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The 'Goldilocks Zone' Of Fatty Acid Metabolism; To Ensure That The Relationship With Cardiac Function Is Just Right.

M. Kerr, M. Dodd, L. Heather
Published 2017 · Medicine

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Fatty acids (FA) are the main fuel used by the healthy heart to power contraction, supplying 60-70% of the ATP required. FA generate more ATP per carbon molecule than glucose, but require more oxygen to produce the ATP, making them a more energy dense but less oxygen efficient fuel compared with glucose. The pathways involved in myocardial FA metabolism are regulated at various subcellular levels, and can be divided into sarcolemmal FA uptake, cytosolic activation and storage, mitochondrial uptake and β-oxidation. An understanding of the critical involvement of each of these steps has been amassed from genetic mouse models, where forcing the heart to metabolize too much or too little fat was accompanied by cardiac contractile dysfunction and hypertrophy. In cardiac pathologies, such as heart disease and diabetes, aberrations in FA metabolism occur concomitantly with changes in cardiac function. In heart failure, FA oxidation is decreased, correlating with systolic dysfunction and hypertrophy. In contrast, in type 2 diabetes, FA oxidation and triglyceride storage are increased, and correlate with diastolic dysfunction and insulin resistance. Therefore, too much FA metabolism is as detrimental as too little FA metabolism in these settings. Therapeutic compounds that rebalance FA metabolism may provide a mechanism to improve cardiac function in disease. Just like Goldilocks and her porridge, the heart needs to maintain FA metabolism in a zone that is 'just right' to support contractile function.
This paper references
db/db) mice
J. Buchanan (2005)
Expression cloning and characterization of a novel adipocyte long chain fatty acid transport protein
J. Schaffer (1994)
Dissociation Between Metabolic and Efficiency Effects of Perhexiline in Normoxic Rat Myocardium
S. Unger (2005)
Metabolism of Palmitate in Isolated Working Hearts From Spontaneously Diabetic “BB” Wistar Rats
G. Lopaschuk (1987)
Differential Translocation of the Fatty Acid Transporter, FAT/CD36, and the Glucose Transporter, GLUT4, Coordinates Changes in Cardiac Substrate Metabolism During Ischemia and Reperfusion
L. Heather (2013)
Freshly isolated mitochondria from failing human hearts exhibit preserved respiratory function.
A. Cordero-Reyes (2014)
metabolism during low-flow ischemia/reperfusion in the isolated rat heart
S. A. Unger (2005)
L-carnitine in isolated myocytes
B. N. Finck (2002)
Cardiac metabolic compensation to hypertension requires lipoprotein lipase.
H. Yamashita (2008)
How useful is the skull x-ray examination in trauma?
J. DeCampo (1980)
Myocardial ATGL Overexpression Decreases the Reliance on Fatty Acid Oxidation and Protects against Pressure Overload-Induced Cardiac Dysfunction
P. Kienesberger (2011)
Effect of Obesity and Insulin Resistance on Myocardial Substrate Metabolism and Efficiency in Young Women
L. R. Peterson (2004)
Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial.
A. Keech (2005)
The Fatty Acid Transport Protein (FATP1) Is a Very Long Chain Acyl-CoA Synthetase*
N. Coe (1999)
The cardiac phenotype induced by PPARalpha overexpression mimics that caused by diabetes mellitus.
B. Finck (2002)
Quantitative studies of human cardiac metabolism by 31P rotating-frame NMR.
M. Blackledge (1987)
CD36 Deficiency Rescues Lipotoxic Cardiomyopathy
J. Yang (2007)
Increased O2 cost of basal metabolism and excitation-contraction coupling in hearts from type 2 diabetic mice.
N. Boardman (2009)
Alpha-keto acid dehydrogenase complexes. XI. Comparative studies of regulatory properties of the pyruvate dehydrogenase complexes from kidney, heart, and liver mitochondria.
