Sphingolipids and their metabolism in physiology and disease

Key Points

  • Bioactive sphingolipids constitute a family of lipids, including sphingosine, ceramide, sphingosine-1-phosphate (S1P) and ceramide-1-phosphate. These molecules act on distinct protein targets, including kinases, phosphatases, lipases and other enzymes and membrane receptors, and they exert distinct cellular functions.

  • This universe of sphingolipids, the sphingolipidome, is highly complex, with distinct molecular species of each of the bioactive lipids and metabolic interconnections that interconvert one bioactive lipid into others (for example, ceramide to sphingosine and then to S1P). Critically, these pathways demonstrate specific subcellular localizations that appear to dictate the specific functions of sphingolipids.

  • A plethora of cell biological processes are critically modulated by bioactive sphingolipids, including growth regulation, cell migration, adhesion, apoptosis, senescence and inflammatory responses.

  • At the tissue and organismal level, bioactive sphingolipids have been implicated in neurodegenerative processes, metabolic disorders, various cancers (and various cancer attributes), immune function, cardiovascular disorders and skin integrity.

  • Major advances have been made in defining the enzymes of sphingolipid metabolism, their mechanisms and their structures. However, a major challenge is to decipher the biochemical mechanisms by which these enzymes and their products are specifically regulated.

  • A key future challenge is to determine the molecular mechanisms of action for specific species or subgroups of bioactive sphingolipids (for example, distinct ceramides and distinct sphingoid bases).

Abstract

Studies of bioactive lipids in general and sphingolipids in particular have intensified over the past several years, revealing an unprecedented and unanticipated complexity of the lipidome and its many functions, which rivals, if not exceeds, that of the genome or proteome. These results highlight critical roles for bioactive sphingolipids in most, if not all, major cell biological responses, including all major cell signalling pathways, and they link sphingolipid metabolism to key human diseases. Nevertheless, the fairly nascent field of bioactive sphingolipids still faces challenges in its biochemical and molecular underpinnings, including defining the molecular mechanisms of pathway and enzyme regulation, the study of lipid–protein interactions and the development of cellular probes, suitable biomarkers and therapeutic approaches.

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Figure 1: Overview of sphingolipid metabolism.
Figure 2: Intracellular compartmentalization and transport of sphingolipids.
Figure 3: Examples of cellular functions and downstream targets of bioactive sphingolipids.

References

  1. 1

    Hannun, Y. A. & Obeid, L. M. Principles of bioactive lipid signalling: lessons from sphingolipids. Nat. Rev. Mol. Cell Biol. 9, 139–150 (2008).

    CAS  Article  PubMed  Google Scholar 

  2. 2

    Thudichum, J. L. W. A Treatise on the Chemical Constitution of the Brain (Archon Books, 1962). This is the first documented isolation of the sphingolipids, and includes the coining of the term 'sphingosin'.

  3. 3

    Hannun, Y. A. & Obeid, L. M. Many ceramides. J. Biol. Chem. 286, 27855–27862 (2011). This review advances the hypothesis that ceramides are indeed a family of distinct molecular species that are products of distinct metabolic enzymes and that the different ceramides may have distinct functions.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4

    Schulze, H. & Sandhoff, K. Sphingolipids and lysosomal pathologies. Biochim. Biophys. Acta 1841, 799–810 (2014).

    CAS  Article  PubMed  Google Scholar 

  5. 5

    Huang, X., Withers, B. R. & Dickson, R. C. Sphingolipids and lifespan regulation. Biochim. Biophys. Acta 1841, 657–664 (2014).

    CAS  Article  PubMed  Google Scholar 

  6. 6

    Astudillo, L. et al. Human genetic disorders of sphingolipid biosynthesis. J. Inherit. Metab. Dis. 38, 65–76 (2015). This is a comprehensive presentation of the various genetic disorders that are directly caused by defects in sphingolipid metabolism.

    CAS  Article  PubMed  Google Scholar 

  7. 7

    Bode, H. et al. HSAN1 mutations in serine palmitoyltransferase reveal a close structure-function-phenotype relationship. Hum. Mol. Genet. 25, 853–865 (2016).

    CAS  Article  PubMed  Google Scholar 

  8. 8

    Hornemann, T. et al. The SPTLC3 subunit of serine palmitoyltransferase generates short chain sphingoid bases. J. Biol. Chem. 284, 26322–26330 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9

    Harmon, J. M. et al. Topological and functional characterization of the ssSPTs, small activating subunits of serine palmitoyltransferase. J. Biol. Chem. 288, 10144–10153 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10

    Cingolani, F., Futerman, A. H. & Casas, J. Ceramide synthases in biomedical research. Chem. Phys. Lipids 197, 25–32 (2016).

    CAS  Article  PubMed  Google Scholar 

  11. 11

    Wegner, M. S., Schiffmann, S., Parnham, M. J., Geisslinger, G. & Grosch, S. The enigma of ceramide synthase regulation in mammalian cells. Prog. Lipid Res. 63, 93–119 (2016). This is a comprehensive presentation of the functions and regulation of the family of CerSs.

    CAS  Article  PubMed  Google Scholar 

  12. 12

    Sassa, T. & Kihara, A. Metabolism of very long-chain Fatty acids: genes and pathophysiology. Biomol. Ther. 22, 83–92 (2014).

    CAS  Article  Google Scholar 

  13. 13

    Grond, S. et al. PNPLA1 deficiency in mice and humans leads to a defect in the synthesis of omega-O-acylceramides. J. Invest. Dermatol. 137, 394–402 (2017).

