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  • Metabolic Messengers
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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.

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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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References

  1. Holland, W. L. et al. Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell Metab. 5, 167–179 (2007).

    CAS  PubMed  Google Scholar 

  2. Chaurasia, B. et al. Targeting a ceramide double bond improves insulin resistance and hepatic steatosis. Science 365, 386–392 (2019).

    CAS  PubMed  Google Scholar 

  3. Raichur, S. et al. CerS2 haploinsufficiency inhibits β-oxidation and confers susceptibility to diet-induced steatohepatitis and insulin resistance. Cell Metab. 20, 687–695 (2014).

    CAS  PubMed  Google Scholar 

  4. Kurek, K. et al. Inhibition of ceramide de novo synthesis reduces liver lipid accumulation in rats with nonalcoholic fatty liver disease. Liver Int. 34, 1074–1083 (2014).

    CAS  PubMed  Google Scholar 

  5. Correnti, J. M., Juskeviciute, E., Swarup, A. & Hoek, J. B. Pharmacological ceramide reduction alleviates alcohol-induced steatosis and hepatomegaly in adiponectin knockout mice. Am. J. Physiol. Gastrointest. Liver Physiol. 306, G959–G973 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Kasumov, T. et al. Ceramide as a mediator of non-alcoholic fatty liver disease and associated atherosclerosis. PLoS One 10, e0126910 (2015).

    PubMed  PubMed Central  Google Scholar 

  7. Chen, T. C. et al. An ANGPTL4-ceramide-PKCzeta axis mediates chronic glucocorticoid exposure-induced hepatic steatosis and hypertriglyceridemia in mice. J. Biol. Chem. 294, 9213–9224 (2019).

    CAS  PubMed  Google Scholar 

  8. Dekker, M. J. et al. Inhibition of sphingolipid synthesis improves dyslipidemia in the diet-induced hamster model of insulin resistance: evidence for the role of sphingosine and sphinganine in hepatic VLDL-apoB100 overproduction. Atherosclerosis 228, 98–109 (2013).

    CAS  PubMed  Google Scholar 

  9. Park, T. S., Rosebury, W., Kindt, E. K., Kowala, M. C. & Panek, R. L. Serine palmitoyltransferase inhibitor myriocin induces the regression of atherosclerotic plaques in hyperlipidemic ApoE-deficient mice. Pharmacol. Res. 58, 45–51 (2008).

    CAS  PubMed  Google Scholar 

  10. Glaros, E. N. et al. Myriocin slows the progression of established atherosclerotic lesions in apolipoprotein E gene knockout mice. J. Lipid Res. 49, 324–331 (2008).

    CAS  PubMed  Google Scholar 

  11. Glaros, E. N. et al. Inhibition of atherosclerosis by the serine palmitoyl transferase inhibitor myriocin is associated with reduced plasma glycosphingolipid concentration. Biochem. Pharmacol. 73, 1340–1346 (2007).

    CAS  PubMed  Google Scholar 

  12. Park, T. S. et al. Modulation of lipoprotein metabolism by inhibition of sphingomyelin synthesis in ApoE knockout mice. Atherosclerosis 189, 264–272 (2006).

    CAS  PubMed  Google Scholar 

  13. Hojjati, M. R. et al. Effect of myriocin on plasma sphingolipid metabolism and atherosclerosis in apoE-deficient mice. J. Biol. Chem. 280, 10284–10289 (2005).

    CAS  PubMed  Google Scholar 

  14. Park, T. S. et al. Inhibition of sphingomyelin synthesis reduces atherogenesis in apolipoprotein E-knockout mice. Circulation 110, 3465–3471 (2004).

    CAS  PubMed  Google Scholar 

  15. Park, T. S. et al. Ceramide is a cardiotoxin in lipotoxic cardiomyopathy. J. Lipid Res. 49, 2101–2112 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Ji, R. et al. Increased de novo ceramide synthesis and accumulation in failing myocardium. JCI Insight 2, 82922 (2017).

    PubMed  Google Scholar 

  17. Holland, W. L. et al. Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid-induced ceramide biosynthesis in mice. J. Clin. Invest. 121, 1858–1870 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Vasiliauskaité-Brooks, I. et al. Structural insights into adiponectin receptors suggest ceramidase activity. Nature 544, 120–123 (2017).

