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Sphingolipid Metabolism and Analysis in Metabolic Disease

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Sphingolipids and Metabolic Disease

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 721))

Abstract

Sphingolipids are an important class of structural and signaling molecules within the cell. As sphingolipids have been implicated in the development and pathogenesis of insulin resistance and the metabolic syndrome, it is important to understand their regulation and metabolism. Although these lipids are initially produced through a common pathway, there is no “generic” sphingolipid. Indeed, the biophysical and signaling properties of lipids may be manipulated by the subunit composition or isoform of their synthetic enzymes, via regulation of substrate integration. Functionally distinct pools of chemically-equivalent lipids may also be generated by de novo synthesis and recycling of existing complex sphingolipids. The highly integrated metabolism of the many bioactive sphingolipids means that manipulation of one enzyme or metabolite can result in a ripple effect, causing unforeseen changes in metabolite levels, enzyme activities, and cellular programmes. Fortunately, a suite of techniques, ranging from thin-layer chromatography to liquid chromatography-mass spectrometry approaches, allows investigators to undertake a functional characterization of all or part of the sphingolipidome in their systems of interest.

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References

  1. Hanada K. Serine palmitoyltransferase, a key enzyme of sphingolipid metabolism. Biochim Biophys Acta 2003; 1632:16–30.

    PubMed  CAS  Google Scholar 

  2. Hannun YA, Obeid LM. Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol cell Biol 2008; 9:139–150.

    PubMed  CAS  Google Scholar 

  3. Pruett ST, Bushnev A, Hagedorn K et al. Biodiversity of sphingoid bases (“sphingosines”) and related amino alcohols. J Lipid Res 2008; 49:1621–1639.

    PubMed  CAS  Google Scholar 

  4. Baldeweg SE, Golay A, Natali A et al. Insulin resistance, lipid and fatty acid concentrations in 867 healthy Europeans. European Group for the Study of Insulin Resistance (EGIR). Eur J Clin Invest 2000; 30:45–52.

    PubMed  CAS  Google Scholar 

  5. UngerRH, Orci L. Lipotoxic diseases of nonadipose tissues in obesity. Int J Obes Relat Metab Disord 2000; 24Suppl 4:S28–S32.

    PubMed  CAS  Google Scholar 

  6. Lewis GF, Carpentier A, Adeli K et al. Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. Endocr Rev 2002; 23:201–229.

    PubMed  CAS  Google Scholar 

  7. Zhang L, Keung W, Samokhvalov V et al. Role of fatty acid uptake and fatty acid beta-oxidation in mediating insulin resistance in heart and skeletal muscle. Biochim Biophys Acta 2010; 1801:1–22.

    PubMed  CAS  Google Scholar 

  8. Baranowski M, Blachnio A, Zabielski P et al. PPA Ralpha agonist induces the accumulation of ceramide in the heart of rats fed high-fat diet. J Physiol Pharmacol 2007; 58:57–72.

    PubMed  CAS  Google Scholar 

  9. Itani SI, Ruderman NB, Schmieder F et al. Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha. Diabetes 2002; 51:2005–2011.

    PubMed  CAS  Google Scholar 

  10. Te Sligte K, Bourass I, Sels JP et al. Non-alcoholic steatohepatitis: review of a growing medical problem. Eur J Intern Med 2004; 15:10–21.

    Google Scholar 

  11. Adams JM 2nd, Pratipanawatr T, Berria R et al. Ceramide content is increased in skeletal muscle from obese insulin-resistant humans. Diabetes 2004; 53:25–31.

    PubMed  CAS  Google Scholar 

  12. Ussher JR, Koves TR, Cadete VJ et al. Inhibition of de novo ceramide synthesis reverses diet-induced insulin resistance and enhances whole-body oxygen consumption. Diabetes 2010; 59(10):2453–2464.

    PubMed  CAS  Google Scholar 

  13. Xiao-Yun X, Zhuo-Xiong C, Min-Xiang L et al. Med Sci Monit 2009; 15:BR254–BR261.

    PubMed  Google Scholar 

  14. Watson ML, Coghlan M, Hundal HS. Modulating serine palmitoyl transferase (SPT) expression and activity unveils a crucial role in lipid-induced insulin resistance in rat skeletal muscle cells. Biochem J 2009; 417:791–801.