T. Linn (1969)
Demonstration of reverse fatty acid transport from rat cardiomyocytes Published, JLR Papers in Press, September 1, 2004. DOI 10.1194/jlr.M400237-JLR200
B. Park (2004)
Isoproterenol induces in vivo functional and metabolic abnormalities: similar to those found in the infarcted rat heart.
L. Heather (2009)
Cardiac contractile dysfunction in insulin-resistant rats fed a high-fat diet is associated with elevated CD36-mediated fatty acid uptake and esterification
D. Ouwens (2007)
Cardiac diastolic dysfunction in high-fat diet fed mice is associated with lipotoxicity without impairment of cardiac energetics in vivo.
D. Abdurrachim (2014)
Rescue of heart lipoprotein lipase-knockout mice confirms a role for triglyceride in optimal heart metabolism and function.
R. Khan (2013)
Utilisation of triacylglycerol and non-esterified fatty acid by the working rat heart: myocardial lipid substrate preference.
D. Hauton (2001)
Fenofibrate reduces cardiac remodeling and improves cardiac function in a rat model of severe left ventricle volume overload.
Wahiba Dhahri (2013)
CD36-null mice and restored by myocyte CD36 expression or medium-chain fatty acids
P. C. Kienesberger (2012)
myocardial uncoupling protein levels
J. M. O’Donnell (2006)
Isolation of myocardial membrane long-chain fatty acid-binding protein: homology with a rat membrane protein implicated in the binding or transport of long-chain fatty acids.
T. Tanaka (1995)
Cardiac Metabolism in Heart Failure: Implications Beyond ATP Production
T. Doenst (2013)
Acetyl-CoA carboxylase involvement in the rapid maturation of fatty acid oxidation in the newborn rabbit heart.
G. Lopaschuk (1994)
Rescue of Cardiomyopathy in Peroxisome Proliferator-Activated Receptor-α Transgenic Mice by Deletion of Lipoprotein Lipase Identifies Sources of Cardiac Lipids and Peroxisome Proliferator-Activated Receptor-α Activators
J. Duncan (2010)
Uptake and metabolism of palmitate by isolated cardiac myocytes from adult rats: involvement of sarcolemmal proteins.
J. J. Luiken (1997)
Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart
S. Sharma (2004)
Myocardial metabolism of free fatty acids. Studies with 14C-labeled substrates in humans.
J. Wisneski (1987)
Inhibition of sarcolemmal FAT/CD36 by sulfo-N-succinimidyl oleate rapidly corrects metabolism and restores function in the diabetic heart following hypoxia/reoxygenation
L. Mansor (2017)
coupling in hearts from type 2 diabetic mice
A. J. Murray (2005)
Cell biology of cardiac mitochondrial phospholipids.
G. Hatch (2004)
liver plasma membranes
J. E. Schaffer (1994)
Altered myocardial high-energy phosphate metabolites in patients with dilated cardiomyopathy.
C. Hardy (1991)
New insights into the roles of proteins and lipids in membrane transport of fatty acids.
J. Hamilton (2007)
Altered myocardial substrate metabolism is associated with myocardial dysfunction in early diabetic cardiomyopathy in rats: studies using positron emission tomography
C. E. van den Brom (2009)
Effects of metabolic modulation by trimetazidine on left ventricular function and phosphocreatine/adenosine triphosphate ratio in patients with heart failure.
G. Fragasso (2006)
Myocardial steatosis is an independent predictor of diastolic dysfunction in type 2 diabetes mellitus.
L. Rijzewijk (2008)
Preferential Oxidation of Triacylglyceride-Derived Fatty Acids in Heart Is Augmented by the Nuclear Receptor PPAR&agr;
Natasha H. Banke (2010)
Cardiac fatty acid uptake and transport in health and disease.
G. J. van der Vusse (2000)
The failing heart--an engine out of fuel.
S. Neubauer (2007)
Increased myocardial oxygen consumption reduces cardiac efficiency in diabetic mice.
Ole-Jakob How (2006)
Absolute concentrations of high-energy phosphate metabolites in normal, hypertrophied, and failing human myocardium measured noninvasively with (31)P-SLOOP magnetic resonance spectroscopy.