    CAS  Article  PubMed  Google Scholar 

  14. 14

    Senkal, C. E. et al. Ceramide is metabolized to acylceramide and stored in lipid droplets. Cell Metab. 25, 686–697 (2017). This study describes a novel pathway by which ceramide can be diverted or stored as O-acyl-ceramide in lipid droplets.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15

    Ferreira, N. S. et al. Regulation of very-long acyl chain ceramide synthesis by acyl-CoA binding protein. J. Biol. Chem. 292, 7588–7597 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16

    Wakashima, T., Abe, K. & Kihara, A. Dual functions of the trans-2-enoyl-CoA reductase TER in the sphingosine 1-phosphate metabolic pathway and in fatty acid elongation. J. Biol. Chem. 289, 24736–24748 (2014). This study identifies a key enzyme involved in the metabolism and recycling of fatty aldehydes after their generation from the breakdown of S1P.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17

    Cabukusta, B. et al. ER residency of the ceramide phosphoethanolamine synthase SMSr relies on homotypic oligomerization mediated by its SAM domain. Sci. Rep. 7, 41290 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18

    Rajagopalan, V. et al. Critical determinants of mitochondria-associated neutral sphingomyelinase (MA-nSMase) for mitochondrial localization. Biochim. Biophys. Acta 1850, 628–639 (2015).

    CAS  Article  PubMed  Google Scholar 

  19. 19

    Murate, M. et al. Transbilayer distribution of lipids at nano scale. J. Cell Sci. 128, 1627–1638 (2015).

    CAS  Article  PubMed  Google Scholar 

  20. 20

    Abe, M. & Kobayashi, T. Imaging local sphingomyelin-rich domains in the plasma membrane using specific probes and advanced microscopy. Biochim. Biophys. Acta 1841, 720–726 (2014).

    CAS  Article  PubMed  Google Scholar 

  21. 21

    Deng, Y., Rivera-Molina, F. E., Toomre, D. K. & Burd, C. G. Sphingomyelin is sorted at the trans Golgi network into a distinct class of secretory vesicle. Proc. Natl Acad. Sci. USA 113, 6677–6682 (2016).

    CAS  Article  PubMed  Google Scholar 

  22. 22

    Nagahashi, M. et al. Sphingosine-1-phosphate transporters as targets for cancer therapy. BioMed Res. Int. 2014, 651727 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Wadsworth, J. M. et al. The chemical basis of serine palmitoyltransferase inhibition by myriocin. J. Am. Chem. Soc. 135, 14276–14285 (2013).

    CAS  Article  PubMed  Google Scholar 

  24. 24

    Zhou, Y. F. et al. Human acid sphingomyelinase structures provide insight to molecular basis of Niemann-Pick disease. Nat. Commun. 7, 13082 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25

    Gorelik, A., Illes, K., Heinz, L. X., Superti-Furga, G. & Nagar, B. Crystal structure of mammalian acid sphingomyelinase. Nat. Commun. 7, 12196 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26

    Xiong, Z. J., Huang, J., Poda, G., Pomes, R. & Prive, G. G. Structure of human acid sphingomyelinase reveals the role of the saposin domain in activating substrate hydrolysis. J. Mol. Biol. 428, 3026–3042 (2016).

    CAS  Article  PubMed  Google Scholar 

  27. 27

    Gorelik, A., Liu, F., Illes, K. & Nagar, B. Crystal structure of the human alkaline sphingomyelinase provides insights into substrate recognition. J. Biol. Chem. 292, 7087–7094 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28

    Dvir, H. et al. X-Ray structure of human acid-β-glucosidase, the defective enzyme in Gaucher disease. EMBO Rep. 4, 704–709 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29

    Wang, Z. et al. Molecular basis of sphingosine kinase 1 substrate recognition and catalysis. Structure 21, 798–809 (2013).

    CAS  Article  PubMed  Google Scholar 

  30. 30

    Airola, M. V. et al. Structural basis for ceramide recognition and hydrolysis by human neutral ceramidase. Structure 23, 1482–1491 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31

    Zhu, G., Koszelak-Rosenblum, M., Connelly, S. M., Dumont, M. E. & Malkowski, M. G. The crystal structure of an integral membrane fatty acid α-hydroxylase. J. Biol. Chem. 290, 29820–29833 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33

    Hanson, M. A. et al. Crystal structure of a lipid G protein-coupled receptor. Science 335, 851–855 (2012). This study describes the crystal structure of S1PR1.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34

    Kudo, N. et al. Crystal structures of the CERT START domain with inhibitors provide insights into the mechanism of ceramide transfer. J. Mol. Biol. 396, 245–251 (2010).

    CAS  Article  PubMed  Google Scholar 

  35. 35

    Simanshu, D. K. et al. Non-vesicular trafficking by a ceramide-1-phosphate transfer protein regulates eicosanoids. Nature 500, 463–467 (2013). This study describes the crystal structure of the C1P transporter.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36

    Samygina, V. R. et al. Enhanced selectivity for sulfatide by engineered human glycolipid transfer protein. Structure 19, 1644–1654 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37

    Sanchez, T. & Hla, T. Structural and functional characteristics of S1P receptors. J. Cell. Biochem. 92, 913–922 (2004).

    CAS  Article  PubMed  Google Scholar 

  38. 38

    Hait, N. C. et al. Regulation of histone acetylation in the nucleus by sphingosine-1-phosphate. Science 325, 1254–1257 (2009). This study identifies HDACs as direct nuclear targets of S1P.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39

    Galadari, S., Rahman, A., Pallichankandy, S. & Thayyullathil, F. Tumor suppressive functions of ceramide: evidence and mechanisms. Apoptosis 20, 689–711 (2015).

    CAS  Article  PubMed  Google Scholar 

  40. 40

    Mehra, V. C. et al. Ceramide-activated phosphatase mediates fatty acid-induced endothelial VEGF resistance and impaired angiogenesis. Am. J. Pathol. 184, 1562–1576 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. 41

    Apostolidis, S. A. et al. Phosphatase PP2A is requisite for the function of regulatory T cells. Nat. Immunol. 17, 556–564 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42

    Teixeira, V. & Costa, V. Unraveling the role of the target of rapamycin signaling in sphingolipid metabolism. Prog. Lipid Res. 61, 109–133 (2016). This is a comprehensive review of sphingolipid metabolism, function and regulation in yeast.

