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Principles of bioactive lipid signalling: lessons from sphingolipids

Key Points

  • The sphingolipids constitute an important class of bioactive lipids, including ceramide and sphingosine-1-phosphate (S1P). Ceramide can be considered to function as a hub in sphingolipid metabolism, and it mediates or regulates antiproliferative responses such as growth inhibition, apoptosis, differentiation and senescence, whereas S1P is a key regulator of cell motility and proliferation.

  • The study of bioactive lipids in general and sphingolipids in particular presents several hurdles to molecular cell biologists. These include the hydrophobicity and biophysical properties of these molecules, the metabolic interconnections of the active metabolites, and the predominantly hydrophobic nature of the enzymes that regulate their metabolism.

  • Enzymes of sphingolipid metabolism function as an interconnected network that regulates the levels and interconversions of the bioactive sphingolipids. Many of these enzymes, such as sphingomyelinases, sphingosine kinases and ceramide synthases, serve to couple the action of extra- and intracellular agonists to downstream effectors.

  • Ceramide can be formed from the de novo pathway or following activation of the sphingomyelinase pathway, in which it functions in metabolic regulation and stress responses. Ceramide action is governed by the specific pathways that regulate its formation, their subcellular localization and their specific mechanisms of regulation.

  • S1P is a product of sphingosine kinases, and acts predominantly on a family of G protein-coupled receptors that, in turn, mediate its action on cell growth, migration, transcription and signal transduction.

  • The cellular actions of ceramide, S1P and other bioactive sphingolipids are increasingly thought to be crucial for the study of angiogenesis, inflammation, immune responses, diabetes, ageing, cancer biology and degenerative diseases.

Abstract

It has become increasingly difficult to find an area of cell biology in which lipids do not have important, if not key, roles as signalling and regulatory molecules. The rapidly expanding field of bioactive lipids is exemplified by many sphingolipids, such as ceramide, sphingosine, sphingosine-1-phosphate (S1P), ceramide-1-phosphate and lyso-sphingomyelin, which have roles in the regulation of cell growth, death, senescence, adhesion, migration, inflammation, angiogenesis and intracellular trafficking. Deciphering the mechanisms of these varied cell functions necessitates an understanding of the complex pathways of sphingolipid metabolism and the mechanisms that regulate lipid generation and lipid action.

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Figure 1: An overview of the roles of sphingolipids in biology.
Figure 2: Sphingolipid metabolism and interconnection of bioactive sphingolipids.
Figure 3: Parallel networks of sphingolipid signalling.
Figure 4: Transport and transbilayer movement of bioactive sphingolipids.
Figure 5: Examples of ceramide signalling pathways and their role in stress responses.
Figure 6: SK–S1P receptors and signalling.

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References

  1. Hokin, M. R. & Hokin, L. E. Enzyme secretion and the incorporation of 32P into phospholipids of pancreas slices. J. Biol. Chem. 203, 967–977 (1953). Earliest study to demonstrate agonist-induced turnover of inositol phospholipids.

    CAS  PubMed  Google Scholar 

  2. Nishizuka, Y. Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science 258, 607–614 (1992). An excellent review, by a pioneer in the field on bioactive lipids, that discusses the discovery of activation of PKC by DAG.

    CAS  PubMed  Google Scholar 

  3. Serhan, C. N. & Savill, J. Resolution of inflammation: the beginning programs the end. Nature Immunol. 6, 1191–1197 (2005).

    CAS  Google Scholar 

  4. Smith, E. R., Merrill, A. H., Obeid, L. M. & Hannun, Y. A. Effects of sphingosine and other sphingolipids on protein kinase C. Methods Enzymol. 312, 361–373 (2000).

    CAS  PubMed  Google Scholar 

  5. Obeid, L. M., Linardic, C. M., Karolak, L. A. & Hannun, Y. A. Programmed cell death induced by ceramide. Science 259, 1769–1771 (1993). A landmark study that implicated ceramide in apoptosis.

    CAS  PubMed  Google Scholar 

  6. Venable, M. E., Lee, J. Y., Smyth, M. J., Bielawska, A. & Obeid, L. M. Role of ceramide in cellular senescence. J. Biol. Chem. 270, 30701–30708 (1995). The first study to implicate ceramide in cellular senescence.