M. Beer (2002)
Fatty Acid Translocase/CD36 Deficiency Does Not Energetically or Functionally Compromise Hearts Before or After Ischemia
M. Kuang (2004)
Mitral regurgitation: impaired systolic function, eccentric hypertrophy, and increased severity are linked to lower phosphocreatine/ATP ratios in humans.
M. A. Conway (1998)
Mice Long-Term High-Fat Diet Feeding Recapitulates Human Cardiovascular Alterations: An Animal Model to Study the Early Phases of Diabetic Cardiomyopathy
Sebastián D Calligaris (2013)
Contribution of oxidative metabolism and glycolysis to ATP production in hypertrophied hearts.
M. Allard (1994)
Lipotoxicity in obesity and diabetes-related cardiac dysfunction.
Igor Zlobine (2016)
Stimulation of non-oxidative glucose utilization by L-carnitine in isolated myocytes.
S. Abdel‐aleem (1995)
Detection of low phosphocreatine to ATP ratio in failing hypertrophied human myocardium by 31P magnetic resonance spectroscopy
M. A. Conway (1991)
Contribution of glycogen to aerobic myocardial glucose utilization.
S. Henning (1996)
Cardiac-specific adipose triglyceride lipase overexpression protects from cardiac steatosis and dilated cardiomyopathy following diet-induced obesity
T. Pulinilkunnil (2014)
Fatty acids as substrates for heart and skeletal muscle.
K. Zierler (1976)
Changes in Cardiac Substrate Transporters and Metabolic Proteins Mirror the Metabolic Shift in Patients with Aortic Stenosis
L. Heather (2011)
Plasma free fatty acids and peroxisome proliferator-activated receptor alpha in the control of myocardial uncoupling protein levels.
A. Murray (2005)
Liver disease induced by perhexiline maleate.
J. Horowitz (1982)
Total mechanical energy of a ventricle model and cardiac oxygen consumption.
H. Suga (1979)
Characterization of a Heart-specific Fatty Acid Transport Protein*
R. Gimeno (2003)
The role of fibrates in the prevention of cardiovascular disease--a pooled meta-analysis of long-term randomized placebo-controlled clinical trials.
S. Saha (2007)
Myocardial Adipose Triglyceride Lipase Overexpression Protects Diabetic Mice From the Development of Lipotoxic Cardiomyopathy
T. Pulinilkunnil (2013)
Cardiac dysfunction induced by high-fat diet is associated with altered myocardial insulin signalling in rats
D. Ouwens (2005)
Absence of fatty acid transporter CD36 protects against Western-type diet-related cardiac dysfunction following pressure overload in mice.
L. Steinbusch (2011)
Metabolic Modulator Perhexiline Corrects Energy Deficiency and Improves Exercise Capacity in Symptomatic Hypertrophic Cardiomyopathy
K. Abozguia (2010)
Good and bad consequences of altered fatty acid metabolism in heart failure: evidence from mouse models.
D. Abdurrachim (2015)
Metabolism of the human heart. II. Studies on fat, ketone and amino acid metabolism.
R. Bing (1954)
Ectopic and Visceral Fat Deposition in Lean and Obese Patients With Type 2 Diabetes
E. Levelt (2016)
A double-blind randomized multicentre clinical trial to evaluate the efficacy and safety of two doses of etomoxir in comparison with placebo in patients with moderate congestive heart failure: the ERGO (etomoxir for the recovery of glucose oxidation) study.
C. Holubarsch (2007)
Cardiac-specific Knock-out of Lipoprotein Lipase Alters Plasma Lipoprotein Triglyceride Metabolism and Cardiac Gene Expression*
A. Augustus (2004)
decreases the reliance on fatty acid oxidation and protects against pressure overload-induced cardiac dysfunction
T. Pulinilkunnil (2014)
Loss of Lipoprotein Lipase-derived Fatty Acids Leads to Increased Cardiac Glucose Metabolism and Heart Dysfunction*
A. Augustus (2006)
Impaired myocardial metabolic reserve and substrate selection flexibility during stress in patients with idiopathic dilated cardiomyopathy.