    CAS  Article  PubMed  Google Scholar 

  43. 43

    Taniguchi, M. et al. Lysosomal ceramide generated by acid sphingomyelinase triggers cytosolic cathepsin B-mediated degradation of X-linked inhibitor of apoptosis protein in natural killer/T lymphoma cell apoptosis. Cell Death Dis. 6, e1717 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44

    Jain, A., Beutel, O., Ebell, K., Korneev, S. & Holthuis, J. C. Diverting CERT-mediated ceramide transport to mitochondria triggers Bax-dependent apoptosis. J. Cell Sci. 130, 360–371 (2017).

    CAS  Article  PubMed  Google Scholar 

  45. 45

    Birbes, H. et al. A mitochondrial pool of sphingomyelin is involved in TNFα-induced Bax translocation to mitochondria. Biochem. J. 386, 445–451 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46

    Spiegel, S. & Milstien, S. The outs and the ins of sphingosine-1-phosphate in immunity. Nat. Rev. Immunol. 11, 403–415 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. 47

    Chaurasia, B. & Summers, S. A. Ceramides — lipotoxic inducers of metabolic disorders. Trends Endocrinol. Metab. 26, 538–550 (2015).

    CAS  Article  PubMed  Google Scholar 

  48. 48

    Montefusco, D. J., Matmati, N. & Hannun, Y. A. The yeast sphingolipid signaling landscape. Chem. Phys. Lipids 177, 26–40 (2014).

    CAS  Article  PubMed  Google Scholar 

  49. 49

    Epstein, S. & Riezman, H. Sphingolipid signaling in yeast: potential implications for understanding disease. Front. Biosci. 5, 97–108 (2013).

    Article  Google Scholar 

  50. 50

    Matmati, N. et al. Identification of C18:1-phytoceramide as the candidate lipid mediator for hydroxyurea resistance in yeast. J. Biol. Chem. 288, 17272–17284 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. 51

    Chauhan, N., Visram, M., Cristobal-Sarramian, A., Sarkleti, F. & Kohlwein, S. D. Morphogenesis checkpoint kinase Swe1 is the executor of lipolysis-dependent cell-cycle progression. Proc. Natl Acad. Sci. USA 112, E1077–E1085 (2015).

    CAS  Article  PubMed  Google Scholar 

  52. 52

    Adada, M. M. et al. Intracellular sphingosine kinase 2-derived sphingosine-1-phosphate mediates epidermal growth factor-induced ezrin-radixin-moesin phosphorylation and cancer cell invasion. FASEB J. 29, 4654–4669 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. 53

    Bretscher, A., Edwards, K. & Fehon, R. G. ERM proteins and merlin: integrators at the cell cortex. Nat. Rev. Mol. Cell Biol. 3, 586–599 (2002).

    CAS  Article  PubMed  Google Scholar 

  54. 54

    van der Weyden, L. et al. Genome-wide in vivo screen identifies novel host regulators of metastatic colonization. Nature 541, 233–236 (2017). In an unbiased screen, this study identifies SPNS2, the S1P transporter, as a key regulator of metastasis.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. 55

    Romero-Guevara, R., Cencetti, F., Donati, C. & Bruni, P. Sphingosine 1-phosphate signaling pathway in inner ear biology. New therapeutic strategies for hearing loss? Front. Aging Neurosci. 7, 60 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Kitajiri, S. et al. Radixin deficiency causes deafness associated with progressive degeneration of cochlear stereocilia. J. Cell Biol. 166, 559–570 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. 57

    Chen, J. et al. Spinster homolog 2 (spns2) deficiency causes early onset progressive hearing loss. PLoS Genet. 10, e1004688 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Canals, D., Roddy, P. & Hannun, Y. A. Protein phosphatase 1α mediates ceramide-induced ERM protein dephosphorylation: a novel mechanism independent of phosphatidylinositol 4, 5-biphosphate (PIP2) and myosin/ERM phosphatase. J. Biol. Chem. 287, 10145–10155 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. 59

    Carreira, A. C., Ventura, A. E., Varela, A. R. & Silva, L. C. Tackling the biophysical properties of sphingolipids to decipher their biological roles. Biol. Chem. 396, 597–609 (2015).

    CAS  Article  PubMed  Google Scholar 

  60. 60

    Trajkovic, K. et al. Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science 319, 1244–1247 (2008). This study ascribes a key role for ceramide and for nSMase2 in the regulation of exocytosis.

    CAS  Article  PubMed  Google Scholar 

  61. 61

    Kosaka, N. et al. Secretory mechanisms and intercellular transfer of microRNAs in living cells. J. Biol. Chem. 285, 17442–17452 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. 62

    Guo, B. B., Bellingham, S. A. & Hill, A. F. The neutral sphingomyelinase pathway regulates packaging of the prion protein into exosomes. J. Biol. Chem. 290, 3455–3467 (2015).

    CAS  Article  PubMed  Google Scholar 

  63. 63

    Yuyama, K., Sun, H., Mitsutake, S. & Igarashi, Y. Sphingolipid-modulated exosome secretion promotes clearance of amyloid-beta by microglia. J. Biol. Chem. 287, 10977–10989 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  64. 64

    Shen, H. et al. Coupling between endocytosis and sphingosine kinase 1 recruitment. Nat. Cell Biol. 16, 652–662 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  65. 65

    Hayashi, Y. et al. Sphingomyelin synthase 2, but not sphingomyelin synthase 1, is involved in HIV-1 envelope-mediated membrane fusion. J. Biol. Chem. 289, 30842–30856 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. 66

    Contreras, F. X. et al. Molecular recognition of a single sphingolipid species by a protein's transmembrane domain. Nature 481, 525–529 (2012). This study identifies a specific molecular species of sphingomyelin, C18 sphingomyelin, as a ligand for p24, a component of the COPI secretion machinery.

