Obesityrelated heart disease is characterized by a signature set of cardiac defects generally referred to as lipotoxic cardiomyopathy lcm. While the primary etiology of lipotoxic cardiomyopathy is an elevation of lipid levels resulting from an imbalance in energy availability and expenditure, increasing evidence suggests a relationship between dysregulation of. To characterize cardiac fatty acid fa and triglyceride tg metabolism in these mice and to determine whether changes in lipid metabolism precede cardiac dysfunction, hearts from young mice were perfused in langendorff mode with 14. Accumulationoflipotoxicmetabolites in nonadipocyte tissues may be a major cause of dilated cardiomyopathy in patients. Sphingomyelin, sphingolipids, cardiovascular implications. Pathophysiological mechanisms linking obesity to heart failure. Diabetic cardiomyopathy is a syndrome in which heart failure is not caused by ischemic heart disease or hypertension. Request pdf sphingolipids, lipotoxic cardiomyopathy, and cardiac failure in the setting of obesity and type 2 diabetes mellitus, the ectopic disposition of lipids. The epidemic of obesity and diabetes is causing an increased incidence of dyslipidemiarelated heart failure. They identified several ceramideinteracting proteins, whose subsequent cardiacspecific manipulation can prevent lcm by altering caspase activation. In addition to being structural elements of membranes, many sphingolipids are bioactive and regulate a. The heart is one of the tissues thought to become dysfunctional due to excess lipid accumulation. For full access to this pdf, sign in to an existing account, or purchase an annual subscription.
Phospholipid homeostasis regulates lipid metabolism and. In rodent models of dbcm, cardiac hypertrophy and dysfunction have been shown to depend upon saturated fatty acid sfa oversupply and. Sphingolipids, lipotoxic cardiomyopathy and cardiac failure pablo v. This leads to deterioration of cardiac contractility and disruptions in the cardiac conduction system, which may culminate in heart failure and arrhythmias, respectively.
Aggregated ldl aggldl internalization is mediated by lowdensity lipoprotein receptorrelated protein1 lrp1 promoting intracellular cholesteryl ester ce accumulation. They were discovered in brain extracts in the 1870s and were named after the mythological sphinx because of their enigmatic nature. The accumulation of neutral lipids in or around the myocardium is observed in humans or animal models with nonischemic heart failure, 1,2,22,23 and it is hypothesized that excess lipid contributes to the development of cardiac dysfunction. Sphingolipids are important structural and signaling molecules. Heart failure hf is a leading cause of morbidity and mortality in the united states, and its prevalence continues to rise despite the overall decline in cardiovascular disease cvd related morbidity and mortality. The functions of sphingolipids are still being discovered, but there are at least three, i. Preservation of acyl coenzyme a attenuates pathological.
Ceramides lipotoxic inducers of metabolic disorders. Sphingolipids are found in essentially all animals, plants, and fungi, as well as some prokaryotic organisms and viruses. Endothelial nogob regulates sphingolipid biosynthesis to. However, fatty acid oxidation yields lower atp production. Despite excess of plasma glucose and lipids, the diabetic heart almost exclusively depends on fatty acid degradation. They are mostly in membranes, but are also major constituents of lipoproteins. These compounds play important roles in signal transduction and cell recognition. Direct cardiac lipotoxicity has been described where lipid accumulation in the heart results in cardiac dysfunction inexplicable of other heart failure risk factors. Adenoviral gene transfer of sphingosine kinase 1 protects. The molecular means by which these particular ceramides drive tissue dysfunction has received considerable attention 10. Therefore, an understanding of myocardial energetic metabolism is essential, in order to comprehend the physiologic basis of the therapeutic management of acute and chronic. Request pdf sphingolipids, lipotoxic cardiomyopathy, and cardiac failure in the setting of obesity and type 2 diabetes mellitus, the ectopic disposition of lipids may be a cause of heart failure.
Sphingolipids, lipotoxic cardiomyopathy, and cardiac failure heart failure clinics, vol. The cardiovascular disease cvd frequently developed during metabolic syndrome and type2 diabetes mellitus is associated with increased levels of aggregationprone small ldl particles. Endurance exercise resistance to lipotoxic cardiomyopathy. They serve as biologically active components of cell membrane and are involved. In some models, the capacity for triglyceride accumulation is associated with less myocardial damage and improved cardiac function. Clinical studies have clearly shown a correlation between the accumulation of triglycerides and heart dysfunction. Manifestations and mechanisms of myocardial lipotoxicity. Association between sphingolipids and cardiopulmonary. Obesity may result in heart failure by inducing hemodynamic and myocardial changes that lead to cardiac dysfunction, or due to an increased predisposition to other heart failure risk factors.