    PubMed  PubMed Central  Google Scholar 

  19. Westra, B. Ceramides, Plasma [A Test in Focus]. Mayo Clinic Laboratories https://news.mayomedicallaboratories.com/2016/07/28/ceramides-plasma-a-test-in-focus/ (2016).

  20. Summers, S. A. Could ceramides become the new cholesterol? Cell Metab. 27, 276–280 (2018).

    CAS  PubMed  Google Scholar 

  21. Merrill, A. H. Jr. De novo sphingolipid biosynthesis: a necessary, but dangerous, pathway. J. Biol. Chem. 277, 25843–25846 (2002).

    CAS  PubMed  Google Scholar 

  22. Park, J. W., Park, W. J. & Futerman, A. H. Ceramide synthases as potential targets for therapeutic intervention in human diseases. Biochim. Biophys. Acta 1841, 671–681 (2014).

    CAS  PubMed  Google Scholar 

  23. Hannun, Y. A. & Obeid, L. M. Ceramide: an intracellular signal for apoptosis. Trends Biochem. Sci. 20, 73–77 (1995).

    CAS  PubMed  Google Scholar 

  24. Kolesnick, R. Ceramide: a novel second messenger. Trends Cell Biol. 2, 232–236 (1992).

    CAS  PubMed  Google Scholar 

  25. Obeid, L. M., Linardic, C. M., Karolak, L. A. & Hannun, Y. A. Programmed cell death induced by ceramide. Science 259, 1769–1771 (1993).

    CAS  PubMed  Google Scholar 

  26. Shimabukuro, M. et al. Lipoapoptosis in beta-cells of obese prediabetic fa/fa rats: role of serine palmitoyltransferase overexpression. J. Biol. Chem. 273, 32487–32490 (1998).

    CAS  PubMed  Google Scholar 

  27. Shimabukuro, M., Zhou, Y. T., Levi, M. & Unger, R. H. Fatty acid-induced beta cell apoptosis: a link between obesity and diabetes. Proc. Natl Acad. Sci. USA 95, 2498–2502 (1998).

    CAS  PubMed  Google Scholar 

  28. Summers, S. A., Garza, L. A., Zhou, H. & Birnbaum, M. J. Regulation of insulin-stimulated glucose transporter GLUT4 translocation and Akt kinase activity by ceramide. Mol. Cell. Biol. 18, 5457–5464 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Wang, C. N., O’Brien, L. & Brindley, D. N. Effects of cell-permeable ceramides and tumor necrosis factor-alpha on insulin signaling and glucose uptake in 3T3-L1 adipocytes. Diabetes 47, 24–31 (1998).

    CAS  PubMed  Google Scholar 

  30. Zhou, H., Summers, S. A., Birnbaum, M. J. & Pittman, R. N. Inhibition of Akt kinase by cell-permeable ceramide and its implications for ceramide-induced apoptosis. J. Biol. Chem. 273, 16568–16575 (1998).

    CAS  PubMed  Google Scholar 

  31. Jay, A. G. & Hamilton, J. A. The enigmatic membrane fatty acid transporter CD36: new insights into fatty acid binding and their effects on uptake of oxidized LDL. Prostaglandins Leukot. Essent. Fat. Acids 138, 64–70 (2018).

    CAS  Google Scholar 

  32. Xu, S., Jay, A., Brunaldi, K., Huang, N. & Hamilton, J. A. CD36 enhances fatty acid uptake by increasing the rate of intracellular esterification but not transport across the plasma membrane. Biochemistry 52, 7254–7261 (2013).

    CAS  PubMed  Google Scholar 

  33. Jiang, C. et al. Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease. J. Clin. Invest. 125, 386–402 (2015).

    PubMed  Google Scholar 

  34. Hyde, R., Hajduch, E., Powell, D. J., Taylor, P. M. & Hundal, H. S. Ceramide down-regulates System A amino acid transport and protein synthesis in rat skeletal muscle cells. FASEB J. 19, 461–463 (2005).