    CAS  PubMed  Google Scholar 

  7. Hla, T. Physiological and pathological actions of sphingosine 1-phosphate. Semin. Cell Dev. Biol. 15, 513–520 (2004).

    CAS  PubMed  Google Scholar 

  8. Chalfant, C. E. & Spiegel, S. Sphingosine 1-phosphate and ceramide 1-phosphate: expanding roles in cell signaling. J. Cell Sci. 118, 4605–4612 (2005).

    CAS  PubMed  Google Scholar 

  9. Mitsutake, S. et al. Ceramide kinase is a mediator of calcium-dependent degranulation in mast cells. J. Biol. Chem. 279, 17570–17577 (2004).

    CAS  PubMed  Google Scholar 

  10. Hinkovska-Galcheva, V. et al. Ceramide 1-phosphate, a mediator of phagocytosis. J. Biol. Chem. 280, 26612–26621 (2005).

    CAS  PubMed  Google Scholar 

  11. Radin, N. S., Shayman, J.A. & Inokuchi, J.-I. Metabolic effects of inhibiting glucosylceramide synthesis with PDMP and other substances. Adv. Lipid Res. 26, 183–211 (1993).

    CAS  PubMed  Google Scholar 

  12. Gouaze-Andersson, V. & Cabot, M. C. Glycosphingolipids and drug resistance. Biochim. Biophys. Acta 1758, 2096–2103 (2006).

    CAS  PubMed  Google Scholar 

  13. Hannun, Y. A. & Obeid, L. M. The ceramide-centric universe of lipid-mediated cell regulation: stress encounters of the lipid kind. J. Biol. Chem. 277, 25847–25850 (2002).

    CAS  PubMed  Google Scholar 

  14. Linn, S. C. et al. Regulation of de novo sphingolipid biosynthesis and the toxic consequences of its disruption. Biochem. Soc. Trans. 29, 831–835 (2001).

    CAS  PubMed  Google Scholar 

  15. Pewzner-Jung, Y., Ben-Dor, S. & Futerman, A. H. When do Lasses (longevity assurance genes) become CerS (ceramide synthases)?: insights into the regulation of ceramide synthesis. J. Biol. Chem. 281, 25001–25005 (2006).

    CAS  PubMed  Google Scholar 

  16. Causeret, C., Geeraert, L., Van der Hoeven, G., Mannaerts, G. P. & van Veldhoven, P. P. Further characterization of rat dihydroceramide desaturase: tissue distribution, subcellular localization, and substrate specificity. Lipids 35, 1117–1125 (2000).

    CAS  PubMed  Google Scholar 

  17. Wijesinghe, D. S. et al. Substrate specificity of human ceramide kinase. J. Lipid Res. 46, 2706–2716 (2005).

    CAS  PubMed  Google Scholar 

  18. Raas-Rothschild, A., Pankova-Kholmyansky, I., Kacher, Y. & Futerman, A. H. Glycosphingolipidoses: beyond the enzymatic defect. Glycoconj. J. 21, 295–304 (2004).

    CAS  PubMed  Google Scholar 

  19. Tafesse, F. G., Ternes, P. & Holthuis, J. C. The multigenic sphingomyelin synthase family. J. Biol. Chem. 281, 29421–29425 (2006).

    CAS  PubMed  Google Scholar 

  20. Hakomori, S. Traveling for the glycosphingolipid path. Glycoconj. J. 17, 627–647 (2000).

    CAS  PubMed  Google Scholar 

  21. Ichikawa, S. & Hirabayashi, Y. Glucosylceramide synthase and glycosphingolipid synthesis. Trends Cell Biol. 8, 198–202 (1998).

    CAS  PubMed  Google Scholar 

  22. Marchesini, N. & Hannun, Y. A. Acid and neutral sphingomyelinases: roles and mechanisms of regulation. Biochem. Cell Biol. 82, 27–44 (2004).

    CAS  PubMed  Google Scholar 

  23. Xu, R. et al. Golgi alkaline ceramidase regulates cell proliferation and survival by controlling levels of sphingosine and S1P. FASEB J. 20, 1813–1825 (2006).