Sphingomyelin, ceramide, exercise, cardiovascular disease. Diabetic cardiomyopathy dcm is a serious cardiac dysfunction induced by changes in the structure and contractility of the myocardium that are initiated in part by alterations in energy substrates. Lipotoxic cardiomyopathy lcm is characterized by abnormal myocardial accumulation of lipids, including ceramide. Tg mice demonstrate increased expression of genes involved in glucose and fatty acid metabolism with no evidence of lipid accumulation or cardiac dysfunction. However, whether ceramide is relevant to cardiac failure in humans is unclear. Alteration of energy substrates and ros production in. However, a recent study in mice showed that inhibition of acid sms does not result in improved heart function or survival after an induced mi despite reducing ischaemiainduced ceramide accumulation. Myristate is a novel potential substrate for sphingoid base synthesis. Ceramideprotein interactions modulate ceramideassociated. In obesity and dyslipidemia, the oversupply of fat to tissues not suited for lipid storage induces cellular dysfunction that underlies diabetes and cardiovascular disease i.
In animal models, the ceramide accumulation within the myocardium is responsible for a direct toxic effect on myocardial fibrils, cardiomyocytes apoptosis, and altered cardiac. Several animal models of myocardial lipotoxicity have. Definition of diabetic or lipotoxic cardiomyopathy. Perfusion of hearts with triglyceriderich particles. In the setting of obesity and type 2 diabetes mellitus, the ectopic disposition of lipids may be a cause of heart failure. In recent years, the role of sphingolipids in physiology and pathophysiology of the heart attracted much attention. Lipids, as key players in cellular heat stress management short presentations from abstracts. This might be a reaction to vessel wall injury that accompanies infections, immune disease, and perhaps diabetes and renal failure. Machine learning reveals serum sphingolipids as cholesterol. Sphingolipids, lipotoxic cardiomyopathy, and cardiac failure.
Dilated lipotoxic cardiomyopathy, thought to be the result of diabetes and severe obesity, has been modeled in several genetically altered mice, including. Plasma ceramides and sphingomyelins in relation to heart. Although several key molecular pathways regulating cardiac hypertrophy have been defined 1, 2, not all hypertrophy is detrimental, and a. Cnprc pathologists published the analysis of 20 years of findings on sudden cardiac death in the cnprc rhesus monkeys in the prominent journal comparative medicine april 4, 2016. For example, overexpression of diacylglycerol acyl transferase 1 dgat1 promotes triglyceride accumulation, decreases ceramide accumulation and preserves cardiac function in the acsl1 lipotoxic cardiomyopathy. Lipotoxicity likely contributes to cardiac dysfunction in i obesityrelated and ii diabetic cardiomyopathy, and pathological assessments reveal lipid accumulation in these specimens. Moreover experimental manipulations that promote cardiacspecific lipid accumulation in mice induce cardiac dysfunction. Sphingolipids, lipotoxic cardiomyopathy, and cardiac failure ncbi. Glycolytic enzymes and transporters are impaired by fatty acid metabolism, leading to accumulation of glucose derivatives. Cells free fulltext lrp1mediated aggldl endocytosis. Changes of myocardial lipidomics profiling in a rat model.
Pdf sphingolipids in cardiovascular diseases and metabolic. Dysfunctional lipid metabolism in failing hearts alters acylderivative formation, such as ceramide sphingolipids, that impact cardiac physiology and consequently, disrupt the balance between cardiotoxic and potentially beneficial ceramides. The underlying mechanisms of dcm are still under controversial. Circulating ceramides are inversely associated with. Reader jr, canfield dr, lane jf, kanthaswamy s, ardeshir a. Many investigations suggest the pivotal role of sphingolipids in the pathogenesis of lifestyle diseases such as myocardial infarction, hypertension, stroke, diabetes mellitus type 2 and obesity. Phospholipid homeostasis regulates lipid metabolism and cardiac function through srebp signaling in drosophila huiying lim,1 weidong wang,2 robert j. Of the myriad lipids that accrue under these conditions, sphingolipids such as ceramide or its metabolites are amongst the most deleterious because they disrupt insulin sensitivity. Lipotoxic cardiomyopathy is caused by excessive lipid accumulation in myocardial cells and it is a form of cardiac dysfunction. The role of sphingolipids in the cardiovascular system sphingolipids are components of the cardiomyocytes. Cardiac hypertrophy induced by pressure overload is associated with pathological myocardial and vascular changes that can lead to cardiac dysfunction and, ultimately, heart failure. Cardiomyopathy in obesity, insulin resistance and diabetes. In lipid storage disorders such as niemannpick and sandhoff diseases and gm1 gangliosidosis, metabolic cardiomyopathy was also diagnosed 24.