    CAS  PubMed  Google Scholar 

  35. Finicle, B. T. et al. Sphingolipids inhibit endosomal recycling of nutrient transporters by inactivating ARF6. J. Cell Sci. 131, jcs213314 (2018).

    PubMed  PubMed Central  Google Scholar 

  36. Guenther, G. G. et al. Ceramide starves cells to death by downregulating nutrient transporter proteins. Proc. Natl Acad. Sci. USA 105, 17402–17407 (2008).

    CAS  PubMed  Google Scholar 

  37. Edinger, A. L. Starvation in the midst of plenty: making sense of ceramide-induced autophagy by analysing nutrient transporter expression. Biochem. Soc. Trans. 37, 253–258 (2009).

    CAS  PubMed  Google Scholar 

  38. Cowart, L. A. & Obeid, L. M. Yeast sphingolipids: recent developments in understanding biosynthesis, regulation, and function. Biochim. Biophys. Acta 1771, 421–431 (2007).

    CAS  PubMed  Google Scholar 

  39. Chung, N., Mao, C., Heitman, J., Hannun, Y. A. & Obeid, L. M. Phytosphingosine as a specific inhibitor of growth and nutrient import in Saccharomyces cerevisiae. J. Biol. Chem. 276, 35614–35621 (2001).

    CAS  PubMed  Google Scholar 

  40. Kogot-Levin, A. & Saada, A. Ceramide and the mitochondrial respiratory chain. Biochimie 100, 88–94 (2014).

    CAS  PubMed  Google Scholar 

  41. Zigdon, H. et al. Ablation of ceramide synthase 2 causes chronic oxidative stress due to disruption of the mitochondrial respiratory chain. J. Biol. Chem. 288, 4947–4956 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Turpin, S. M. et al. Obesity-induced CerS6-dependent C16:0 ceramide production promotes weight gain and glucose intolerance. Cell Metab. 20, 678–686 (2014).

    CAS  PubMed  Google Scholar 

  43. Hajduch, E. et al. Targeting of PKCzeta and PKB to caveolin-enriched microdomains represents a crucial step underpinning the disruption in PKB-directed signalling by ceramide. Biochem. J. 410, 369–379 (2008).

    CAS  PubMed  Google Scholar 

  44. Powell, D. J., Hajduch, E., Kular, G. & Hundal, H. S. Ceramide disables 3-phosphoinositide binding to the pleckstrin homology domain of protein kinase B (PKB)/Akt by a PKCzeta-dependent mechanism. Mol. Cell. Biol. 23, 7794–7808 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Bourbon, N. A., Sandirasegarane, L. & Kester, M. Ceramide-induced inhibition of Akt is mediated through protein kinase Czeta: implications for growth arrest. J. Biol. Chem. 277, 3286–3292 (2002).

    CAS  PubMed  Google Scholar 

  46. Xia, J. Y. et al. Targeted induction of ceramide degradation leads to improved systemic metabolism and reduced hepatic steatosis. Cell Metab. 22, 266–278 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Taniguchi, C. M. et al. Divergent regulation of hepatic glucose and lipid metabolism by phosphoinositide 3-kinase via Akt and PKClambda/zeta. Cell Metab. 3, 343–353 (2006).

    CAS  PubMed  Google Scholar 

  48. Blouin, C. M. et al. Plasma membrane subdomain compartmentalization contributes to distinct mechanisms of ceramide action on insulin signaling. Diabetes 59, 600–610 (2010).

    CAS  PubMed  Google Scholar 

  49. Stratford, S., Hoehn, K. L., Liu, F. & Summers, S. A. Regulation of insulin action by ceramide: dual mechanisms linking ceramide accumulation to the inhibition of Akt/protein kinase B. J. Biol. Chem. 279, 36608–36615 (2004).

    CAS  PubMed  Google Scholar 

  50. Chavez, J. A. & Summers, S. A. Characterizing the effects of saturated fatty acids on insulin signaling and ceramide and diacylglycerol accumulation in 3T3-L1 adipocytes and C2C12 myotubes. Arch. Biochem. Biophys. 419, 101–109 (2003).

