Lipid Metabolism and Toxicity in the Heart

Overview

Journal Cell Metab

Publisher Cell Press

Specialties Cell Biology
Endocrinology

Date 2012 Jun 12

PMID 22682221

Citations 262

Authors

Ira J Goldberg

Chad M Trent

P Christian Schulze

Affiliations

Soon will be listed here.

Abstract

The heart has both the greatest caloric needs and the most robust oxidation of fatty acids (FAs). Under pathological conditions such as obesity and type 2 diabetes, cardiac uptake and oxidation are not balanced and hearts accumulate lipid potentially leading to cardiac lipotoxicity. We will first review the pathways utilized by the heart to acquire FAs from the circulation and to store triglyceride intracellularly. Then we will describe mouse models in which excess lipid accumulation causes heart dysfunction and experiments performed to alleviate this toxicity. Finally, the known relationships between heart lipid metabolism and dysfunction in humans will be summarized.

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References

Yagyu H, Chen G, Yokoyama M, Hirata K, Augustus A, Kako Y . Lipoprotein lipase (LpL) on the surface of cardiomyocytes increases lipid uptake and produces a cardiomyopathy. J Clin Invest. 2003; 111(3):419-26. PMC: 151861. DOI: 10.1172/JCI16751. View

Regan T, LYONS M, Ahmed S, LEVINSON G, OLDEWURTEL H, Ahmad M . Evidence for cardiomyopathy in familial diabetes mellitus. J Clin Invest. 1977; 60(4):884-99. PMC: 372437. DOI: 10.1172/JCI108843. View

Liu L, Yu S, Khan R, Ables G, Bharadwaj K, Hu Y . DGAT1 deficiency decreases PPAR expression and does not lead to lipotoxicity in cardiac and skeletal muscle. J Lipid Res. 2011; 52(4):732-44. PMC: 3284165. DOI: 10.1194/jlr.M011395. View

Duncan J, Bharadwaj K, Fong J, Mitra R, Sambandam N, Courtois M . 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(3):426-35. PMC: 2825753. DOI: 10.1161/CIRCULATIONAHA.109.888735. View

Irie H, Krukenkamp I, Brinkmann J, Gaudette G, Saltman A, Jou W . 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(11):6819-24. PMC: 164530. DOI: 10.1073/pnas.1132094100. View

Suzuki J, Shen W, Nelson B, Patel S, Veerkamp J, Selwood S . Absence of cardiac lipid accumulation in transgenic mice with heart-specific HSL overexpression. Am J Physiol Endocrinol Metab. 2001; 281(4):E857-66. DOI: 10.1152/ajpendo.2001.281.4.E857. View

Barouch L, Berkowitz D, Harrison R, ODonnell C, Hare J . Disruption of leptin signaling contributes to cardiac hypertrophy independently of body weight in mice. Circulation. 2003; 108(6):754-9. DOI: 10.1161/01.CIR.0000083716.82622.FD. View

Finck B, Lehman J, Leone T, Welch M, Bennett M, Kovacs A . The cardiac phenotype induced by PPARalpha overexpression mimics that caused by diabetes mellitus. J Clin Invest. 2002; 109(1):121-30. PMC: 150824. DOI: 10.1172/JCI14080. View

Bharadwaj K, Hiyama Y, Hu Y, Huggins L, Ramakrishnan R, Abumrad N . 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(49):37976-86. PMC: 2992231. DOI: 10.1074/jbc.M110.174458. View

10.

Park T, Hu Y, Noh H, Drosatos K, Okajima K, Buchanan J . Ceramide is a cardiotoxin in lipotoxic cardiomyopathy. J Lipid Res. 2008; 49(10):2101-12. PMC: 2533410. DOI: 10.1194/jlr.M800147-JLR200. View

11.

Kannel W, Hjortland M, CASTELLI W . Role of diabetes in congestive heart failure: the Framingham study. Am J Cardiol. 1974; 34(1):29-34. DOI: 10.1016/0002-9149(74)90089-7. View

12.

Rijzewijk L, van der Meer R, Lamb H, W A M de Jong H, Lubberink M, Romijn J . 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. DOI: 10.1016/j.jacc.2009.04.074. View

13.

Nakai A, Yamaguchi O, Takeda T, Higuchi Y, Hikoso S, Taniike M . The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress. Nat Med. 2007; 13(5):619-24. DOI: 10.1038/nm1574. View

14.

Marfella R, Di Filippo C, Portoghese M, Barbieri M, Ferraraccio F, Siniscalchi M . Myocardial lipid accumulation in patients with pressure-overloaded heart and metabolic syndrome. J Lipid Res. 2009; 50(11):2314-23. PMC: 2759838. DOI: 10.1194/jlr.P900032-JLR200. View

15.

Chang B, Li L, Paul A, Taniguchi S, Nannegari V, Heird W . Protection against fatty liver but normal adipogenesis in mice lacking adipose differentiation-related protein. Mol Cell Biol. 2006; 26(3):1063-76. PMC: 1347045. DOI: 10.1128/MCB.26.3.1063-1076.2006. View

16.

Yokoyama M, Yagyu H, Hu Y, Seo T, Hirata K, Homma S . Apolipoprotein B production reduces lipotoxic cardiomyopathy: studies in heart-specific lipoprotein lipase transgenic mouse. J Biol Chem. 2003; 279(6):4204-11. DOI: 10.1074/jbc.M311995200. View

17.

Halbirk M, Norrelund H, Moller N, Schmitz O, Gotzsche L, Nielsen R . Suppression of circulating free fatty acids with acipimox in chronic heart failure patients changes whole body metabolism but does not affect cardiac function. Am J Physiol Heart Circ Physiol. 2010; 299(4):H1220-5. DOI: 10.1152/ajpheart.00475.2010. View

18.

Boudina S, Sena S, ONeill B, Tathireddy P, Young M, Abel E . Reduced mitochondrial oxidative capacity and increased mitochondrial uncoupling impair myocardial energetics in obesity. Circulation. 2005; 112(17):2686-95. DOI: 10.1161/CIRCULATIONAHA.105.554360. View

19.

Kankaanpaa M, Lehto H, Parkka J, Komu M, Viljanen A, Ferrannini E . Myocardial triglyceride content and epicardial fat mass in human obesity: relationship to left ventricular function and serum free fatty acid levels. J Clin Endocrinol Metab. 2006; 91(11):4689-95. DOI: 10.1210/jc.2006-0584. View

20.

Perman J, Bostrom P, Lindbom M, Lidberg U, Stahlman M, Hagg D . The VLDL receptor promotes lipotoxicity and increases mortality in mice following an acute myocardial infarction. J Clin Invest. 2011; 121(7):2625-40. PMC: 3223818. DOI: 10.1172/JCI43068. View