D. Neglia (2007)
Diastolic dysfunction in hypertensive heart disease is associated with altered myocardial metabolism.
H. Lamb (1999)
The metabolism of the heart.
R. Bing (1955)
15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma.
B. Forman (1995)
Myocardial metabolism of fatty acids.
F. B. Ballard (1960)
Effect of perhexiline and oxfenicine on myocardial function and metabolism during low-flow ischemia/reperfusion in the isolated rat heart.
J. Kennedy (2000)
Accelerated triacylglycerol turnover kinetics in hearts of diabetic rats include evidence for compartmented lipid storage.
J. M. O'donnell (2006)
Sphingolipids in cardiovascular diseases and metabolic disorders
Sonia Borodzicz (2015)
Glucose transport and phosphorylation in single cardiac myocytes: rate-limiting steps in glucose metabolism.
J. Manchester (1994)
The role of citric acid in intermediate metabolism in animal tissues
H. Krebs (1980)
Metabolic Gene Expression in Fetal and Failing Human Heart
P. Razeghi (2001)
Cardiac Lipotoxicity: Molecular Pathways and Therapeutic Implications
Konstantinos Drosatos (2013)
The Effect of Free Fatty Acids on Myocardial Oxygen Consumption During Atrial Pacing and Catecholamine Infusion in Man
S. Simonsen (1978)
Cardiomyocyte Triglyceride Accumulation and Reduced Ventricular Function in Mice with Obesity Reflect Increased Long Chain Fatty Acid Uptake and De Novo Fatty Acid Synthesis
F. Ge (2012)
PPARgamma activators improve glucose homeostasis by stimulating fatty acid uptake in the adipocytes.
G. Martin (1998)
Efficacy Comparison of Trimetazidine with Therapeutic Alternatives in Stable Angina Pectoris: A Network Meta-Analysis
N. Danchin (2011)
Binding of sulfosuccinimidyl fatty acids to adipocyte membrane proteins: Isolation and ammo-terminal sequence of an 88-kD protein implicated in transport of long-chain fatty acids
C. Harmon (2004)
mice with obesity reflect increased long chain fatty acid uptake and de novo fatty acid synthesis
A. Augustus (2012)
glucose metabolism and heart dysfunction
R. S. Khan (2013)
Reduced cardiac efficiency and altered substrate metabolism precedes the onset of hyperglycemia and contractile dysfunction in two mouse models of insulin resistance and obesity.
J. Buchanan (2005)
A high fat diet increases mitochondrial fatty acid oxidation and uncoupling to decrease efficiency in rat heart
Mark A. Cole (2011)
Malonyl Coenzyme A Decarboxylase Inhibition Protects the Ischemic Heart by Inhibiting Fatty Acid Oxidation and Stimulating Glucose Oxidation
J. Dyck (2004)
Targeted Deletion of Fatty Acid Transport Protein-4 Results in Early Embryonic Lethality*
R. Gimeno (2003)
Age-dependent changes in metabolism, contractile function, and ischemic sensitivity in hearts from db/db mice.
E. Aasum (2003)
Altered metabolism causes cardiac dysfunction in perfused hearts from diabetic (db/db) mice.
D. Belke (2000)
The new clinical trials with thiazolidinediones – DREAM, ADOPT, and CHICAGO: promises fulfilled?
R. Goldberg (2007)
Potentiation of abnormalities in myocardial metabolism with the development of diabetes in women with obesity and insulin resistance
J. McGill (2011)
Unbound free fatty acid levels in human serum.
G. V. Richieri (1995)
Insulin-Stimulated Cardiac Glucose Oxidation Is Increased in High-Fat Diet–Induced Obese Mice Lacking Malonyl CoA Decarboxylase
J. Ussher (2009)
Summarizing the FIELD study: lessons from a ‘negative' trial
V. Tsimihodimos (2013)
Expression of the CD36 homolog (FAT) in fibroblast cells: effects on fatty acid transport.