    CAS  Article  PubMed  Google Scholar 

  67. 67

    Capasso, S. et al. Sphingolipid metabolic flow controls phosphoinositide turnover at the trans-Golgi network. EMBO J. 36, 1736–1754 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. 68

    Heffernan-Stroud, L. A. et al. Defining a role for sphingosine kinase 1 in p53-dependent tumors. Oncogene 31, 1166–1175 (2012).

    CAS  Article  PubMed  Google Scholar 

  69. 69

    Wang, Y. et al. Alkaline ceramidase 2 is a novel direct target of p53 and induces autophagy and apoptosis through ROS generation. Sci. Rep. 7, 44573 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  70. 70

    Shamseddine, A. A. et al. P53-dependent upregulation of neutral sphingomyelinase-2: role in doxorubicin-induced growth arrest. Cell Death Dis. 6, e1947 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  71. 71

    Guillas, I. et al. C26-CoA-dependent ceramide synthesis of Saccharomyces cerevisiae is operated by Lag1p and Lac1p. EMBO J. 20, 2655–2665 (2001). This study identifies the genes encoding CerSs ( lag1 and lac1 ) in yeast and demonstrates that these genes are in fact the first genes to be implicated in regulation of yeast lifespan.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. 72

    Mosbech, M. B. et al. Functional loss of two ceramide synthases elicits autophagy-dependent lifespan extension in C. elegans. PLoS ONE 8, e70087 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. 73

    Jazwinski, S. M. et al. HRAS1 and LASS1 with APOE are associated with human longevity and healthy aging. Aging Cell 9, 698–708 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  74. 74

    Dany, M. & Ogretmen, B. Ceramide induced mitophagy and tumor suppression. Biochim. Biophys. Acta 1853, 2834–2845 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  75. 75

    Siddique, M. M., Li, Y., Chaurasia, B., Kaddai, V. A. & Summers, S. A. Dihydroceramides: from bit players to lead actors. J. Biol. Chem. 290, 15371–15379 (2015). This is an informative summary of the roles of ceramides and dihydroceramides in metabolic pathways.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  76. 76

    Hernandez-Tiedra, S. et al. Dihydroceramide accumulation mediates cytotoxic autophagy of cancer cells via autolysosome destabilization. Autophagy 12, 2213–2229 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. 77

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

    CAS  Article  PubMed  Google Scholar 

  78. 78

    Siskind, L. J. et al. The BCL-2 protein BAK is required for long-chain ceramide generation during apoptosis. J. Biol. Chem. 285, 11818–11826 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  79. 79

    Brinkmann, V. & Lynch, K. R. FTY720: targeting G-protein-coupled receptors for sphingosine 1-phosphate in transplantation and autoimmunity. Curr. Opin. Immunol. 14, 569–575 (2002).

    CAS  Article  PubMed  Google Scholar 

  80. 80

    Benechet, A. P. et al. T cell-intrinsic S1PR1 regulates endogenous effector T-cell egress dynamics from lymph nodes during infection. Proc. Natl Acad. Sci. USA 113, 2182–2187 (2016).

    CAS  Article  PubMed  Google Scholar 

  81. 81

    Hla, T., Venkataraman, K. & Michaud, J. The vascular S1P gradient-cellular sources and biological significance. Biochim. Biophys. Acta 1781, 477–482 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  82. 82

    Allende, M. L., Dreier, J. L., Mandala, S. & Proia, R. L. Expression of the sphingosine 1-phosphate receptor, S1P1, on T-cells controls thymic emigration. J. Biol. Chem. 279, 15396–15401 (2004).

    CAS  Article  PubMed  Google Scholar 

  83. 83

    Breart, B. et al. Lipid phosphate phosphatase 3 enables efficient thymic egress. J. Exp. Med. 208, 1267–1278 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  84. 84

    Blaho, V. A. et al. HDL-bound sphingosine-1-phosphate restrains lymphopoiesis and neuroinflammation. Nature 523, 342–346 (2015). This study demonstrates specific immune functions for HDL-bound S1P in the circulation.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  85. 85

    Pettus, B. J. et al. The coordination of prostaglandin E2 production by sphingosine-1-phosphate and ceramide-1-phosphate. Mol. Pharmacol. 68, 330–335 (2005).

    CAS  Article  PubMed  Google Scholar 

  86. 86

    Xiong, Y. et al. Sphingosine kinases are not required for inflammatory responses in macrophages. J. Biol. Chem. 291, 11465 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  87. 87

    Jenkins, R. W. et al. Regulation of CC ligand 5/RANTES by acid sphingomyelinase and acid ceramidase. J. Biol. Chem. 286, 13292–13303 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  88. 88

    Kott, M. et al. Acid sphingomyelinase serum activity predicts mortality in intensive care unit patients after systemic inflammation: a prospective cohort study. PLoS ONE 9, e112323 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Hannun, Y. A., Luberto, C., Mao, C. & Obeid, L. M. Bioactive Sphingolipids in Cancer Biology and Therapy (Springer, 2015).

    Google Scholar 

  90. 90

    Morad, S. A. & Cabot, M. C. Ceramide-orchestrated signalling in cancer cells. Nat. Rev. Cancer 13, 51–65 (2013).

    CAS  Article  PubMed  Google Scholar 

  91. 91

    Pettus, B. J. et al. The sphingosine kinase 1/sphingosine-1-phosphate pathway mediates COX-2 induction and PGE2 production in response to TNF-α. FASEB J. 17, 1411–1421 (2003).

    CAS  Article  PubMed  Google Scholar 

  92. 92

    Tan, S. S. et al. Sphingosine kinase 1 promotes malignant progression in colon cancer and independently predicts survival of patients with colon cancer by competing risk approach in South asian population. Clin. Transl Gastroenterol. 5, e51 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  93. 93

    Kawamori, T. et al. Role for sphingosine kinase 1 in colon carcinogenesis. FASEB J. 23, 405–414 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  94. 94

    Liang, J. et al. Sphingosine-1-phosphate links persistent STAT3 activation, chronic intestinal inflammation, and development of colitis-associated cancer. Cancer Cell 23, 107–120 (2013).

