Ceramide is a cardiotoxin in lipotoxic cardiomyopathy

Park, Tae Sik; Hu, Yixin; Noh, Hye Lim; Drosatos, Konstantinos; Okajima, Kazue; Buchanan, Jonathan; Tuinei, Joseph; Homma, Shunichi; Jiang, Xian Cheng; Abel, E. Dale; Goldberg, Ira J.

doi:10.1194/jlr.m800147-jlr200

Cited by 342 publications

(302 citation statements)

References 57 publications

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“…Genetic and pharmacological interventions that decrease total plasma ceramides prevent diet‐ and glucocorticoid‐induced insulin resistance, atherosclerosis, and metabolic cardiomyopathy in mice 2, 3, 4. These studies provided early evidence that total ceramides might serve as a useful diagnostic tool or therapeutic target.…”

Section: Introductionmentioning

confidence: 95%

Ceramide Remodeling and Risk of Cardiovascular Events and Mortality

Peterson

Xanthakis

Duncan

et al. 2018

JAHA

119

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BackgroundRecent studies suggest that circulating concentrations of specific ceramide species may be associated with coronary risk and mortality. We sought to determine the relations between the most abundant plasma ceramide species of differing acyl chain lengths and the risk of coronary heart disease (CHD) and mortality in community‐based samples.Methods and ResultsWe developed a liquid chromatography/mass spectrometry assay to quantify plasma C24:0, C22:0, and C16:0 ceramides and ratios of these very–long‐chain/long‐chain ceramides in 2642 FHS (Framingham Heart Study) participants and in 3134 SHIP (Study of Health in Pomerania) participants. Over a mean follow‐up of 6 years in FHS, there were 88 CHD and 90 heart failure (HF) events and 239 deaths. Over a median follow‐up time in SHIP of 5.75 years for CHD and HF and 8.24 years for mortality, there were 209 CHD and 146 HF events and 377 deaths. In meta‐analysis of the 2 cohorts and adjusting for standard CHD risk factors, C24:0/C16:0 ceramide ratios were inversely associated with incident CHD (hazard ratio per average SD increment, 0.79; 95% confidence interval, 0.71–0.89; P<0.0001) and inversely associated with incident HF (hazard ratio, 0.78; 95% confidence interval, 0.61–1.00; P=0.046). Moreover, the C24:0/C16:0 and C22:0/C16:0 ceramide ratios were inversely associated with all‐cause mortality (C24:0/C16:0: hazard ratio, 0.60; 95% confidence interval, 0.56–0.65; P<0.0001; C22:0/C16:0: hazard ratio, 0.65; 95% confidence interval, 0.60–0.70; P<0.0001).ConclusionsThe ratio of C24:0/C16:0 ceramides in blood may be a valuable new biomarker of CHD risk, HF risk, and all‐cause mortality in the community.

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Section: Introductionmentioning

confidence: 95%

Ceramide Remodeling and Risk of Cardiovascular Events and Mortality

Peterson

Xanthakis

Duncan

et al. 2018

JAHA

119

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“…3 Ultimately, however, increased lipid accumulation in islets causes dysfunction and death of nonadipocytes through lipoapoptosis. [6][7][8] The loss of b-cells ultimately leads to overt T2DM. 7 In Zucker diabetic fatty (ZDF) rats, a model of genetic obesity with T2DM, b-cell loss and hyperglycemia appear within 4 weeks of the accumulation of excess islet fat.…”

Section: Introductionmentioning

confidence: 99%

Pancreatic steatosis: harbinger of type 2 diabetes in obese rodents

et al. 2009

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Objective: The aim of this study was to determine if the fat accumulation in the exocrine pancreas fat of obese Zucker diabetic fatty (ZDF) rodents, like that in their endocrine pancreas, precedes the onset of type 2 diabetes mellitus (T2DM). As the fat content of whole pancreas, but not islets, can now be measured in humans by magnetic resonance spectroscopy (MRS), such measurements could be used as a predictor of impending T2DM and an indication for preventive intervention. Animals: Obese ZDF (fa/fa) rats and lean ( þ / þ ) controls on a 6% fat diet were killed at time points from 6 to 16 weeks and total pancreatic fat was measured biochemically and electronmicroscopic examination of tissue for fat droplets was carried out. Results: Compared to lean ZDF controls, pancreatic fat was elevated above lean controls from 6 to 16 weeks of age, peaking at 10 weeks of age when hyperglycemia first appeared. The pancreatic profile of fat content in whole pancreas paralleled that of islets. Electronmicroscopic examination identified the acinar location of the fat droplets and ruled out a major contribution of intrapancreatic adipocytes. Conclusion: The almost identical pattern of triglyceride overaccumulation in the exocrine and endocrine pancreas of obese rodents before the onset of T2DM suggests that MRS of the human pancreas might predict T2DM in obese subjects and permit timely interventions to prevent the disease.

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“…For the cardiomyocyte metabolism, fatty acid plays an important role however detrimental effect is induced due to the imbalance of cellular uptake and usage results in lipid accumulation [23,24]. Indeed, the main cause of lipotoxicity in heart is known due to ceramide metabolized from free fatty acid (FFA) [25]. In addition, high cholesterol increased the incidence of coronary heart disease compared to the polyunsaturated fatty acid [26][27][28][29].…”

Section: Lipotoxicity In Pathogenesis Of Heartmentioning

confidence: 99%

“…Thus, obesity increases intracellular lipid leading to diabetes. Enhanced by WD via O-GlcNAcylation of autophagy proteins [80] Inhibition protects against FA-induced cell death in endothelium [81] Ceramide Enhances PP2A-eNOS mediated endothelial dysfunction [82] Inhibition protects against FA-induced cell death [25,83] ER stress Enhanced by FA-induced activation of Ca 2+ -mediated activation of BCL-2, BAX, and BAK [22] Leptin Treatment protects against cardiac dysfunction by reducing lipid accumulation and restoring PPAR signaling [84] Lipid (TG) storage…”

Section: Apoptotic Pathwaysmentioning

confidence: 99%

“…In addition, declining of fatty acid and elevation of glucose oxidation in lipoprotein lipase (LpL)-overexpressed heart by blocking of SPT reduced the cardiac sphingomyelin and ceramide and then inally improved systolic function and survival was prolonged [25]. Therefore, reduction of the ceramide might be the selective target of the drug for the treatment of lipid-induced heart disease in obese and diabetic patients.…”

Section: Apoptotic Pathwaysmentioning

confidence: 99%

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Lipid-induced cardiovascular diseases

Manandhar¹,

Ju²,

Choi³

et al. 2017

J Cardiol Cardiovasc Med

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Cardiovascular diseases are the leading cause of death worldwide. There are many evidences that the dysfunctioning lipotoxicity is the one of major factors of cardiovascular diseases such as, atherosclerosis, hypertension, and coronary heart disease. Obesity and diabetes increase circulating lipids that are likely with more generation of toxic intermediates, which leading to the complications associated with cardiovascular diseases. Indeed, lipotoxicity is a metabolic syndrome caused by abnormal lipid accumulation, which leads to cellular dysfunction and necrosis. Here we review the factors that induced pathogenesis of cardiovascular diseases by lipid accumulation and the mechanisms underlying the lipotoxicity.

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Ceramide is a cardiotoxin in lipotoxic cardiomyopathy

Cited by 342 publications

References 57 publications

Ceramide Remodeling and Risk of Cardiovascular Events and Mortality

Ceramide Remodeling and Risk of Cardiovascular Events and Mortality

Pancreatic steatosis: harbinger of type 2 diabetes in obese rodents

Lipid-induced cardiovascular diseases

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