A. Ibrahimi (1996)
Myocardial recovery from ischemia is impaired in CD36-null mice and restored by myocyte CD36 expression or medium-chain fatty acids
H. Irie (2003)
Mayuresh Dixit (2016)
Abnormal Cardiac and Skeletal Muscle Energy Metabolism in Patients With Type 2 Diabetes
Michaela Scheuermann-Freestone (2003)
Fatty acid oxidation enzyme gene expression is downregulated in the failing heart.
M. Sack (1996)
Activation of Malonyl-CoA Decarboxylase in Rat Skeletal Muscle by Contraction and the AMP-activated Protein Kinase Activator 5-Aminoimidazole-4-carboxamide-1-β-d-ribofuranoside*
A. Saha (2000)
Labeling of adipocyte membranes by sulfo-N-succinimidyl derivatives of long-chain fatty acids: Inhibition of fatty acid transport
C. Harmon (2005)
triglyceride in optimal heart metabolism and function
H. Yamashita (2008)
Impaired In Vivo Mitochondrial Krebs Cycle Activity After Myocardial Infarction Assessed Using Hyperpolarized Magnetic Resonance Spectroscopy
M. Dodd (2014)
Clinical significance of iodine-123-15-(p-iodophenyl)-3-R, S-methylpentadecanoic acid myocardial scintigraphy in patients with aortic valve disease.
Y. Otsuka (2002)
Characterization of cardiac malonyl-CoA decarboxylase and its putative role in regulating fatty acid oxidation.
J. Dyck (1998)
Contraction-induced fatty acid translocase/CD36 translocation in rat cardiac myocytes is mediated through AMP-activated protein kinase signaling.
J. J. Luiken (2003)
Effect of Trimetazidine on Carnitine Palmitoyltransferase-1 in the Rat Heart
J. Kennedy (2004)
Impact of altered substrate utilization on cardiac function in isolated hearts from Zucker diabetic fatty rats.
P. Wang (2005)
Reverse changes in cardiac substrate oxidation in dogs recovering from heart failure.
K. Qanud (2008)
Critical role of complex III in the early metabolic changes following myocardial infarction.
L. Heather (2010)
First clinical trial with etomoxir in patients with chronic congestive heart failure.
S. Schmidt-Schweda (2000)
Increased myocardial fatty acid metabolism in patients with type 1 diabetes mellitus.
P. Herrero (2006)
Early structural and metabolic cardiac remodelling in response to inducible adipose triglyceride lipase ablation.
P. Kienesberger (2013)
Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes.
S. Nissen (2007)
Measurement of coronary blood flow in man.
R. Bing (1960)
Altered myocardial fatty acid and glucose metabolism in idiopathic dilated cardiomyopathy.
V. Dávila-Román (2002)
Lipoprotein Secretion and Triglyceride Stores in the Heart*
J. Björkegren (2001)
AMP-activated protein kinase regulation of fatty acid oxidation in the ischaemic heart.
T. A. Hopkins (2003)
disturbances of diabetes mellitus
H. A. Krebs (1937)
Cellular fatty acid transport in heart and skeletal muscle as facilitated by proteins
J. J. Luiken (2007)
Trimetazidine, a Metabolic Modulator, Has Cardiac and Extracardiac Benefits in Idiopathic Dilated Cardiomyopathy
H. Tuunanen (2008)
Effect of free fatty acids on myocardial function and oxygen consumption in intact dogs.
O. Mjøs (1971)
Cardiac energetics, oxygenation, and perfusion during increased workload in patients with type 2 diabetes mellitus
E. Levelt (2016)
Zucker Diabetic Fatty Rats for Research in Diabetes
Marcela Capcarová (2019)
Perfused hearts from Type 2 diabetic (db/db) mice show metabolic responsiveness to insulin.
A. Hafstad (2006)
The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus.
P. Randle (1963)
Fatty acid oxidation and mechanical performance of volume-overloaded rat hearts.
Z. el Alaoui-Talibi (1992)
Role of changes in cardiac metabolism in development of diabetic cardiomyopathy.