    CAS  PubMed  Google Scholar 

  24. Galadari, S. et al. Identification of a novel amidase motif in neutral ceramidase. Biochem. J. 393, 687–695 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Hait, N. C., Oskeritzian, C. A., Paugh, S. W., Milstien, S. & Spiegel, S. Sphingosine kinases, sphingosine 1-phosphate, apoptosis and diseases. Biochim. Biophys. Acta 1758, 2016–2026 (2006).

    CAS  PubMed  Google Scholar 

  26. Johnson, K. R. et al. Role of human sphingosine-1-phosphate phosphatase 1 in the regulation of intra- and extracellular sphingosine-1-phosphate levels and cell viability. J. Biol. Chem. 278, 34541–34547 (2003).

    CAS  PubMed  Google Scholar 

  27. Brindley, D. N. Lipid phosphate phosphatases and related proteins: signaling functions in development, cell division, and cancer. J. Cell Biochem. 92, 900–912 (2004).

    CAS  PubMed  Google Scholar 

  28. Sigal, Y. J., McDermott, M. I. & Morris, A. J. Integral membrane lipid phosphatases/phosphotransferases: common structure and diverse functions. Biochem. J. 387, 281–293 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Bandhuvula, P. & Saba, J. D. Sphingosine-1-phosphate lyase in immunity and cancer: silencing the siren. Trends Mol. Med. 13, 210–217 (2007).

    CAS  PubMed  Google Scholar 

  30. Bielawski, J., Szulc, Z. M., Hannun, Y. A. & Bielawska, A. Simultaneous quantitative analysis of bioactive sphingolipids by high-performance liquid chromatography–tandem mass spectrometry. Methods 39, 82–91 (2006).

    CAS  PubMed  Google Scholar 

  31. Merrill, A. H. Jr, Sullards, M. C., Allegood, J. C., Kelly, S. & Wang, E. Sphingolipidomics: high-throughput, structure-specific, and quantitative analysis of sphingolipids by liquid chromatography tandem mass spectrometry. Methods 36, 207–224 (2005). A comprehensive and cutting-edge review on mass spectrometry methodology to analyse the sphingolipidome.

    CAS  PubMed  Google Scholar 

  32. Romiti, E. et al. Characterization of sphingomyelinase activity released by thrombin-stimulated platelets. Mol. Cell. Biochem. 205, 75–81 (2000).

    CAS  PubMed  Google Scholar 

  33. Delon, C. et al. Sphingosine kinase 1 is an intracellular effector of phosphatidic acid. J. Biol. Chem. 279, 44763–44774 (2004).

    CAS  PubMed  Google Scholar 

  34. Lopez-Montero, I. et al. Rapid transbilayer movement of ceramides in phospholipid vesicles and in human erythrocytes. J. Biol. Chem. 280, 25811–25819 (2005).

    CAS  PubMed  Google Scholar 

  35. Khan, W. A. et al. Use of D-erythro-sphingosine as a pharmacologic inhibitor of protein kinase C in human platelets. Biochem. J. 278, 387–392 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Xia, P. et al. Tumor necrosis factor-α induces adhesion molecule expression through the sphingosine kinase pathway. Proc. Natl Acad. Sci. USA 95, 14196–14201 (1998). An important study that first demonstrated the activation of sphingosine kinase by TNFα.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 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). An important study that implicates the SK1–S1P pathway in inflammation.

    CAS  PubMed  Google Scholar 

  38. Hla, T., Lee, M. J., Ancellin, N., Paik, J. H. & Kluk, M. J. Lysophospholipids — receptor revelations. Science 294, 1875–1878 (2001).

    CAS  PubMed  Google Scholar 

  39. Boujaoude, L. C. et al. Cystic fibrosis transmembrane regulator regulates uptake of sphingoid base phosphates and lysophosphatidic acid: modulation of cellular activity of sphingosine 1-phosphate. J. Biol. Chem. 276, 35258–35264 (2001).

    CAS  PubMed  Google Scholar 

  40. Mitra, P. et al. Role of ABCC1 in export of sphingosine-1-phosphate from mast cells. Proc. Natl Acad. Sci. USA 103, 16394–16399 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Hanada, K. et al. Molecular machinery for non-vesicular trafficking of ceramide. Nature 426, 803–809 (2003). A breakthrough study on the discovery of ceramide transfer protein.