    CAS  Article  PubMed  Google Scholar 

  95. 95

    Kohno, M. et al. Intracellular role for sphingosine kinase 1 in intestinal adenoma cell proliferation. Mol. Cell. Biol. 26, 7211–7223 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  96. 96

    Oskouian, B. et al. Sphingosine-1-phosphate lyase potentiates apoptosis via p53- and p38-dependent pathways and is down-regulated in colon cancer. Proc. Natl Acad. Sci. USA 103, 17384–17389 (2006).

    CAS  Article  PubMed  Google Scholar 

  97. 97

    Ju, T., Gao, D. & Fang, Z. Y. Targeting colorectal cancer cells by a novel sphingosine kinase 1 inhibitor PF-543. Biochem. Biophys. Res. Commun. 470, 728–734 (2016).

    CAS  Article  PubMed  Google Scholar 

  98. 98

    Chumanevich, A. A. et al. Suppression of colitis-driven colon cancer in mice by a novel small molecule inhibitor of sphingosine kinase. Carcinogenesis 31, 1787–1793 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  99. 99

    García-Barros, M. et al. Role of neutral ceramidase in colon cancer. FASEB J. 30, 4159–4171 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    Heffernan-Stroud, L. A. & Obeid, L. M. Sphingosine kinase 1 in cancer. Adv. Cancer Res. 117, 201–235 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  101. 101

    Galvani, S. et al. HDL-bound sphingosine 1-phosphate acts as a biased agonist for the endothelial cell receptor S1P1 to limit vascular inflammation. Sci. Signal. 8, ra79 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. 102

    Nagahashi, M. et al. Sphingosine-1-phosphate in chronic intestinal inflammation and cancer. Adv. Biol. Regul. 54, 112–120 (2014).

    CAS  Article  PubMed  Google Scholar 

  103. 103

    Anelli, V., Gault, C. R., Snider, A. J. & Obeid, L. M. Role of sphingosine kinase-1 in paracrine/transcellular angiogenesis and lymphangiogenesis in vitro. FASEB J. 24, 2727–2738 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  104. 104

    Mahdy, A. E. et al. Acid ceramidase upregulation in prostate cancer cells confers resistance to radiation: AC inhibition, a potential radiosensitizer. Mol. Ther. 17, 430–438 (2009).

    CAS  Article  PubMed  Google Scholar 

  105. 105

    Frohbergh, M., He, X. & Schuchman, E. H. The molecular medicine of acid ceramidase. Biol. Chem. 396, 759–765 (2015).

    CAS  Article  PubMed  Google Scholar 

  106. 106

    Realini, N. et al. Acid ceramidase in melanoma: expression, localization, and effects of pharmacological inhibition. J. Biol. Chem. 291, 2422–2434 (2016).

    CAS  Article  PubMed  Google Scholar 

  107. 107

    Bizzozero, L. et al. Acid sphingomyelinase determines melanoma progression and metastatic behaviour via the microphtalmia-associated transcription factor signalling pathway. Cell Death Differ. 21, 507–520 (2014).

    CAS  Article  PubMed  Google Scholar 

  108. 108

    Sanger, N. et al. Acid ceramidase is associated with an improved prognosis in both DCIS and invasive breast cancer. Mol. Oncol. 9, 58–67 (2015).

    Article  CAS  PubMed  Google Scholar 

  109. 109

    Carpinteiro, A. et al. Regulation of hematogenous tumor metastasis by acid sphingomyelinase. EMBO Mol. Med. 7, 714–734 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  110. 110

    Truman, J. P. et al. Endothelial membrane remodeling is obligate for anti-angiogenic radiosensitization during tumor radiosurgery. PLoS ONE 5, e12310 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. 111

    Daemen, A. et al. Metabolite profiling stratifies pancreatic ductal adenocarcinomas into subtypes with distinct sensitivities to metabolic inhibitors. Proc. Natl Acad. Sci. USA 112, E4410–E4417 (2015).

    CAS  Article  PubMed  Google Scholar 

  112. 112

    Dubois, N. et al. Plasma ceramide, a real-time predictive marker of pulmonary and hepatic metastases response to stereotactic body radiation therapy combined with irinotecan. Radiother. Oncol. 119, 229–235 (2016).

    CAS  Article  PubMed  Google Scholar 

  113. 113

    Abdul Aziz, N. A. et al. 19-Gene expression signature as a predictor of survival in colorectal cancer. BMC Med. Genom. 9, 58 (2016). This study identifies CERS6 as a key gene component of a 19-gene signature for prediction of survival in colon cancer.

    Article  CAS  Google Scholar 

  114. 114

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. 115

    Boini, K. M., Zhang, C., Xia, M., Poklis, J. L. & Li, P. L. Role of sphingolipid mediator ceramide in obesity and renal injury in mice fed a high-fat diet. J. Pharmacol. Exp. Ther. 334, 839–846 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  116. 116

    Choi, S. & Snider, A. J. Sphingolipids in high fat diet and obesity-related diseases. Mediators Inflamm. 2015, 520618 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. 117

    Hodson, A. E., Tippetts, T. S. & Bikman, B. T. Insulin treatment increases myocardial ceramide accumulation and disrupts cardiometabolic function. Cardiovasc. Diabetol. 14, 153 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. 118

    Kurek, K. et al. Inhibition of ceramide de novo synthesis with myriocin affects lipid metabolism in the liver of rats with streptozotocin-induced type 1 diabetes. BioMed Res. Int. 2014, 980815 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. 119

    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  Article  PubMed  Google Scholar 

  120. 120

    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  Article  PubMed  PubMed Central  Google Scholar 

  121. 121

    Chavez, J. A. et al. Ceramides and glucosylceramides are independent antagonists of insulin signaling. J. Biol. Chem. 289, 723–734 (2014).

