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Metabolic Messengers: ceramides

Nature Metabolism volume 1, pages 1051–1058 (2019)Cite this article

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Abstract

Ceramides are products of metabolism that accumulate in individuals with obesity or dyslipidaemia and alter cellular processes in response to fuel surplus. Their actions, when prolonged, elicit the tissue dysfunction that underlies diabetes and heart disease. Here, we review the history of research on these enigmatic molecules, exploring their discovery and mechanisms of action, the evolutionary pressures that have given them their unique attributes and the potential of ceramide-reduction therapies as treatments for cardiometabolic disease.

The accumulation of ectopic lipid metabolites in tissues not suited for fat storage drives the cellular dysfunction that underlies diabetes and heart disease. Of the numerous types of lipids that accumulate, sphingolipids such as ceramides are amongst the most deleterious, because they modulate signalling and metabolic pathways driving insulin resistance, triglyceride production, apoptosis and fibrosis. Inhibition of ceramide biosynthesis in rodents ameliorates insulin resistance1,2, hepatic steatosis1,2,3,4,5,6,7, hypertriglyceridemia1,2,8, atherosclerosis9,10,11,12,13,14, type 2 diabetes1 and heart failure15,16. Moreover, ceramide degradation is a primary means by which adiponectin receptors, which are ligand-activated ceramidases, exert their anti-diabetic, cardioprotective and insulin-sensitizing actions17,18. Owing to a strong association between serum ceramides and both insulin resistance and major adverse cardiac events, the Mayo Clinic is now marketing tests to measure circulating ceramides as markers of cardiovascular mortality19,20. Here, we review the history of research on these important molecules and discuss the evolutionary pressures that may have endowed them with such important roles as signals of lipid overload.

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Fig. 1: Discovery of ceramides as metabolic messengers.
Fig. 2: Ceramides as signals of lipid excess.
Fig. 3: Target tissues and metabolic activities of ceramides.

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Acknowledgements

The authors receive research support from the National Institutes of Health (DK112826 and DK108833 to W.L.H. and DK115824 and DK116450 to S.A.S.), the Juvenile Diabetes Research Foundation (JDRF 3-SRA-2019-768-A-B to W.L.H.), the American Diabetes Association (to S.A.S.), the American Heart Association (to S.A.S.), the Margolis Foundation (to S.A.S.) and the USDA (2019-67018-29250 to B.C.). B.C. received a pilot grant from the Diabetes Research Center at Washington University in St. Louis from the NIH under award number P30DK020579.

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  1. Department of Nutrition and Integrative Physiology and the Diabetes and Metabolism Center, University of Utah, Salt Lake City, UT, USA

    Scott A. Summers, Bhagirath Chaurasia & William L. Holland

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  1. Scott A. Summers
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Correspondence to Scott A. Summers.

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S.A.S. is a co-founder and consultant for Centaurus Therapeutics.

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Peer review information Primary Handling Editor: Pooja Jha.

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Summers, S.A., Chaurasia, B. & Holland, W.L. Metabolic Messengers: ceramides. Nat Metab 1, 1051–1058 (2019). https://doi.org/10.1038/s42255-019-0134-8

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