    PubMed  CAS  Google Scholar 

  15. Abdul-Ghani MA, Muller FL, Liu Y et al. Am J Physiol Endocrinol Metab 2008; 295:E678–E685.

    PubMed  CAS  Google Scholar 

  16. Dyntar D, Eppenberger-Eberhardt M, Maedler K et al. Glucose and palmitic acid induce degeneration of myofibrils and modulate apoptosis in rat adult cardiomyocytes. Diabetes 2001; 50:2105–2113.

    PubMed  CAS  Google Scholar 

  17. Shimabukuro M, Higa M, Zhou YT et al. Lipoapoptosis in beta-cells of obese prediabetic fa/fa rats. Role of serine palmitoyltransferase overexpression. J Biol Chem 1998; 273:32487–32490.

    PubMed  CAS  Google Scholar 

  18. Islam MS, Loots du T. Experimental rodent models of type 2 diabetes: a review. Methods Find Exp Clin Pharmacol 2009; 31:249–261.

    PubMed  CAS  Google Scholar 

  19. Chatzigeorgiou A, Halapas A, Kalafatakis K et al. The use of animal models in the study of diabetes mellitus. In Vivo 2009; 23:245–258.

    PubMed  CAS  Google Scholar 

  20. Williams RD, Wang E, Merrill AH Jr. Enzymology of long-chain base synthesis by liver: characterization of serine palmitoyltransferase in rat liver microsomes. Arch Biochem Biophys 1984; 228:282–291.

    PubMed  CAS  Google Scholar 

  21. Krisnangkura K, Sweeley CC. Studies on the mechanism of 3-ketosphinganine synthetase. J Biol Chem 1976; 251:1597–1602.

    PubMed  CAS  Google Scholar 

  22. Mandon EC, Ehses I, Rother J et al. Subcellular localization and membrane topology of serine palmitoyltransferase, 3-dehydrosphinganine reductase, and sphinganine N-acyltransferase in mouse liver. J Biol chem 1992; 267:11144–11148.

    PubMed  CAS  Google Scholar 

  23. Hornemann T, Wei Y, von Eckardstein A. Is the mammalian serine palmitoyltransferase a high-molecular-mass complex? Biochem J 2007; 405:157–164.

    PubMed  CAS  Google Scholar 

  24. Hornemann T, Richard S, Rutti MF et al. Cloning and initial characterization of a new subunit formammalian serine-palmitoyltransferase. J Biol Chem 2006; 281:37275–37281.

    PubMed  CAS  Google Scholar 

  25. Breslow DK, Collins SR, Bodenmiller B et al. Orm family proteins mediate sphingolipid homeostasis. Nature 2010; 463:1048–1053.

    PubMed  CAS  Google Scholar 

  26. Han S, Lone Ma, Schneiter R etal. Orm1 and Orm2 are conserved endoplasmic reticulum membrane proteins regulating lipid homeostasis and protein quality control. Proc Natl Acad Sci USA 2010; 107:5851–5856.

    PubMed  CAS  Google Scholar 

  27. Han G, Gupta SD, Gable K et al. Identification of small subunits of mammalian serine palmitoyltransferase that confer distinct acyl-CoA substrate specificities. Proc Natl Acad Sci USA 2009; 106:8186–8191.

    PubMed  CAS  Google Scholar 

  28. Hanada K, Nishijima M, Fujita T et al. Specificity of inhibitors of serine palmitoyltransferase (SPT), a key enzyme in sphingolipid biosynthesis, in intact cells. A novel evaluation system using an SPT-defective mammalian cell mutant. Biochem Pharmacol 2000; 59:1211–1216.

    PubMed  CAS  Google Scholar 

  29. Miyake Y, Kozutsumi Y, Nakamura S et al. Serine palmitoyltransferase is the primary target of a sphingosine-like immunosuppressant, ISP-1/myriocin. Biochem Biophys Res Commun 1995; 211:396–403.

    PubMed  CAS  Google Scholar 

  30. Ikushiro H, Hayashi H, Kagamiyama H. Reactions of serine palmitoyltransferase with serine and molecular mechanisms of the actions of serine derivatives as inhibitors. Biochemistry 2004; 43:1082–1092.

    PubMed  CAS  Google Scholar 

  31. Wong DT, Fuller RW, Molloy BB. Inhibition of amino acid transaminases by L-cycloserine. Adv Enzyme Regul 1973; 11:139–154.