    CAS  PubMed  Google Scholar 

  51. Russo, S. B. et al. Ceramide synthase 5 mediates lipid-induced autophagy and hypertrophy in cardiomyocytes. J. Clin. Invest. 122, 3919–3930 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Westermann, B. Bioenergetic role of mitochondrial fusion and fission. Biochim. Biophys. Acta 1817, 1833–1838 (2012).

    CAS  PubMed  Google Scholar 

  53. Hammerschmidt, P. et al. CerS6-derived sphingolipids interact with MFF and promote mitochondrial fragmentation in obesity. Cell 177, 1536–1552.e1523 (2019).

    CAS  PubMed  Google Scholar 

  54. Smith, M. E. et al. Mitochondrial fission mediates ceramide-induced metabolic disruption in skeletal muscle. Biochem. J. 456, 427–439 (2013).

    CAS  PubMed  Google Scholar 

  55. Ehehalt, R. et al. Uptake of long chain fatty acids is regulated by dynamic interaction of FAT/CD36 with cholesterol/sphingolipid enriched microdomains (lipid rafts). BMC Cell Biol. 9, 45 (2008).

    PubMed  PubMed Central  Google Scholar 

  56. Pohl, J. et al. Long-chain fatty acid uptake into adipocytes depends on lipid raft function. Biochemistry 43, 4179–4187 (2004).

    CAS  PubMed  Google Scholar 

  57. Covey, S. D. et al. Cholesterol depletion inhibits fatty acid uptake without affecting CD36 or caveolin-1 distribution in adipocytes. Biochem. Biophys. Res. Commun. 355, 67–71 (2007).

    CAS  PubMed  Google Scholar 

  58. Chaurasia, B., Holland, W. L. & Summers, S. A. Does this Schlank make me look fat? Trends Endocrinol. Metab. 29, 597–599 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Sociale, M. et al. Ceramide synthase Schlank is a transcriptional regulator adapting gene expression to energy requirements. Cell Rep. 22, 967–978 (2018).

    CAS  PubMed  Google Scholar 

  60. Marra, F. & Svegliati-Baroni, G. Lipotoxicity and the gut-liver axis in NASH pathogenesis. J. Hepatol. 68, 280–295 (2018).

    CAS  PubMed  Google Scholar 

  61. Alkhouri, N., Dixon, L. J. & Feldstein, A. E. Lipotoxicity in nonalcoholic fatty liver disease: not all lipids are created equal. Expert Rev. Gastroenterol. Hepatol. 3, 445–451 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Hoekstra, D. Ceramide-mediated apoptosis of hepatocytes in vivo: a matter of the nucleus? J. Hepatol. 31, 161–164 (1999).

    CAS  PubMed  Google Scholar 

  63. Nikolova-Karakashian, M. Sphingolipids at the crossroads of NAFLD and senescence. Adv. Cancer Res. 140, 155–190 (2018).

    PubMed  Google Scholar 

  64. Garcia-Ruiz, C., Marí, M., Colell, A., Morales, A. & Fernandez-Checa, J. C. Metabolic therapy: lessons from liver diseases. Curr. Pharm. Des. 17, 3933–3944 (2011).

    CAS  PubMed  Google Scholar 

  65. Brown, M. S. & Goldstein, J. L. Selective versus total insulin resistance: a pathogenic paradox. Cell Metab. 7, 95–96 (2008).

    CAS  PubMed  Google Scholar 

  66. Ussher, J. R. et al. Inhibition of de novo ceramide synthesis reverses diet-induced insulin resistance and enhances whole-body oxygen consumption. Diabetes 59, 2453–2464 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Yang, G. et al. Central role of ceramide biosynthesis in body weight regulation, energy metabolism, and the metabolic syndrome. Am. J. Physiol. Endocrinol. Metab. 297, E211–E224 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Blachnio-Zabielska, A. U. et al. Inhibition of ceramide de novo synthesis affects adipocytokine secretion and improves systemic and adipose tissue insulin sensitivity. Int. J. Mol. Sci. 19, E3995 (2018).