    CAS  PubMed  Google Scholar 

  42. Fugmann, T. et al. Regulation of secretory transport by protein kinase D-mediated phosphorylation of the ceramide transfer protein. J. Cell Biol. 178, 15–22 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Chalfant, C. E., Szulc, Z., Roddy, P., Bielawska, A. & Hannun, Y. A. The structural requirements for ceramide activation of serine–threonine protein phosphatases. J. Lipid Res. 45, 496–506 (2004).

    CAS  PubMed  Google Scholar 

  44. Dbaibo, G. et al. Rb as a downstream target for a ceramide-dependent pathway of growth arrest. Proc. Natl Acad. Sci. USA 92, 1347–1351 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Lee, J. Y., Hannun, Y. A. & Obeid, L. M. Ceramide inactivates cellular protein kinase Cα. J. Biol. Chem. 271, 13169–13174 (1996).

    CAS  PubMed  Google Scholar 

  46. Zhou, H. L., Summers, S. K., 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 

  47. Müller, G. et al. PKCζ is a molecular switch in signal transduction of TNF-α, bifunctionally regulated by ceramide and arachidonic acid. EMBO J. 14, 1961–1969 (1995).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  49. Zhang, Y. H. et al. Kinase suppressor of Ras is ceramide-activated protein kinase. Cell 89, 63–72 (1997).

    CAS  PubMed  Google Scholar 

  50. Heinrich, M. et al. Cathepsin D links TNF-induced acid sphingomyelinase to Bid-mediated caspase-9 and -3 activation. Cell Death Differ. 11, 550–563 (2004).

    CAS  PubMed  Google Scholar 

  51. Wang, G. et al. Direct binding to ceramide activates protein kinase Cζ before the formation of a pro-apoptotic complex with PAR-4 in differentiating stem cells. J. Biol. Chem. 280, 26415–26424 (2005).

    CAS  PubMed  Google Scholar 

  52. Okajima, F. Plasma lipoproteins behave as carriers of extracellular sphingosine 1-phosphate: is this an atherogenic mediator or an anti-atherogenic mediator? Biochim. Biophys. Acta 1582, 132–137 (2002).

    CAS  PubMed  Google Scholar 

  53. Lee, M. J. et al. Sphingosine-1-phosphate as a ligand for the G protein coupled receptor EDG-1. Science 279, 1552–1555 (1998). The first study to identify and characterize an S1P receptor.

    CAS  PubMed  Google Scholar 

  54. Bose, R. et al. Ceramide synthase mediates daunorubicin-induced apoptosis: an alternative mechanism for generating death signals. Cell 82, 405–414 (1995). An important study implicating ceramide synthase in chemotherapy-induced apoptosis.

    CAS  PubMed  Google Scholar 

  55. Perry, D. K. et al. Serine palmitoyltransferase regulates de novo ceramide generation during etoposide-induced apoptosis. J. Biol. Chem. 275, 9078–9084 (2000).

    CAS  PubMed  Google Scholar 

  56. Kroesen, B. J. et al. BcR-induced apoptosis involves differential regulation of C16 and C24-ceramide formation and sphingolipid-dependent activation of the proteasome. J. Biol. Chem. 278, 14723–14731 (2003).

    CAS  PubMed  Google Scholar 

  57. Chalfant, C. E. et al. De novo ceramide regulates the alternative splicing of caspase 9 and Bcl-x in A549 lung adenocarcinoma cells. Dependence on protein phosphatase-1. J. Biol. Chem. 277, 12587–12595 (2002).

    CAS  PubMed  Google Scholar 

  58. Merrill, A. H. Jr, Wang, E. & Mullins, R. E. Kinetics of long-chain (sphingoid) base biosynthesis in intact LM cells: effects of varying the extracellular concentrations of serine and fatty acid precursors of this pathway. Biochemistry 27, 340–345 (1988).

    CAS  PubMed  Google Scholar 

  59. 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  PubMed  Google Scholar 

  60. Dickson, R. C., Sumanasekera, C. & Lester, R. L. Functions and metabolism of sphingolipids in Saccharomyces cerevisiae. Prog. Lipid Res. 45, 447–465 (2006).

