation of 12/15-lipoxygenase. Atherosclerosis 238: 313-320.
  21. Sharma S, Adrogue JV, Golfman L, Uray I, Lemm J, et al. (2004) Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart. FASEB J 18: 1692-1700.
  22. Borradaile NM, Schaffer JE (2005) Lipotoxicity in the heart. Curr Hypertens Rep 7: 412-417.
  23. van de Weijer T, Schrauwen-Hinderling VB, Schrauwen P (2011) Lipotoxicity in type 2 diabetic cardiomyopathy. Cardiovasc Res 92: 10-18.
  24. Goldberg IJ, Trent CM, Schulze PC (2012) Lipid metabolism and toxicity in the heart. Cell Metab 15: 805-812.
  25. Zhou YT, Grayburn P, Karim A, Shimabukuro M, Higa M, et al. (2000) Lipotoxic heart disease in obese rats: implications for human obesity. Proc Natl Acad Sci USA 97: 1784-1789.
  26. Glenn DJ, Wang F, Nishimoto M, Cruz MC, Uchida Y, et al. (2011) A murine model of isolated cardiac steatosis leads to cardiomyopathy. Hypertension 57: 216-222.
  27. Sung MM, Hamza SM, Dyck JR (2015) Myocardial metabolism in diabetic cardiomyopathy: potential therapeutic targets. Antioxid Redox Signal 22: 1606-1630.
  28. Elezaby A, Sverdlov AL, Tu VH, Soni K, Luptak I, et al. (2015) Mitochondrial remodeling in mice with cardiomyocyte-specific lipid overload. J Mol Cell Cardiol 79: 275-283.
  29. Cosson S, Kevorkian JP (2003) Left ventricular diastolic dysfunction: an early sign of diabetic cardiomyopathy? Diabetes Metab 29: 455-466.
  30. Galderisi M (2006) Diastolic dysfunction and diabetic cardiomyopathy: evaluation by Doppler echocardiography. J Am Coll Cardiol 48: 1548-1551.
  31. Rijzewijk LJ, van der Meer RW, Smit JW, Diamant M, Bax JJ, et al. (2008) Myocardial steatosis is an independent predictor of diastolic dysfunction in type 2 diabetes mellitus. J Am Coll Cardiol 52: 1793-1799.
  32. Chakrabarti P, Kandror KV (2015) The role of mTOR in lipid homeostasis and diabetes progression. Curr Opin Endocrinol Diabetes Obes 22: 340-346.
  33. Dobrzyn P, Bednarski T, Dobrzyn A (2015) Metabolic reprogramming of the heart through stearoyl-CoA desaturase. Prog Lipid Res 57: 1-12.
  34. Dobrzyn P, Sampath H, Dobrzyn A, Miyazaki M, Ntambi JM (2008) Loss of stearoyl-CoA desaturase 1 inhibits fatty acid oxidation and increases glucose utilization in the heart. Am J Physiol Endocrinol Metab 294: E357-E364.
  35. Miyazaki M, Jacobson MJ, Man WC, Cohen P, Asilmaz E, et al. (2003) Identification and characterization of murine SCD4, a novel heart-specific stearoyl-CoA desaturase isoform regulated by leptin and dietary factors. J Biol Chem 278: 33904-33911.
  36. Leifheit-Nestler M, Wagner NM, Gogiraju R, Didié M, Konstantinides S, et al. (2013) Importance of leptin signaling and signal transducer and activator of transcription-3 activation in mediating the cardiac hypertrophy associated with obesity. J Transl Med 11: 170.
  37. Hall ME, Harmancey R, Stec DE (2015) Lean heart: Role of leptin in cardiac hypertrophy and metabolism. World J Cardiol 7: 511-524.
  38. Wei J, Xu H, Shi L, Tong J, Zhang J (2015) Trimetazidine protects cardiomyocytes against hypoxia-induced injury through ameliorates calcium homeostasis. Chem Biol Interact 236: 47-56.
  39. Chu Y, Lund DD, Weiss RM, Brooks RM, Doshi H, et al. (2013) Pioglitazone attenuates valvular calcification induced by hypercholesterolemia. Arterioscler Thromb Vasc Biol 33: 523-532.
  40. Meng C, Liu JL, Du AL (2014) Cardioprotective effect of resveratrol on atherogenic diet-fed rats. Int J Clin Exp Pathol 7: 7899-7906.