    PubMed  Google Scholar 

  69. Zhang, Q. J. et al. Ceramide mediates vascular dysfunction in diet-induced obesity by PP2A-mediated dephosphorylation of the eNOS-Akt complex. Diabetes 61, 1848–1859 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Chaurasia, B. et al. Adipocyte ceramides regulate subcutaneous adipose browning, inflammation, and metabolism. Cell Metab. 24, 820–834 (2016).

    CAS  PubMed  Google Scholar 

  71. Turpin-Nolan, S. M. et al. CerS1-derived C18:0 ceramide in skeletal muscle promotes obesity-induced insulin resistance. Cell Rep. 26, 1–10.e17 (2019).

    CAS  PubMed  Google Scholar 

  72. Stancevic, B. & Kolesnick, R. Ceramide-rich platforms in transmembrane signaling. FEBS Lett. 584, 1728–1740 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Mantovani, A. et al. Association of plasma ceramides with myocardial perfusion in patients with coronary artery disease undergoing stress myocardial perfusion scintigraphy. Arterioscler. Thromb. Vasc. Biol. 38, 2854–2861 (2018).

    CAS  PubMed  Google Scholar 

  74. Anroedh, S. et al. Plasma concentrations of molecular lipid species predict long-term clinical outcome in coronary artery disease patients. J. Lipid Res. 59, 1729–1737 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Hilvo, M. et al. PCSK9 inhibition alters the lipidome of plasma and lipoprotein fractions. Atherosclerosis 269, 159–165 (2018).

    CAS  PubMed  Google Scholar 

  76. Havulinna, A. S. et al. Circulating ceramides predict cardiovascular outcomes in the population-based FINRISK 2002 Cohort. Arterioscler. Thromb. Vasc. Biol. 36, 2424–2430 (2016).

    CAS  PubMed  Google Scholar 

  77. Laaksonen, R. et al. Plasma ceramides predict cardiovascular death in patients with stable coronary artery disease and acute coronary syndromes beyond LDL-cholesterol. Eur. Heart J. 37, 1967–1976 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Tarasov, K. et al. Molecular lipids identify cardiovascular risk and are efficiently lowered by simvastatin and PCSK9 deficiency. J. Clin. Endocrinol. Metab. 99, E45–E52 (2014).

    PubMed  Google Scholar 

  79. Cheng, J. M. et al. Plasma concentrations of molecular lipid species in relation to coronary plaque characteristics and cardiovascular outcome: results of the ATHEROREMO-IVUS study. Atherosclerosis 243, 560–566 (2015).

    CAS  PubMed  Google Scholar 

  80. Yu, J. et al. Ceramide is upregulated and associated with mortality in patients with chronic heart failure. Can. J. Cardiol. 31, 357–363 (2015).

    PubMed  Google Scholar 

  81. Pan, W. et al. Elevation of ceramide and activation of secretory acid sphingomyelinase in patients with acute coronary syndromes. Coron. Artery Dis. 25, 230–235 (2014).

    PubMed  Google Scholar 

  82. Lemaitre, R. N. et al. Circulating sphingolipids, insulin, HOMA-IR and HOMA-B: the Strong Heart Family Study. Diabetes 67, 1663–1672 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Jensen, P. N. et al. Circulating sphingolipids, fasting glucose, and impaired fasting glucose: the Strong Heart Family Study. EBioMedicine 41, 44–49 (2019).

    PubMed  Google Scholar 

  84. Lemaitre, R. N. et al. Circulating sphingolipids, insulin, HOMA-IR, and HOMA-b: the Strong Heart Family Study. Diabetes 67, 1663–1672 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Bergman, B. C. et al. Serum sphingolipids: relationships to insulin sensitivity and changes with exercise in humans. Am. J. Physiol. Endocrinol. Metab. 309, E398–E408 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Haus, J. M. et al. Plasma ceramides are elevated in obese subjects with type 2 diabetes and correlate with the severity of insulin resistance. Diabetes 58, 337–343 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Boon, J. et al. Ceramides contained in LDL are elevated in type 2 diabetes and promote inflammation and skeletal muscle insulin resistance. Diabetes 62, 401–410 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Lopez, X., Goldfine, A. B., Holland, W. L., Gordillo, R. & Scherer, P. E. Plasma ceramides are elevated in female children and adolescents with type 2 diabetes. J. Pediatr. Endocrinol. Metab. 26, 995–998 (2013).

