ArticleFASEB journal : official publication of the Federation of American Societies for Experimental Biology2018
Lipotoxic very-long-chain ceramides cause mitochondrial dysfunction, oxidative stress, and cell death in cardiomyocytes.
Article in FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 140 papers, 1 of them a synthesis that pooled it.
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Who cites it
140 citing papers in PubMed, 1 synthesis or guideline pooled it, 210 citations in OpenAlex.
- Ceramide Remodeling and Risk of Cardiovascular Events and Mortality.Journal of the American Heart Association · 2018Pooled it
- Novel Insight in Idiopathic Normal Pressure Hydrocephalus (iNPH) Biomarker Discovery in CSF.International journal of molecular sciences · 2021Trial
- Alterations in plasma triglycerides and ceramides: links with cardiac function in humans with type 2 diabetes.Journal of lipid research · 2020Trial
- Integrative multi-omics Mendelian randomization reveals key lipid metabolism genes as therapeutic targets for diabetic nephropathy pathogenesis.Renal failure · 2026Article
- CerS2-mediated lipotoxicity and calcium signaling: a novel sequential mechanism of apoptosis in cancer.The Biochemical journal · 2026Review
- Reversing diastolic dysfunction in diabetes: a mitochondrial quality control-centric pharmacological approach.Acta diabetologica · 2026Review
- Sphingolipids and Atherosclerosis.Current atherosclerosis reports · 2026Review
- Diet-Associated Regulation of Cardiac Metabolism: Molecular Determinants and Pathophysiological Consequences.Nutrients · 2026Review
- Bioenergetic failure in diabetic peripheral neuropathy: from glucotoxicity to multidimensional metabolic imbalance.Journal of neurology · 2026Review
- Cardiac Lipid Metabolism: Cells, Metabolites, and Rhythms.Circulation research · 2026Review
- Elevated Circulating Ceramides 18:0 and 24:1 as a Risk Factor for Sarcopenia: In Vitro, Animal, and Clinical Evidence.Journal of cachexia, sarcopenia and muscle · 2026Article
- Catestatin restores cardiac metabolic flexibility and enhances mitochondrial function.Communications biology · 2026Article
- Modulation of the gut-heart axis by exercise in diabetic cardiomyopathy: Microbial mechanisms and clinical implications.iScience · 2026Review
- Lipid droplets beyond storage: Cellular metabolic modulator in the diabetic heart (Review).International journal of molecular medicine · 2026Review
- Lipotoxicity in Diabetic Cardiomyopathy: Molecular Basis and Emerging Therapeutic Targets.International journal of molecular sciences · 2026Review
- Detergents without a drain: the evolutionary logic (and liability) of sphingolipids.Journal of lipid research · 2026Review
- Effect of fat deposition on placental function in Shaziling sows and modulation by resveratrol.Animal nutrition (Zhongguo xu mu shou yi xue hui) · 2026Article
- Integrative insights into fatty acid metabolism in diabetic cardiomyopathy: From molecular mechanisms to therapeutic strategies.iScience · 2026Review
- Sphingolipids in Emotional Well-Being.Journal of neurochemistry · 2026Review
- Biomarkers of Cardiac Metabolic Flexibility in Health, HFrEF and HFpEF.International journal of molecular sciences · 2026Review
80 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
Abstract
Accumulating data support a role for bioactive lipids as mediators of lipotixicity in cardiomyocytes. One class of these, the ceramides, constitutes a family of molecules that differ in structure and are synthesized by distinct enzymes, ceramide synthase (CerS)1-CerS6. Data support that specific ceramides and the enzymes that catalyze their formation play distinct roles in cell function. In a mouse model of diabetic cardiomyopathy, sphingolipid profiling revealed increases in not only the CerS5-derived ceramides but also in very long chain (VLC) ceramides derived from CerS2. Overexpression of CerS2 elevated VLC ceramides caused insulin resistance, oxidative stress, mitochondrial dysfunction, and mitophagy. Palmitate induced CerS2 and oxidative stress, mitophagy, and apoptosis, which were prevented by depletion of CerS2. Neither overexpression nor knockdown of CerS5 had any function in these processes, suggesting a chain-length dependent impact of ceramides on mitochondrial function. This concept was also supported by the observation that synthetic mitochondria-targeted ceramides led to mitophagy in a manner proportional to N-acyl chain length. Finally, blocking mitophagy exacerbated cell death. Taken together, our results support a model by which CerS2 and VLC ceramides have a distinct role in lipotoxicity, leading to mitochondrial damage, which results in subsequent adaptive mitophagy. Our data reveal a novel lipotoxic pathway through CerS2.-Law, B. A., Liao, X., Moore, K. S., Southard, A., Roddy, P., Ji, R., Szulc, Z., Bielawska, A., Schulze, P. C., Cowart, L. A. Lipotoxic very-long-chain ceramides cause mitochondrial dysfunction, oxidative stress, and cell death in cardiomyocytes.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.