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I want to know the significance of sphingolipids in human. I have learnt that sphingomyelin is the most significant type of sphingolipid in human. Also that the sphingomyelin serves as a structural constituent of myelin sheath of nerve fibres.

Is that all? I need to clarify this. Please help me. Thank you

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It turns out sphingilipids have many functions in humans, many of which might still remain unknown. I will discuss here only the general, known functions of sphingolipids, not about specific sphingolipids (as it'll make the answer too long).

  • Sphingolipids are believed to protect the cell surface from harmful external factors by forming a mechanically stable and chemically resistant outer leaflet of plasma membrane lipid bilayer.

  • Certain complex sphingolipids are known to be involved in cell signalling and cell recognition. It has been suggested that ceramide on the cell surface of one cell can be recognized by proteins on another cell's surface. Also, antibodies have been created which recognize the ceramide on a cell's surface1. All this suggests that sphingolipids play an important role in cell-cell interactions which lead to cell recognition and cell signalling.

  • Some simple sphingolipids, like ceramide and sphingosine-1-phosphate, have recently been shown to be mediators in signalling cascades involved in apoptosis2, proliferation3, necrosis4, inflammation5, autophagy6, senescence7, etc.

  • Ceramide-based lipids self-aggregate in cell membranes and form separate phases less fluid than the bulk phospholipids. These sphingolipid-based microdomains, or lipid rafts were originally proposed to sort membrane proteins along the cellular pathways of membrane transport8.

  • Studies indicate that proper sphingoid base synthesis is required to control protein phosphorylation events that are crucial for endocytosis and overexpression of protein kinase C1 (PKC1) and PKH1 or PKH2 (ortholgues of mammalian protein-phosphoinositide dependent protein kinase 1 or PDK1) restores the actin localization defects in the lcb1-100 mutant9,10. A suggested pathway representation would be like this11:

    pathway

  • Decreased levels of ceramide and increased levels of sphingosine-1-phosphate are known to be mechanisms of tumor progression and drug resistance in cancer cells, and are hence being targeted in pharmacological experiments as possible cancer cures12.

  • Sphingolipid (mainly sphingomyelin, ceramide and gangliosides) reorganization and interaction with proteins within cellular membranes is suggested to cause many neurodegenerative disorders13.

  • Sphingolipids are also known to play an important role in microbial pathogenesis since in the context of bacterium- and virus-host interaction, the host is typically the source of sphingolipids, whereas in the context of the protozoan- and fungus-host interaction, both host and pathogen sphingolipids are involved14.

  • Sphingolipids also act as immune response modulators. Exogenously added sphingolipids (especially sphingosine) changed the receptor expression in immunological synapses, including CD3, CD4, CD8, CD45, CD54, etc. disrupting T-helper cell differentiation and prevelance of Th2 cells over Th1 cells. Sphingolipids activate macrophage function via elevation of receptor F4/80 expression and chemokine production. Fumonisin B1 regulates memory cell formation and secondary immune response, and inhibits the DNA synthesis in normal lymphocytes in response to mitogenes, more effective in T cells compared with B cells15.

  • Sphingosine-1-phosphate (S1P) level in lymphoid tissues, especially in thymus, is lowered as compared to blood. This creates S1P gradient that attracts lymphocytes and promotes S1PR1-dependent egress into the blood. When T cells are ready to exit the thymus and enter the blood, S1PR1 is re-expressed so that T cells can respond to the chemotactic effect of high S1P levels in circulation. When T cells re-enter the blood, S1P downregulates S1PR1. Increased lymphoid tissue S1P. blocks egress of lymphocytes by disruption of the S1P gradient or desensitization of S1PR1 on T cells. See the diagram below for representation16:

    S1P

References:

1. Gerrit van Meer, Sandra Hoetzl, Sphingolipid topology and the dynamic organization and function of membrane proteins, FEBS Letters, Volume 584, Issue 9, 3 May 2010, Pages 1800-1805, ISSN 0014-5793, https://doi.org/10.1016/j.febslet.2009.10.020.