    CAS  PubMed  Google Scholar 

  89. Brozinick, J. T. et al. Plasma sphingolipids are biomarkers of metabolic syndrome in non-human primates maintained on a Western-style diet. Int. J. Obes. (Lond.) 37, 1064–1070 (2013).

    CAS  Google Scholar 

  90. Warshauer, J. T. et al. Effect of pioglitazone on plasma ceramides in adults with metabolic syndrome. Diabetes Metab. Res. Rev. 31, 734–744 (2015).

    CAS  PubMed  Google Scholar 

  91. Wigger, L. et al. Plasma dihydroceramides are diabetes susceptibility biomarker candidates in mice and humans. Cell Rep. 18, 2269–2279 (2017).

    CAS  PubMed  Google Scholar 

  92. Luukkonen, P. K. et al. Hepatic ceramides dissociate steatosis and insulin resistance in patients with non-alcoholic fatty liver disease. J. Hepatol. 64, 1167–1175 (2016).

    CAS  PubMed  Google Scholar 

  93. Luukkonen, P. K. et al. Saturated fat is more metabolically harmful for the human liver than unsaturated fat or simple sugars. Diabetes Care 41, 1732–1739 (2018).

    CAS  PubMed  Google Scholar 

  94. Amati, F. et al. Skeletal muscle triglycerides, diacylglycerols, and ceramides in insulin resistance: another paradox in endurance-trained athletes? Diabetes 60, 2588–2597 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Coen, P. M. et al. Insulin resistance is associated with higher intramyocellular triglycerides in type I but not type II myocytes concomitant with higher ceramide content. Diabetes 59, 80–88 (2010).

    CAS  PubMed  Google Scholar 

  96. Coen, P. M. & Goodpaster, B. H. Role of intramyocelluar lipids in human health. Trends Endocrinol. Metab. 23, 391–398 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Coen, P. M. et al. Reduced skeletal muscle oxidative capacity and elevated ceramide but not diacylglycerol content in severeobesity. Obes. (Silver Spring) 21, 2362–2371 (2013).

    CAS  Google Scholar 

  98. Dubé, J. J. et al. Effects of weight loss and exercise on insulin resistance, and intramyocellular triacylglycerol, diacylglycerol and ceramide. Diabetologia 54, 1147–1156 (2011).

    PubMed  PubMed Central  Google Scholar 

  99. Adams, J. M. II et al. Ceramide content is increased in skeletal muscle from obese insulin-resistant humans. Diabetes 53, 25–31 (2004).

    CAS  PubMed  Google Scholar 

  100. Othman, A. et al. Plasma 1-deoxysphingolipids are predictive biomarkers for type 2 diabetes mellitus. BMJ Open Diabetes Res. Care 3, e000073 (2015).

    PubMed  PubMed Central  Google Scholar 

  101. Othman, A. et al. Plasma deoxysphingolipids: a novel class of biomarkers for the metabolic syndrome? Diabetologia 55, 421–431 (2012).

    CAS  PubMed  Google Scholar 

  102. Mwinyi, J. et al. Plasma 1-deoxysphingolipids are early predictors of incident type 2 diabetes mellitus. PLoS One 12, e0175776 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Khan, A. & Hornemann, T. Correlation of the plasma sphingoid base profile with results from oral glucose tolerance tests in gestational diabetes mellitus. EXCLI J. 16, 497–509 (2017).

    PubMed  PubMed Central  Google Scholar 

  104. Bertea, M. et al. Deoxysphingoid bases as plasma markers in diabetes mellitus. Lipids Health Dis. 9, 84 (2010).

    PubMed  PubMed Central  Google Scholar 

  105. Russo, S. B., Tidhar, R., Futerman, A. H. & Cowart, L. A. Myristate-derived d16:0 sphingolipids constitute a cardiac sphingolipid pool with distinct synthetic routes and functional properties. J. Biol. Chem. 288, 13397–13409 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Skovbro, M. et al. Human skeletal muscle ceramide content is not a major factor in muscle insulin sensitivity. Diabetologia 51, 1253–1260 (2008).