    CAS  Article  PubMed  Google Scholar 

  122. 122

    Li, Z. et al. Reducing plasma membrane sphingomyelin increases insulin sensitivity. Mol. Cell. Biol. 31, 4205–4218 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  123. 123

    Yano, M. et al. Increased oxidative stress impairs adipose tissue function in sphingomyelin synthase 1 null mice. PLoS ONE 8, e61380 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  124. 124

    Taguchi, Y. et al. Sphingosine-1-phosphate phosphatase 2 regulates pancreatic islet β-cell endoplasmic reticulum stress and proliferation. J. Biol. Chem. 291, 12029–12038 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  125. 125

    Chen, J. et al. Deletion of sphingosine kinase 1 ameliorates hepatic steatosis in diet-induced obese mice: role of PPARγ. Biochim. Biophys. Acta 1861, 138–147 (2016).

    CAS  Article  PubMed  Google Scholar 

  126. 126

    Park, K. et al. ER stress stimulates production of the key antimicrobial peptide, cathelicidin, by forming a previously unidentified intracellular S1P signaling complex. Proc. Natl Acad. Sci. USA 113, E1334–E1342 (2016).

    CAS  Article  PubMed  Google Scholar 

  127. 127

    Wong, M. L. et al. Acute systemic inflammation up-regulates secretory sphingomyelinase in vivo: A possible link between inflammatory cytokines and atherogenesis. Proc. Natl Acad. Sci. USA 97, 8681–8686 (2000).

    CAS  Article  PubMed  Google Scholar 

  128. 128

    Fan, J., Wu, B. X. & Crosson, C. E. Suppression of acid sphingomyelinase protects the retina from ischemic injury. Invest. Ophthalmol. Vis. Sci. 57, 4476–4484 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  129. 129

    Reforgiato, M. R. et al. Inhibition of ceramide de novo synthesis as a postischemic strategy to reduce myocardial reperfusion injury. Basic Res. Cardiol. 111, 12 (2016).

    CAS  Article  PubMed  Google Scholar 

  130. 130

    Hammad, S. M. et al. Increased plasma levels of select deoxy-ceramide and ceramide species are associated with increased odds of diabetic neuropathy in type 1 diabetes: a pilot study. Neuromolecular Med. 19, 46–56 (2017).

    CAS  Article  PubMed  Google Scholar 

  131. 131

    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  Article  PubMed  Google Scholar 

  132. 132

    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  Article  PubMed  Google Scholar 

  133. 133

    Sigruener, A. et al. Glycerophospholipid and sphingolipid species and mortality: the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. PLoS ONE 9, e85724 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. 134

    Saleem, M. et al. Ceramides predict verbal memory performance in coronary artery disease patients undertaking exercise: a prospective cohort pilot study. BMC Geriatr. 13, 135 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. 135

    Soltau, I. et al. Serum-sphingosine-1-phosphate concentrations are inversely associated with atherosclerotic diseases in humans. PLoS ONE 11, e0168302 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. 136

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

    Article  PubMed  PubMed Central  Google Scholar 

  137. 137

    Hama, H. Fatty acid 2-hydroxylation in mammalian sphingolipid biology. Biochim. Biophys. Acta 1801, 405–414 (2010).

    CAS  Article  PubMed  Google Scholar 

  138. 138

    Edvardson, S. et al. Deficiency of the alkaline ceramidase ACER3 manifests in early childhood by progressive leukodystrophy. J. Med. Genet. 53, 389–396 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  139. 139

    Zhao, L. et al. Elevation of 20-carbon long chain bases due to a mutation in serine palmitoyltransferase small subunit b results in neurodegeneration. Proc. Natl Acad. Sci. USA 112, 12962–12967 (2015).

    CAS  Article  PubMed  Google Scholar 

  140. 140

    Vanni, N. et al. Impairment of ceramide synthesis causes a novel progressive myoclonus epilepsy. Ann. Neurol. 76, 206–212 (2014).

    CAS  Article  PubMed  Google Scholar 

  141. 141

    Mosbech, M. B. et al. Reduced ceramide synthase 2 activity causes progressive myoclonic epilepsy. Ann. Clin. Transl Neurol. 1, 88–98 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  142. 142

    Boustany, R. M. Ceramide center stage in progressive myoclonus epilepsies. Ann. Neurol. 76, 162–164 (2014).

    CAS  Article  PubMed  Google Scholar 

  143. 143

    Spassieva, S. D. et al. Ectopic expression of ceramide synthase 2 in neurons suppresses neurodegeneration induced by ceramide synthase 1 deficiency. Proc. Natl Acad. Sci. USA 113, 5928–5933 (2016). This study, by using genetic interactions between Cers1 and Cers2 , demonstrates that sphingosine is likely the key lipid species responsible for mediating neurodegeneration in the Cers1 -knockout mouse.

    CAS  Article  PubMed  Google Scholar 

  144. 144

    Dinkins, M. B. et al. Neutral sphingomyelinase-2 deficiency ameliorates Alzheimer's disease pathology and improves cognition in the 5XFAD mouse. J. Neurosci. 36, 8653–8667 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  145. 145

    Novgorodov, S. A. et al. Essential roles of neutral ceramidase and sphingosine in mitochondrial dysfunction due to traumatic brain injury. J. Biol. Chem. 289, 13142–13154 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  146. 146

    Jennemann, R. et al. Loss of ceramide synthase 3 causes lethal skin barrier disruption. Hum. Mol. Genet. 21, 586–608 (2012).

    CAS  Article  PubMed  Google Scholar 

  147. 147

    Behne, M. et al. Omega-hydroxyceramides are required for corneocyte lipid envelope (CLE) formation and normal epidermal permeability barrier function. J. Invest. Dermatol. 114, 185–192 (2000).

    CAS  Article  PubMed  Google Scholar 

  148. 148

    Jennemann, R. et al. Integrity and barrier function of the epidermis critically depend on glucosylceramide synthesis. J. Biol. Chem. 282, 3083–3094 (2007).