2. Hannun YA, Obeid LM (July 2002). "The Ceramide-centric universe of lipid-mediated cell regulation: stress encounters of the lipid kind". The Journal of Biological Chemistry. 277 (29): 25847–50. doi:10.1074/jbc.R200008200

3. Spiegel S, Milstien S (July 2002). "Sphingosine 1-phosphate, a key cell signaling molecule". The Journal of Biological Chemistry. 277 (29): 25851–4. doi:10.1074/jbc.R200007200

4. Hetz CA, Hunn M, Rojas P, Torres V, Leyton L, Quest AF (December 2002). "Caspase-dependent initiation of apoptosis and necrosis by the Fas receptor in lymphoid cells: onset of necrosis is associated with delayed ceramide increase". Journal of Cell Science. 115 (Pt 23): 4671–83. doi:10.1242/jcs.00153

5. Snider AJ, Orr Gandy KA, Obeid LM (June 2010). "Sphingosine kinase: Role in regulation of bioactive sphingolipid mediators in inflammation". Biochimie. 92 (6): 707–15. doi:10.1016/j.biochi.2010.02.008.

6. Lavieu G, Scarlatti F, Sala G, Carpentier S, Levade T, Ghidoni R, Botti J, Codogno P (March 2006). "Regulation of autophagy by sphingosine kinase 1 and its role in cell survival during nutrient starvation". The Journal of Biological Chemistry. 281 (13): 8518–27. doi:10.1074/jbc.M506182200

7. Venable ME, Lee JY, Smyth MJ, Bielawska A, Obeid LM (December 1995). "Role of ceramide in cellular senescence". The Journal of Biological Chemistry. 270 (51): 30701–8. doi:10.1074/jbc.270.51.30701.

8. Brown DA, London E (June 2000). "Structure and function of sphingolipid- and cholesterol-rich membrane rafts". The Journal of Biological Chemistry. 275 (23): 17221–4. doi:10.1074/jbc.R000005200

9. Friant S, Zanolari B, Riezman H. Increased protein kinase or decreased PP2A activity bypasses sphingoid base requirement in endocytosis. Embo J. 2000;19:2834–2844.

10. Friant S, Lombardi R, Schmelzle T, Hall MN, Riezman H. Sphingoid base signaling via Pkh kinases is required for endocytosis in yeast. Embo J. 2001;20:6783–6792.

11. Rao, Raghavendra Pralhada, and Jairaj K Acharya. “Sphingolipids and Membrane Biology as Determined from Genetic Models.” Prostaglandins & other lipid mediators 85.1-2 (2008): 1–16. PMC. Web. 5 May 2017.

12. Oskouian, Babak, and Julie D. Saba. “Cancer Treatment Strategies Targeting Sphingolipid Metabolism.” Advances in experimental medicine and biology 688 (2010): 185–205. Print.

13. Elena Posse de Chaves, Simonetta Sipione, Sphingolipids and gangliosides of the nervous system in membrane function and dysfunction, FEBS Letters, Volume 584, Issue 9, 3 May 2010, Pages 1748-1759, ISSN 0014-5793, https://doi.org/10.1016/j.febslet.2009.12.010.

14. Heung LJ, Luberto C, Del Poeta M: Role of sphingolipids in microbial pathogenesis. Infect Immun. 2006;74(1):28–39. 10.1128/IAI.74.1.28-39.2006

15. Sphingolipid modulation of immune cell function: The Association of the Sphingolipidologists

16. Maceyka M., Spiegel S. Sphingolipid metabolites in inflammatory disease. Nature. 2014;510:58–67. doi: 10.1038/nature13475.

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    $\begingroup$ An interesting note about S1P: it mediates leukocyte trafficking. The major source of S1P in the blood is erythrocytes. What you can imagine is a gradient of S1P exists where it's high in the blood and perfuses to the tissues. Leukocytes express an S1PR that promotes re-entry to the blood, which is blocked by known tissue retention signals such as CD69. Fingolimod (FTY720), an S1PR inhibitor, is used to prevent T cell egress from lymphoid tissues in the treatment of multiple sclerosis. You can add sphingolipids to your list as immune response modulators! $\endgroup$ – CKM May 5 '17 at 17:04
  • $\begingroup$ @CMosychuk thanks, thats a very nice point! But I can't add it now since I've got some work, I had to finish it up at this much...but I'll do that as soon as I get free. Thanks again :) $\endgroup$ – another 'Homo sapien' May 5 '17 at 17:10

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