    PubMed  CAS  Google Scholar 

  32. Williams RD, Sgoutas DS, Zaatari GS et al. Inhibition of serine palmitoyltransferase activity in rabbit aorta by L-cycloserine. J Lipid Res 1987; 28:1478–1481.

    PubMed  CAS  Google Scholar 

  33. Gable K, Gupta SD, Han G et al. A disease-causing mutation in the active site of serine palmitoyltransferase causes catalytic promiscuity. J Biol Chem 2010; 285(30):22846–22852.

    PubMed  CAS  Google Scholar 

  34. Eichler FS, Hornemann T, McCampbell A et al. Overexpression of the wild-type SPT1 subunit lowers desoxysphingolipid levels and rescues the phenotype of HSAN1. J Neurosci 2009; 29:14646–14651.

    PubMed  CAS  Google Scholar 

  35. Penno A, Reilly MM, Houlden H et al. Hereditary sensory neuropathy type 1 is caused by the accumulation of two neurotoxic sphingolipids. J Biol Chem 2010; 285:11178–11187.

    PubMed  CAS  Google Scholar 

  36. Holleran WM, Williams ML, Gao WN et al. Serine-palmitoyl transferase activity in cultured human keratinocytes. J Lipid Res 1990; 31:1655–1661.

    PubMed  CAS  Google Scholar 

  37. Merrill AH Jr, Wang E, Mullins RE. 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 1988; 27:340–345.

    PubMed  CAS  Google Scholar 

  38. Williams RD, Sgoutas DS, Zaatari GS. Enzymology of long-chain base synthesis by aorta: induction of serine palmitoyltransferase activity in rabbit aorta during atherogenesis. J Lipid Res 1986; 27:763–770.

    PubMed  CAS  Google Scholar 

  39. Merrill AH Jr, Nixon DW, Williams RD. Activities of serine palmitoyltransferase (3-ketosphinganine synthase) in microsomes from different rat tissues. J Lipid Res 1985; 26:617–622.

    PubMed  CAS  Google Scholar 

  40. Merrill AH Jr. Characterization of serine palmitoyltransferase activity in Chinese hamster ovary cells. Biochim Biophys Acta 1983; 754:284–291.

    PubMed  CAS  Google Scholar 

  41. Kihara A, Igarashi Y. FVT-1 is a mammalian 3-ketodihydrosphingosine reductase with an active site that faces the cytosolic side of the endoplasmic reticulum membrane. J Biol Chem 2004; 279:49243–49250.

    PubMed  CAS  Google Scholar 

  42. Pewzner-Jung Y, Ben-Dor S, Futerman AH. When do lasses (longevity assurance genes) become CerS (ceramide synthases)?: Insights into the regulation of ceramide synthesis. J Biol Chem 2006; 281:25001–25005.

    PubMed  CAS  Google Scholar 

  43. Laviad EL, Albee L, Pankova-Kholmyansky I et al. Characterization of ceramide synthase 2: tissue distribution, substrate specificity, and inhibition by sphingosine 1-phosphate. J Biol Chem 2008; 283:5677–5684.

    PubMed  CAS  Google Scholar 

  44. Mizutani Y, Kihara A, Igarashi Y. Mammalian Lass6 and its related family members regulate synthesis of specific ceramides. Biochem J 2005; 390:263–271.

    PubMed  CAS  Google Scholar 

  45. Mizutani Y, Kihara A, Igarashi Y. LASS3 (longevity assurance homologue 3) is a mainly testis-specific (dihydro)ceramide synthase with relatively broad substrate specificity. Biochem J 2006; 398:531–538.

    PubMed  CAS  Google Scholar 

  46. Lahiri S, Futerman AH. LASS5 is a bonafidedihydroceramide synthase that selectively utilizes palmitoyl-CoA as acyl donor. J Biol Chem 2005; 280:33735–33738.

    PubMed  CAS  Google Scholar 

  47. Spassieva SD, Mullen TD, Townsend DM et al. Disruption of ceramide synthesis by CerS2 down-regulation leads to autophagy and the unfolded protein response. Biochem J 2009; 424:273–283.