    CAS  PubMed  Google Scholar 

  61. 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 

  62. Friant, S., Lombardi, R., Schmelzle, T., Hall, M. N. & Riezman, H. Sphingoid base signaling via Pkh kinases is required for endocytosis in yeast. EMBO J. 20, 6783–6792 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Meier, K. D., Deloche, O., Kajiwara, K., Funato, K. & Riezman, H. Sphingoid base is required for translation initiation during heat stress in Saccharomyces cerevisiae. Mol. Biol. Cell 17, 1164–1175 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Unger, R. H. Minireview: weapons of lean body mass destruction: the role of ectopic lipids in the metabolic syndrome. Endocrinology 144, 5159–5165 (2003).

    CAS  PubMed  Google Scholar 

  65. Holland, W. L. et al. Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell Metab. 5, 167–179 (2007). An important study that implicates ceramide in insulin resistance.

    CAS  PubMed  Google Scholar 

  66. Rotolo, J. A. et al. Caspase-dependent and -independent activation of acid sphingomyelinase signaling. J. Biol. Chem. 280, 26425–26434 (2005).

    CAS  PubMed  Google Scholar 

  67. Lozano, J. et al. Cell autonomous apoptosis defects in acid sphingomyelinase knockout fibroblasts. J. Biol. Chem. 276, 442–448 (2001).

    CAS  PubMed  Google Scholar 

  68. Garcia-Barros, M. et al. Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science 300, 1155–1159 (2003).

    CAS  PubMed  Google Scholar 

  69. Zeidan, Y. H., Wu, B. X., Jenkins, R. W., Obeid, L. M. & Hannun, Y. A. A novel role for protein kinase Cδ-mediated phosphorylation of acid sphingomyelinase in UV light-induced mitochondrial injury. FASEB J. 13 Aug 2007 (doi:10.1096/fj.07-8967com).

    CAS  PubMed  Google Scholar 

  70. Grassme, H., Riehle, A., Wilker, B. & Gulbins, E. Rhinoviruses infect human epithelial cells via ceramide-enriched membrane platforms. J. Biol. Chem. 280, 26256–26262 (2005).

    CAS  PubMed  Google Scholar 

  71. Zeidan, Y. H. et al. Acid ceramidase but not acid sphingomyelinase is required for tumor necrosis factor-α-induced PGE2 production. J. Biol. Chem. 281, 24695–24703 (2006).

    CAS  PubMed  Google Scholar 

  72. Zeidan, Y. H. & Hannun, Y. A. Activation of acid sphingomyelinase by protein kinase Cδ-mediated phosphorylation. J. Biol. Chem. 282, 11549–11561 (2007).

    CAS  PubMed  Google Scholar 

  73. Lin, T. et al. Role of acidic sphingomyelinase in Fas/CD95-mediated cell death. J. Biol. Chem. 275, 8657–8663 (2000).

    CAS  PubMed  Google Scholar 

  74. Nix, M. & Stoffel, W. Perturbation of membrane microdomains reduces mitogenic signaling and increases susceptibility to apoptosis after T cell receptor stimulation. Cell Death Differ. 7, 413–424 (2000).

    CAS  PubMed  Google Scholar 

  75. Castillo, S. S., Levy, M., Thaikoottathil, J. V. & Goldkorn, T. Reactive nitrogen and oxygen species activate different sphingomyelinases to induce apoptosis in airway epithelial cells. Exp. Cell Res. 313, 2680–2686 (2007).

    CAS  PubMed  Google Scholar 

  76. Becker, K. P., Kitatani, K., Idkowiak-Baldys, J., Bielawski, J. & Hannun, Y. A. Selective inhibition of juxtanuclear translocation of protein kinase C βII by a negative feedback mechanism involving ceramide formed from the salvage pathway. J. Biol. Chem. 280, 2606–2612 (2005).

    CAS  PubMed  Google Scholar 

  77. Clarke, C. J. et al. The extended family of neutral sphingomyelinases. Biochemistry 45, 11247–11256 (2006).

    CAS  PubMed  Google Scholar 

  78. Hofmann, K., Tomiuk, S., Wolff, G. & Stoffel, W. Cloning and characterization of the mammalian brain-specific, Mg2+-dependent neutral sphingomyelinase. Proc. Natl Acad. Sci. USA 97, 5895–5900 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Marchesini, N., Luberto, C. & Hannun, Y. A. Biochemical properties of mammalian neutral sphingomyelinase 2 and its role in sphingolipid metabolism. J. Biol. Chem. 278, 13775–13783 (2003).