Sphingolipids are a class of lipids containing a backbone of sphingoid bases, a set of aliphatic amino alcohols that includes sphingosine. Elevated ceramide correlates with lipotoxic cardiomyopathy the accumulation of neutral lipids in or around the myocardium is observed in humans or animal models with nonischemic heart failure,1,2,22,23 and it is hypothesized that excess lipid contributes. Perilipin 2 plin2 is a lipid droplet ldassociated protein. Cardiac overexpression of perilipin 2 induces dynamic. Left ventricular hypertrophy in rhesus macaques macaca mulatta at the california national primate research center 1992 2014. The plasma levels of s1p significantly decreased, but the plasma levels of cer significantly increased at 1 and 6 h after myocardial infarction, but both sphingolipids returned to the control values after 24 h from the cardiac incident. Sphingolipids and their metabolism in physiology and. Some studies suggest that sphingolipids are important factors in cellular signal transduction. Association between sphingolipids and cardiopulmonary fitness in. Pdf the long term benefits conferred by cardiac rehabilitation cr in those with cad are strongly linked with an improvement in cardiopulmonary. The prevalence of hf is 23% of the population in industrialized countries.
Coronary artery disease cad is the most common type of cardiovascular. Dilated lipotoxic cardiomyopathy, thought to be the result of diabetes and severe obesity, has been modeled in several genetically altered mice, including animals with cardiac. Heart sphingolipids in health and disease springerlink. Alteration of sphingolipid biology has recently been correlated with various forms of cardiovascular disease, including atherosclerotic heart disease, cardiomyopathy, heart failure, and hypertension 43 46, suggesting a potential role for sphingolipids in. The observation of lipids, especially lipidomics profiling, can provide an insight into the know.
Jci insight endothelial nogob regulates sphingolipid. Hf in obesity may be due to an increased predisposition to other hf risk factors such as coronary artery disease cad, diabetes mellitus, hypertension, dyslipidemia, insulin resistance ir, metabolic syndrome, kidney disease, obstructive sleep apnea osa, and cardiac conduction abnormalities, or occur solely as a. Cardiac intracellular lipid accumulation steatosis is a pathophysiological phenomenon observed in starvation and diabetes mellitus. Jci ceramide synthase 5 mediates lipidinduced autophagy. Cardiomyopathy in patients with obesity, insulin resistance, or diabetes in the absence of other comorbidities, including hypertension, coronary artery disease and valvular heart disease, is defined as diabetic cardiomyopathy or lipotoxic cardiomyopathy. Hearts with overexpression of anchored lipoprotein lipase lpl by cardiomyocytes hlpl gpi mice develop a lipotoxic cardiomyopathy. Sphingolipids, lipotoxic cardiomyopathy, and cardiac failure taesik park, phda, ira j. In this process, it is likely that there are also changes in the contents of sphingolipids. Goldberg, mdb, introduction obesity is associated with an elevated risk of chronic diseases, including diabetes and cardiovasculardisease. Diabetic cardiomyopathy dbcm, which consists of cardiac hypertrophy and failure in the absence of traditional risk factors, is a major contributor to increased heart failure risk in type 2 diabetes patients. Ceramide was found to be involved in the pathogenesis of cardiac dysfunction in animal models of ischemiareperfusion injury, type 2 diabetes and lipotoxic cardiomyopathy. Classic hallmarks of lcm recapitulated in animal models include left ventricular hypertrophy, diastolic with or without systolic dysfunction, contractile defects, and cardiac steatosis goldberg et al. Sphingolipids in cardiovascular diseases and metabolic.
While the primary etiology of lipotoxic cardiomyopathy is an elevation of lipid levels resulting from an imbalance in energy availability and expenditure, increasing evidence suggests a relationship between dysregulation of membrane phospholipid homeostasis and. These observations strongly support the therapeutic potential of pharmaceuticals targeting sphingolipids, as well as diagnostic tests using the c16c24 ceramide ratio as a marker of risk. Animal experiments suggest that ceramide is implicated in pathogenesis of cardiac dysfunction associated with obesity and diabetes. Association between sphingolipids and cardiopulmonary fitness in coronary artery disease patients undertaking cardiac rehabilitation. Sphingolipids are a major class of lipids, comprising various species with diverse functions. For example, in a lipotoxic cardiomyopathic mouse model with cardiacspecific overexpression of glycosylphosphatidylinositolanchored human lipoprotein lipase, it was observed that ceramide levels increased by 45% compared to control mice. Myocardial sphingoid base synthesis utilizes myristate. Diabetic cardiomyopathy is initiated by alterations in energy substrates.