    CAS  PubMed  Google Scholar 

  107. Petersen, M. C. & Shulman, G. I. Roles of diacylglycerols and ceramides in hepatic insulin resistance. Trends Pharmacol. Sci. 38, 649–665 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Itani, S. I., Ruderman, N. B., Schmieder, F. & Boden, G. Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IκB-alpha. Diabetes 51, 2005–2011 (2002).

    CAS  PubMed  Google Scholar 

  109. Szendroedi, J. et al. Role of diacylglycerol activation of PKCθ in lipid-induced muscle insulin resistance in humans. Proc. Natl Acad. Sci. USA 111, 9597–9602 (2014).

    CAS  PubMed  Google Scholar 

  110. Nowotny, B. et al. Mechanisms underlying the onset of oral lipid-induced skeletal muscle insulin resistance in humans. Diabetes 62, 2240–2248 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Petersen, M. C. & Jurczak, M. J. CrossTalk opposing view: intramyocellular ceramide accumulation does not modulate insulin resistance. J. Physiol. (Lond.) 594, 3171–3174 (2016).

    CAS  Google Scholar 

  112. Summers, S. A. & Goodpaster, B. H. CrossTalk proposal: intramyocellular ceramide accumulation does modulate insulin resistance. J. Physiol. (Lond.) 594, 3167–3170 (2016).

    CAS  Google Scholar 

  113. Holland, W. L. & Scherer, P. E. PAQRs: a counteracting force to ceramides? Mol. Pharmacol. 75, 740–743 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Blachnio-Zabielska, A. U., Koutsari, C., Tchkonia, T. & Jensen, M. D. Sphingolipid content of human adipose tissue: relationship to adiponectin and insulin resistance. Obes. (Silver Spring) 20, 2341–2347 (2012).

    CAS  Google Scholar 

  115. de Mello, V. D. et al. Link between plasma ceramides, inflammation and insulin resistance: association with serum IL-6 concentration in patients with coronary heart disease. Diabetologia 52, 2612–2615 (2009).

    CAS  PubMed  Google Scholar 

  116. Sims, K. et al. Kdo2-lipid A, a TLR4-specific agonist, induces de novo sphingolipid biosynthesis in RAW264.7 macrophages, which is essential for induction of autophagy. J. Biol. Chem. 285, 38568–38579 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Schilling, J. D. et al. Palmitate and lipopolysaccharide trigger synergistic ceramide production in primary macrophages. J. Biol. Chem. 288, 2923–2932 (2013).

    CAS  PubMed  Google Scholar 

  118. Shi, H. et al. TLR4 links innate immunity and fatty acid-induced insulin resistance. J. Clin. Invest. 116, 3015–3025 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Kim, J. K. et al. Prevention of fat-induced insulin resistance by salicylate. J. Clin. Invest. 108, 437–446 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Cai, D. et al. Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB. Nat. Med. 11, 183–190 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Majumdar, I. & Mastrandrea, L. D. Serum sphingolipids and inflammatory mediators in adolescents at risk for metabolic syndrome. Endocrine 41, 442–449 (2012).

    CAS  PubMed  Google Scholar 

  122. Gonzalez, F. J., Jiang, C., Xie, C. & Patterson, A. D. Intestinal farnesoid X receptor signalling modulates metabolic disease. Dig. Dis. 35, 178–184 (2017).

    PubMed  PubMed Central  Google Scholar 

  123. Xie, C. et al. An intestinal farnesoid X receptor-ceramide signaling axis modulates hepatic gluconeogenesis in mice. Diabetes 66, 613–626 (2017).

    CAS  PubMed  Google Scholar 

  124. Gonzalez, F. J., Jiang, C. & Patterson, A. D. An intestinal microbiota-farnesoid X receptor axis modulates metabolic disease. Gastroenterology 151, 845–859 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Jiang, C. et al. Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction. Nat. Commun. 6, 10166 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Curran, J. E. et al. 63rd Annual Meeting Am. Soc. Hum. Genet. https://www.ashg.org/2013meeting/abstracts/fulltext/f130122450.htm (2013).

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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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  2. Bhagirath Chaurasia
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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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