    CAS  PubMed  Google Scholar 

  80. Aubin, I. et al. A deletion in the gene encoding sphingomyelin phosphodiesterase 3 (Smpd3) results in osteogenesis and dentinogenesis imperfecta in the mouse. Nature Genet. 37, 803–805 (2005).

    CAS  PubMed  Google Scholar 

  81. Stoffel, W. et al. Neutral sphingomyelinase (SMPD3) deficiency causes a novel form of chondrodysplasia and dwarfism that is rescued by Col2A1-driven smpd3 transgene expression. Am. J. Pathol. 171, 153–161 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Karakashian, A. A., Giltiay, N. V., Smith, G. M. & Nikolova-Karakashian, M. N. Expression of neutral sphingomyelinase-2 (NSMase-2) in primary rat hepatocytes modulates IL-β-induced JNK activation. FASEB J. 18, 968–970 (2004).

    CAS  PubMed  Google Scholar 

  83. De Palma, C., Meacci, E., Perrotta, C., Bruni, P. & Clementi, E. Endothelial nitric oxide synthase activation by tumor necrosis factor α through neutral sphingomyelinase 2, sphingosine kinase 1, and sphingosine 1 phosphate receptors: a novel pathway relevant to the pathophysiology of endothelium. Arterioscler. Thromb. Vasc. Biol. 26, 99–105 (2006).

    CAS  PubMed  Google Scholar 

  84. Rutkute, K., Karakashian, A. A., Giltiay, N. V., Dobierzewska, A. & Nikolova-Karakashian, M. N. Aging in rat causes hepatic hyperresponsiveness to interleukin-1β which is mediated by neutral sphingomyelinase-2. Hepatology 46, 1166–1176 (2007). A crucial study that demonstrates a role for ceramide and sphingomyelin in ageing in vivo.

    CAS  PubMed  Google Scholar 

  85. Clarke, C. J., Truong, T. G. & Hannun, Y. A. Role for neutral sphingomyelinase-2 in tumor necrosis factor α-stimulated expression of vascular cell adhesion molecule-1 (VCAM) and intercellular adhesion molecule-1 (ICAM) in lung epithelial cells: p38 MAPK is an upstream regulator of nSMase2. J. Biol. Chem. 282, 1384–1396 (2007).

    CAS  PubMed  Google Scholar 

  86. Grimm, M. O. et al. Regulation of cholesterol and sphingomyelin metabolism by amyloid-β and presenilin. Nature Cell Biol. 7, 1118–1123 (2005).

    CAS  PubMed  Google Scholar 

  87. Zeng, C. et al. Amyloid-β peptide enhances tumor necrosis factor-α-induced iNOS through neutral sphingomyelinase/ceramide pathway in oligodendrocytes. J. Neurochem. 94, 703–712 (2005).

    CAS  PubMed  Google Scholar 

  88. Hayashi, Y., Kiyono, T., Fujita, M. & Ishibashi, M. cca1 is required for formation of growth-arrested confluent monolayer of rat 3Y1 cells. J. Biol. Chem. 272, 18082–18086 (1997).

    CAS  PubMed  Google Scholar 

  89. Marchesini, N. et al. Role for mammalian neutral sphingomyelinase 2 in confluence-induced growth arrest of MCF7 cells. J. Biol. Chem. 279, 25101–25111 (2004).

    CAS  PubMed  Google Scholar 

  90. Tani, M. & Hannun, Y. A. Analysis of membrane topology of neutral sphingomyelinase 2. FEBS Lett. 581, 1323–1328 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Spiegel, S. & Milstien, S. Sphingosine-1-phosphate: an enigmatic signalling lipid. Nature Rev. Mol. Cell Biol. 4, 397–407 (2003).

    CAS  Google Scholar 

  92. Johnson, K. R., Becker, K. P., Facchinetti, M. M., Hannun, Y. A. & Obeid, L. M. PKC-dependent activation of sphingosine kinase 1 and translocation to the plasma membrane. Extracellular release of sphingosine-1-phosphate induced by phorbol 12-myristate 13-acetate (PMA). J. Biol. Chem. 277, 35257–35262 (2002).