    CAS  Article  PubMed  Google Scholar 

  149. 149

    Westerberg, R. et al. Role for ELOVL3 and fatty acid chain length in development of hair and skin function. J. Biol. Chem. 279, 5621–5629 (2004).

    CAS  Article  PubMed  Google Scholar 

  150. 150

    Cameron, D. J. et al. Essential role of Elovl4 in very long chain fatty acid synthesis, skin permeability barrier function, and neonatal survival. Int. J. Biol. Sci. 3, 111–119 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  151. 151

    Peters, F. et al. Ceramide synthase 4 regulates stem cell homeostasis and hair follicle cycling. J. Invest. Dermatol. 135, 1501–1509 (2015).

    CAS  Article  PubMed  Google Scholar 

  152. 152

    Liakath-Ali, K. et al. Alkaline ceramidase 1 is essential for mammalian skin homeostasis and regulating whole-body energy expenditure. J. Pathol. 239, 374–383 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  153. 153

    Stoffel, W., Jenke, B., Block, B., Zumbansen, M. & Koebke, J. Neutral sphingomyelinase 2 (smpd3) in the control of postnatal growth and development. Proc. Natl Acad. Sci. USA 102, 4554–4559 (2005).

    CAS  Article  PubMed  Google Scholar 

  154. 154

    Li, J. et al. Smpd3 expression in both chondrocytes and osteoblasts is required for normal endochondral bone development. Mol. Cell. Biol. 36, 2282–2299 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  155. 155

    Kakoi, H. et al. Bone morphogenic protein (BMP) signaling up-regulates neutral sphingomyelinase 2 to suppress chondrocyte maturation via the Akt protein signaling pathway as a negative feedback mechanism. J. Biol. Chem. 289, 8135–8150 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  156. 156

    Somenzi, G. et al. Disruption of retinoic acid receptor alpha reveals the growth promoter face of retinoic acid. PLoS ONE 2, e836 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. 157

    Clarke, C. J. et al. ATRA transcriptionally induces nSMase2 through CBP/p300-mediated histone acetylation. J. Lipid Res. 57, 868–881 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  158. 158

    Cowart, L. A. & Hannun, Y. A. Selective substrate supply in the regulation of yeast de novo sphingolipid synthesis. J. Biol. Chem. 282, 12330–12340 (2007).

    CAS  Article  PubMed  Google Scholar 

  159. 159

    Sun, Y. et al. Orm protein phosphoregulation mediates transient sphingolipid biosynthesis response to heat stress via the Pkh-Ypk and Cdc55-PP2A pathways. Mol. Biol. Cell 23, 2388–2398 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  160. 160

    Muir, A., Ramachandran, S., Roelants, F. M., Timmons, G. & Thorner, J. TORC2-dependent protein kinase Ypk1 phosphorylates ceramide synthase to stimulate synthesis of complex sphingolipids. eLife 3, e03779 (2014).

    Article  CAS  PubMed Central  Google Scholar 

  161. 161

    Novgorodov, S. A. et al. SIRT3 deacetylates ceramide synthases: implications for mitochondrial dysfunction and brain injury. J. Biol. Chem. 291, 1957–1973 (2016).

    CAS  Article  PubMed  Google Scholar 

  162. 162

    Sassa, T., Hirayama, T. & Kihara, A. Enzyme activities of the ceramide synthases CERS2-6 are regulated by phosphorylation in the C-terminal region. J. Biol. Chem. 291, 7477–7487 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  163. 163

    Jensen, S. A. et al. Bcl2L13 is a ceramide synthase inhibitor in glioblastoma. Proc. Natl Acad. Sci. USA 111, 5682–5687 (2014).

    CAS  Article  PubMed  Google Scholar 

  164. 164

    McNaughton, M., Pitman, M., Pitson, S. M., Pyne, N. J. & Pyne, S. Proteasomal degradation of sphingosine kinase 1 and inhibition of dihydroceramide desaturase by the sphingosine kinase inhibitors, SKi or ABC294640, induces growth arrest in androgen-independent LNCaP-AI prostate cancer cells. Oncotarget 7, 16663–16675 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  165. 165

    Filosto, S., Ashfaq, M., Chung, S., Fry, W. & Goldkorn, T. Neutral sphingomyelinase 2 activity and protein stability are modulated by phosphorylation of five conserved serines. J. Biol. Chem. 287, 514–522 (2012).

    CAS  Article  PubMed  Google Scholar 

  166. 166

    Shamseddine, A. A., Airola, M. V. & Hannun, Y. A. Roles and regulation of neutral sphingomyelinase-2 in cellular and pathological processes. Adv. Biol. Reg. 57, 24–41 (2015).

    CAS  Article  Google Scholar 

  167. 167

    Rhein, C. et al. Functional implications of novel human acid sphingomyelinase splice variants. PLoS ONE 7, e35467 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  168. 168

    Sasaki, H. et al. Regulation of alkaline ceramidase activity by the c-Src-mediated pathway. Arch. Biochem. Biophys. 550–551, 12–19 (2014).

    Article  CAS  PubMed  Google Scholar 

  169. 169

    Tanaka, K. et al. Role of down-regulated neutral ceramidase during all-trans retinoic acid-induced neuronal differentiation in SH-SY5Y neuroblastoma cells. J. Biochem. 151, 611–620 (2012).

    CAS  Article  PubMed  Google Scholar 

  170. 170

    Wu, B. X., Zeidan, Y. H. & Hannun, Y. A. Downregulation of neutral ceramidase by gemcitabine: Implications for cell cycle regulation. Biochim. Biophys. Acta 1791, 730–739 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  171. 171

    Rahmaniyan, M. et al. Identification of dihydroceramide desaturase as a direct in vitro target for fenretinide. J. Biol. Chem. 286, 24754–24764 (2011). This study identifies dihydroceramide desaturase, the enzyme responsible for introducing the 4–5 double bond into ceramide, as a direct target for the action of the chemotherapeutic agent fenretinide (4-HPR).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  172. 172

    Schnute, M. E. et al. Modulation of cellular S1P levels with a novel, potent and specific inhibitor of sphingosine kinase-1. Biochem. J. 444, 79–88 (2012).