    PubMed  CAS  Google Scholar 

  48. Schiffmann S, Ziebell S, Sandner J et al. Activation of ceramide synthase 6 by celecoxib leads to a selective induction of C(16:0)-ceramide. Biochem Pharmacol 2010.

    Google Scholar 

  49. Michel C, van Echten-Deckert G, Rother J et al. Characterization of ceramide synthesis. A dihydroceramide desaturase introduces the 4,5-trans-double bond of sphingosine at the level of dihydroceramide. J Biol Chem 1997; 272:22432–22437.

    PubMed  CAS  Google Scholar 

  50. Venable ME, Lee JY, Smyth MJ et al. Role of ceramide in cellular senescence. J Biol Chem 1995; 270:30701–30708.

    PubMed  CAS  Google Scholar 

  51. Jayadev S, Liu B, Bielawska AE et al. Role for ceramide in cell cycle arrest. J Biol Chem 1995;270:2047–2052.

    PubMed  CAS  Google Scholar 

  52. Obeid LM, Linardic CM, Karolak LA et al. Programmed cell death induced by ceramide. Science 1993; 259:1769–1771.

    PubMed  CAS  Google Scholar 

  53. Riboni L, Prinetti A, Bassi R et al. A mediator role of ceramide in the regulation of neuroblastoma Neuro2a cell differentiation. J Biol Chem 1995; 270:26868–26875.

    PubMed  CAS  Google Scholar 

  54. Cowart LA. Sphingolipids: players in the pathology of metabolic disease. Trends Endocrinol Metab 2009; 20:34–42.

    PubMed  CAS  Google Scholar 

  55. Nica AF, Tsao CC, Watt JC et al. Ceramide promotes apoptosis in chronic myelogenous leukemia-derived K562 cells by a mechanism involving caspase-8 and JNk. Cell Cycle 2008; 7:3362–3370.

    PubMed  CAS  Google Scholar 

  56. Park MA, Zhang G, Norris J et al. Regulation of autophagy by ceramide-CD95-PERK signaling. Autophagy 2008; 4:929–931.

    PubMed  CAS  Google Scholar 

  57. Ferrari D, Pinton P, Campanella M et al. Functional and structural alterations in the endoplasmic reticulum and mitochondria during apoptosis triggered by C2-ceramide and CD95/APO-1/FAS receptor stimulation. Biochem Biophys Res Commun 2010; 391:575–581.

    PubMed  CAS  Google Scholar 

  58. Lei X, Zhang S, Bohrer A et al. Calcium-independent phospholipase A2 (iPLA2 beta)-mediated ceramide generation plays a key role in the cross-talk between the endoplasmic reticulum (Er) and mitochondria during Er stress-induced insulin-secreting cell apoptosis. J Biol Chem 2008; 283:34819–34832.

    PubMed  CAS  Google Scholar 

  59. Novgorodov SA, Szulc ZM, Luberto C et al. Positively charged ceramide is a potent inducer of mitochondrial permeabilization. J Biol Chem 2005; 280:16096–16105.

    PubMed  CAS  Google Scholar 

  60. Lin CF, Chen CL, Chang WT et al. Bcl-2 rescues ceramide-and etoposide-induced mitochondrial apoptosis through blockage of caspase-2 activation. J Biol Chem 2005; 280:23758–23765.

    PubMed  CAS  Google Scholar 

  61. Nieto FL, Pescio LG, Favale NO et al. Sphingolipid metabolism is a crucial determinant of cellular fate in nonstimulated proliferating Madin-Darby canine kidney (MDCK) cells. J Biol Chem 2008; 283:25682–25691.

    PubMed  CAS  Google Scholar 

  62. Kitatani K, Idkowiak-Baldys J, Hannun YA. The sphingolipid salvage pathway in ceramide metabolism and signaling. Cell Signal 2008; 20:1010–1018.

    PubMed  CAS  Google Scholar 

  63. Becker KP, Kitatani K, Idkowiak-Baldys J et al. Selective inhibition of juxtanuclear translocation of protein kinase C betaII by a negative feedback mechanism involving ceramide formed from the salvage pathway. J Biol chem 2005; 280:2606–2612.

    PubMed  CAS  Google Scholar 

  64. Wittenberg JB. The separation of sphingosine and related compounds by reversed phase partition chromatography. J Biol Chem 1955; 216:379–390.