    CAS  PubMed  Google Scholar 

  93. Melendez, A., Floto, R. A., Gillooly, D. J., Harnett, M. M. & Allen, J. M. FcγRI coupling to phospholipase D initiates sphingosine kinase-mediated calcium mobilization and vesicular trafficking. J. Biol. Chem. 273, 9393–9402 (1998).

    CAS  PubMed  Google Scholar 

  94. Pitson, S. M. et al. Activation of sphingosine kinase 1 by ERK1/2-mediated phosphorylation. EMBO J. 22, 5491–5500 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Taha, T. A., Argraves, K. M. & Obeid, L. M. Sphingosine-1-phosphate receptors: receptor specificity versus functional redundancy. Biochim. Biophys. Acta 1682, 48–55 (2004).

    CAS  PubMed  Google Scholar 

  96. Xia, P. et al. Sphingosine kinase interacts with TRAF2 and dissects tumor necrosis factor-α signaling. J. Biol. Chem. 277, 7996–8003 (2002).

    CAS  PubMed  Google Scholar 

  97. Billich, A. et al. Basal and induced sphingosine kinase 1 activity in A549 carcinoma cells: function in cell survival and IL-1β and TNF-α induced production of inflammatory mediators. Cell Signal. 17, 1203–1217 (2005).

    CAS  PubMed  Google Scholar 

  98. Lee, M. J. et al. Vascular endothelial cell adherens junction assembly and morphogenesis induced by sphingosine-1-phosphate. Cell 99, 301–312 (1999).

    CAS  PubMed  Google Scholar 

  99. Liu, Y. et al. Edg-1, the G protein-coupled receptor for sphingosine-1-phosphate, is essential for vascular maturation. J. Clin. Invest. 106, 951–961 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Mizugishi, K. et al. Essential role for sphingosine kinases in neural and vascular development. Mol. Cell. Biol. 25, 11113–11121 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Peters, S. L. & Alewijnse, A. E. Sphingosine-1-phosphate signaling in the cardiovascular system. Curr. Opin. Pharmacol. 7, 186–192 (2007).

    CAS  PubMed  Google Scholar 

  102. Rosen, H., Sanna, G. & Alfonso, C. Egress: a receptor-regulated step in lymphocyte trafficking. Immunol. Rev. 195, 160–177 (2003).

    CAS  PubMed  Google Scholar 

  103. Gonsette, R. E. New immunosuppressants with potential implication in multiple sclerosis. J. Neurol. Sci. 223, 87–93 (2004).

    CAS  PubMed  Google Scholar 

  104. Taha, T. A. et al. Loss of sphingosine kinase-1 activates the intrinsic pathway of programmed cell death: modulation of sphingolipid levels and the induction of apoptosis. FASEB J. 20, 482–484 (2006).

    CAS  PubMed  Google Scholar 

  105. Pettus, B. J. et al. Ceramide 1-phosphate is a direct activator of cytosolic phospholipase A2. J. Biol. Chem. 279, 11320–11326 (2004).

    CAS  PubMed  Google Scholar 

  106. Mitsutake, S. & Igarashi, Y. Calmodulin is involved in the Ca2+-dependent activation of ceramide kinase as a calcium sensor. J. Biol. Chem. 280, 40436–40441 (2005).

    CAS  PubMed  Google Scholar 

  107. Gomez-Munoz, A. Ceramide 1-phosphate/ceramide, a switch between life and death. Biochim. Biophys. Acta 1758, 2049–2056 (2006).

    CAS  PubMed  Google Scholar 

  108. Raggers, R. J., van Helvoort, A., Evers, R. & van Meer, G. The human multidrug resistance protein MRP1 translocates sphingolipid analogs across the plasma membrane. J. Cell Sci. 112, 415–422 (1999).

    CAS  PubMed  Google Scholar 

  109. Schulz, A. et al. The CLN9 protein, a regulator of dihydroceramide synthase. J. Biol. Chem. 281, 2784–2794 (2006).

    CAS  PubMed  Google Scholar 

  110. Kraveka, J. M. et al. Involvement of dihydroceramide desaturase in cell cycle progression in human neuroblastoma cells. J. Biol. Chem. 282, 16718–16728 (2007).