    CAS  Article  PubMed  Google Scholar 

  173. 173

    Rex, K. et al. Sphingosine kinase activity is not required for tumor cell viability. PLoS ONE 8, e68328 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  174. 174

    Santos, W. L. & Lynch, K. R. Drugging sphingosine kinases. ACS Chem. Biol. 10, 225–233 (2015).

    CAS  Article  PubMed  Google Scholar 

  175. 175

    Realini, N. et al. Discovery of highly potent acid ceramidase inhibitors with in vitro tumor chemosensitizing activity. Sci. Rep. 3, 1035 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. 176

    Sandborn, W. J. et al. Ozanimod induction and maintenance treatment for ulcerative colitis. N. Engl. J. Med. 374, 1754–1762 (2016).

    CAS  Article  PubMed  Google Scholar 

  177. 177

    Zhang, L. et al. Anti-S1P antibody as a novel therapeutic strategy for VEGFR TKI-resistant renal cancer. Clin. Cancer Res. 21, 1925–1934 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  178. 178

    Rollin-Pinheiro, R., Singh, A., Barreto-Bergter, E. & Del Poeta, M. Sphingolipids as targets for treatment of fungal infections. Future Med. Chem. 8, 1469–1484 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  179. 179

    Kumagai, K., Kawano-Kawada, M. & Hanada, K. Phosphoregulation of the ceramide transport protein CERT at serine 315 in the interaction with VAMP-associated protein (VAP) for inter-organelle trafficking of ceramide in mammalian cells. J. Biol. Chem. 289, 10748–10760 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  180. 180

    D'Angelo, G. et al. Glycosphingolipid synthesis requires FAPP2 transfer of glucosylceramide. Nature 449, 62–67 (2007). This study identifies that the transfer protein FAPP2 is involved in the selective binding and transport of neutral glycolipids among Golgi cisternae.

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

The authors thank the members of their laboratories and M. Airola, C. Luberto, C. Clarke, D. Canals, C. Senkal, C. Rhein and F. Velazquez for helpful discussions. The authors are very grateful for the contribution of M. Hernandez for assembling table 1 and supplementary information tables S2 and S3. Due to space limitations, the authors have striven to reference the more recent studies pertinent to the presentation while directing the readers to more in-depth targeted reviews. The authors apologize for the multitude of sphingolipid investigators whose works they could not cite in this Review.

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Contributions

Both authors conducted extensive research of primary data and reviews for the article and collaborated in defining the scope and content of the Review, in writing the Review and in preparation of the figures and editing the manuscript.

Corresponding authors

Correspondence to Yusuf A. Hannun or Lina M. Obeid.

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The authors declare no competing financial interests.

Supplementary information

Supplementary information S1 (box)

Studying sphingolipids: limitations and technical advancements. (PDF 59 kb)

Supplementary information S2 (table)

Sphingolipid species and key cellular functions (PDF 402 kb)

Supplementary information S3 (table)

Sphingolipid metabolizing enzymes (PDF 315 kb)

PowerPoint slides

Glossary

Prostaglandins

Bioactive, acidic lipids with various hormone-like activities, including modulation of inflammation, regulation of blood flow and blood pressure and reproduction.

Gangliosides

A major subtype of sphingolipids composed of ceramide and an oligosaccharide that contains at least one sialic acid residue.

ω-Acylation

Acylation of fatty acids at the ω-position (last position) in the acyl chain.

Freeze–fracture studies

A form of electron microscopy involving freezing in order to preserve lipid membrane structures.

G protein-coupled receptors

(GPCRs). Heptahelical membrane receptors that bind and regulate G proteins.

Globosides

A subtype of sphingolipids with a ceramide associated with at least two sugars, but no sialic acid.

Diauxic shift

The shift in growth from rapid fermentative to aerobic glycolysis.

Microglia

A type of neural cell arising from macrophages or their precursors that serves supportive and protective functions in the central nervous system.

ER stress

Endoplasmic reticulum (ER) dysfunction due to stress stimuli that result in increased accumulation of misfolded proteins in the ER.

Necroptosis

A regulated form of necrotic cell death associated with immune and inflammatory responses.

Multiple sclerosis

A degenerative disease of the nervous system associated with a loss of myelination (covering) of axonal sheaths.

T cell egress

Lymphocyte migration from the thymus and lymph nodes into the bloodstream.

von Hippel–Lindau (VHL) gene

A gene whose mutations can result in von Hippel–Lindau disease. It encodes a protein that participates in the regulation of the levels of hypoxia-inducible factor (HIF) through degradation.

Luminal A type breast cancer

A subtype of breast cancer in which the cells appear to resemble most cells of the luminal lining of the breast ducts.

Insulin resistance

A state in which cells, tissues or organisms fail to respond normally to insulin.

Glucose intolerance

Also known as impaired glucose tolerance. A pre-diabetic state involving hyperglycaemia and usually poor responsiveness to insulin.

Hepatic steatosis

Condition associated with non-alcoholic fatty liver disease with increased accumulation of fat in liver cells, usually in the form of triglycerides.

Ischaemic injury

Tissue and cell injury that results from a decrease in or interruption of the blood supply.

Reperfusion injury

Injury or damage to tissues resulting from the reoxygenation of previously ischaemic tissues.

Diabetic neuropathy

Dysfunction of the peripheral and autonomic nervous system that arises from long-standing diabetes.

Coronary angiography

An invasive procedure using dyes in the bloodstream to visualize the coronary circulation using radiography.

Osteogenesis imperfecta

A group of genetic disorders characterized by brittle bones.

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Hannun, Y., Obeid, L. Sphingolipids and their metabolism in physiology and disease. Nat Rev Mol Cell Biol 19, 175–191 (2018). https://doi.org/10.1038/nrm.2017.107

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