D. An (2006)
Formation of malonyl coenzyme A in rat heart. Identification and purification of an isozyme of A carboxylase from rat heart.
K. Thampy (1989)
31P Magnetic Resonance Spectroscopy in Dilated Cardiomyopathy and Coronary Artery Disease: Altered Cardiac High‐Energy Phosphate Metabolism in Heart Failure
Stefan Neubauer (1992)
Absence of Malonyl Coenzyme A Decarboxylase in Mice Increases Cardiac Glucose Oxidation and Protects the Heart From Ischemic Injury
J. Dyck (2006)
Decreased mitochondrial oxidative phosphorylation capacity in the human heart with left ventricular systolic dysfunction
N. Stride (2013)
Glycolipids at the cell surface and their biological functions
T. Yamakawa (1978)
Progressive caloric restriction induces dose-dependent changes in myocardial triglyceride content and diastolic function in healthy men.
S. Hammer (2008)
Regulation of pyruvate dehydrogenase complex in ischemic rat heart.
T. Patel (1984)
infusion in man
O. D. Mjøs (1971)
Glucose kinetics during acute and chronic treatment of rats with 2[6(4-chloro-phenoxy)hexyl]oxirane-2-carboxylate, etomoxir.
Y. Kruszynska (1987)
Dietary fat and heart failure: moving from lipotoxicity to lipoprotection.
W. Stanley (2012)
Myocardial Fatty Acid Metabolism: Independent Predictor of Left Ventricular Mass in Hypertensive Heart Disease
L. de Las Fuentes (2003)
Structure, function, and regulation of the mammalian facilitative glucose transporter gene family.
A. L. Olson (1996)
Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators
I. Issemann (1990)
High Rates of Fatty Acid Oxidation during Reperfusion of Ischemic Hearts Are Associated with a Decrease in Malonyl-CoA Levels Due to an Increase in 5′-AMP-activated Protein Kinase Inhibition of Acetyl-CoA Carboxylase (*)
N. Kudo (1995)
high-fat diet-induced obese mice lacking malonyl CoA decarboxylase. Diabetes
S. Abdel-aleem (1995)
Changes in fatty acid transport and transporters are related to the severity of insulin deficiency.
J. J. Luiken (2002)
Altered myocardial substrate metabolism and decreased diastolic function in nonischemic human diabetic cardiomyopathy: studies with cardiac positron emission tomography and magnetic resonance imaging.
L. Rijzewijk (2009)
Assessment of myocardial metabolic flexibility and work efficiency in human type 2 diabetes using 16-[18F]fluoro-4-thiapalmitate, a novel PET fatty acid tracer.
K. Mather (2016)
Isolation and partial characterization of a fatty acid binding protein in rat liver plasma membranes.
W. Stremmel (1985)
Asymmetrical Dimethyl Arginine (ADMA) is a Novel Marker of Coronary Stent Restenosis
M. Fujita (2002)
15-Deoxy-Δ12,14-Prostaglandin J2 is a ligand for the adipocyte determination factor PPARγ
B. Forman (1995)
Increased oxidative metabolism following hypoxia in the type 2 diabetic heart, despite normal hypoxia signalling and metabolic adaptation
Latt S. Mansor (2016)
The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase.
P. Kantor (2000)
Effect of rosiglitazone on cardiac electrophysiology, infarct size and mitochondrial function in ischaemia and reperfusion of swine and rat heart
S. Palee (2011)
Lipoprotein lipase: structure, function, regulation, and role in disease
J. R. Mead (2002)
Fatty acid transporter levels and palmitate oxidation rate correlate with ejection fraction in the infarcted rat heart.
L. Heather (2006)
Glucose and insulin improve cardiac efficiency and postischemic functional recovery in perfused hearts from type 2 diabetic (db/db) mice.
A. Hafstad (2007)
Perhexiline maleate and peripheral neuropathy
P. Bouche (1979)
The efficacy of trimetazidine on stable angina pectoris: a meta-analysis of randomized clinical trials.
Song Peng (2014)

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