    CAS  PubMed  Google Scholar 

  111. Zheng, W. et al. Ceramides and other bioactive sphingolipid backbones in health and disease: lipidomic analysis, metabolism and roles in membrane structure, dynamics, signaling and autophagy. Biochim. Biophys. Acta 1758, 1864–1884 (2006).

    CAS  PubMed  Google Scholar 

  112. Ignatov, A. et al. Role of the G-protein-coupled receptor GPR12 as high-affinity receptor for sphingosylphosphorylcholine and its expression and function in brain development. J. Neurosci. 23, 907–914 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Zeidan, Y. H. & Hannun, Y. A. Translational aspects of sphingolipid metabolism. Trends Mol. Med. 13, 327–336 (2007).

    CAS  PubMed  Google Scholar 

  114. Radin, N. S. Designing anticancer drugs via the achilles heel: ceramide, allylic ketones, and mitochondria. Bioorg. Med. Chem. 11, 2123–2142 (2003).

    CAS  PubMed  Google Scholar 

  115. Summers, S. A. Ceramides in insulin resistance and lipotoxicity. Prog. Lipid Res. 45, 42–72 (2006).

    CAS  PubMed  Google Scholar 

  116. Wattenberg, B. W., Pitson, S. M. & Raben, D. M. The sphingosine and diacylglycerol kinase superfamily of signaling kinases: localization as a key to signaling function. J. Lipid Res. 47, 1128–1139 (2006).

    CAS  PubMed  Google Scholar 

  117. Alvarez-Vasquez, F. et al. Simulation and validation of modelled sphingolipid metabolism in Saccharomyces cerevisiae. Nature 433, 425–430 (2005).

    CAS  PubMed  Google Scholar 

  118. D'Angelo, G. et al. Glycosphingolipid synthesis requires FAPP2 transfer of glucosylceramide. Nature 449, 62–67 (2007).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to thank all past and present members of our laboratories. This work was supported by a Veterans Affairs Merit Award (L.M.O.) and the National Institutes of Health (Y.A.H.).

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DATABASES

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Niemann–Pick disease

FURTHER INFORMATION

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Ceramide web site

Glossary

DAG

sn-1,2-diacylglycerol is a key metabolic intermediate in glycerolipid synthesis that also serves as a second messenger in regulating classical and novel protein kinase C enzymes.

Protein kinase C

(PKC). A family of closely related protein kinases that are highly conserved in their catalytic domains. Classical PKCs are regulated by diacylglycerol (DAG) and calcium; novel PKCs are regulated by DAG only; and atypical PKCs are not regulated by either DAG or calcium.

Ceramide synthase

(CerS, Lass). An enzyme that introduces the acyl chain to sphingoid bases, thereby forming dihydroceramides and ceramides with specific N-linked fatty acids.

Acid SMase

A sphingomyelinase enzyme with an acid pH optimum that removes the phosphorylcholine head group from sphingomyelin, generating ceramide (or dihydroceramides). Activity is defective in patients with type A or B Niemann–Pick disease.

Neutral SMase

(nSMases). An emerging family of sphingomyelinase enzymes with a neutral pH optimum that removes the phosphorylcholine head group from sphingomyelin, generating ceramide (or dihydroceramides).

Ceramidase

A hydrolase that removes the fatty acyl groups from ceramides and dihydroceramides. Three distinct enzyme families are recognized on the basis of their pH optima (acid, neutral and alkaline).

Glycosphingolipid

A complex sphingolipid with a carbohydrate head group that is attached to the 1-hydroxy group of ceramide. The simplest glycosphingolipids are glucosylceramide and galactosylceramide with a glucose or galactose group, respectively, from which more complex glycosphingolipids can be synthesized by the incorporation of additional glycose subunits.

Salvage pathway

In addition to de novo synthesis, sphingolipids can be resynthesized following the breakdown of complex sphingolipids (mostly in the lysosome) through the re-incorporation of the liberated sphingosine into ceramide.

ABC transporter superfamily

A family of membrane proteins that regulate the transport of small molecules in an ATP-dependent process.

Ceramide transfer protein

(CERT). Belongs to a family of lipid transporters, and selectively transports ceramide from its site of synthesis in the ER to the site of sphingomyelin biosynthesis in the Golgi.

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Hannun, Y., Obeid, L. Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol 9, 139–150 (2008). https://doi.org/10.1038/nrm2329

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