    PubMed  CAS  Google Scholar 

  65. Brady RO, Formica JV, Koval GJ. The enzymatic synthesis of sphingosine. II. Further studies on the mechanism of the reaction. J Biol Chem 1958; 233:1072–1076.

    PubMed  CAS  Google Scholar 

  66. Brady RO, Koval GJ. The enzymatic synthesis of sphingosine. J Biol Chem 1958; 233:26–31.

    PubMed  CAS  Google Scholar 

  67. Mao C, Obeid LM. Ceramidases: regulators of cellular responses mediated by ceramide, sphingosine, and sphingosine-1-phosphate. Biochim Biophys Acta 2008; 1781:424–434.

    PubMed  CAS  Google Scholar 

  68. Gillard BK, Clement RG, Marcus DM. Variations among cell lines in the synthesis of sphingolipids in de novo and recycling pathways. Glycobiology 1998; 8:885–890.

    PubMed  CAS  Google Scholar 

  69. Stoffel WH, Bruno; Heimann, Gerhard. Hoppe-Seyler’s Zeitschrift fur physiologische Chemie 1973; 354:1311–1316.

    PubMed  CAS  Google Scholar 

  70. Kennedy S, Kane KA, Pyne NJ et al. Targeting sphingosine-1-phosphate signalling for cardioprotection. Curr Opin Pharmacol 2009; 9:194–201.

    PubMed  CAS  Google Scholar 

  71. Maceyka M, Milstien S, Spiegel S. Sphingosine-1-phosphate: the Swiss armyknife of sphingolipid signaling. J Lipid Res 2009; 50 Suppl:S272–S276.

    PubMed  Google Scholar 

  72. Hait NC, Allegood J, Maceyka M et al. Regulation of histone acetylation in the nucleus by sphingosine-1-phosphate. Science 2009; 325:1254–1257.

    PubMed  CAS  Google Scholar 

  73. Rosen H, Gonzalez-Cabrera PJ, Sanna MG et al. Sphingosine 1-phosphate receptor signaling. Annu Rev Biochem 2009; 78:743–768.

    PubMed  CAS  Google Scholar 

  74. Means CK, Brown JH. Sphingosine-1-phosphate receptor signalling in the heart. Cardiovasc Res 2009; 82:193–200.

    PubMed  CAS  Google Scholar 

  75. Kohama T, Olivera A, Edsall L et al. Molecular cloning and functional characterization of murine sphingosine kinase. J Biol Chem 1998; 273:23722–23728.

    PubMed  CAS  Google Scholar 

  76. Liu H, Sugiura M, Nava VE et al. Molecular cloning and functional characterization of a novel mammalian sphingosine kinase type 2 isoform. J Biol Chem 2000; 275:19513–19520.

    PubMed  CAS  Google Scholar 

  77. Liu H, Toman RE, Goparaju SK et al. Sphingosine kinase type 2 is aputative BH3-only protein that induces apoptosis. J Biol Chem 2003; 278:40330–40336.

    PubMed  CAS  Google Scholar 

  78. Maceyka M, Sankala H, Hait NC et al. SphK1 and SphK2, sphingosine kinase isoenzymes with opposing functions in sphingolipid metabolism. J Biol Chem 2005; 280:37118–37129.

    PubMed  CAS  Google Scholar 

  79. Hofmann LP, Ren S, Schwalm S et al. Sphingosine kinase 1 and 2 regulate the capacity of mesangial cells to resist apoptotic stimuli in an opposing manner. Biol chem 2008; 389:1399–1407.

    PubMed  CAS  Google Scholar 

  80. Tao R, Hoover HE, Honbo N et al. Am J Physiol Heart Circ Physiol 2010; 298:H1022–H1028.

    PubMed  CAS  Google Scholar 

  81. Diab KJ, Adamowicz JJ, Kamocki K et al. Stimulation of sphingosine 1-phosphate signaling as an alveolar cell survival strategy in emphysema. Am J Respir Crit Care Med 2010; 181:344–352.

    PubMed  CAS  Google Scholar 

  82. Colie S, Van Veldhoven PP, Kedjouar B et al. Disruption of sphingosine 1-phosphate lyase confers resistance to chemotherapy and promotes oncogenesis through Bcl-2/Bcl-xL upregulation. Cancer Res 2009; 69:9346–9353.

    PubMed  CAS  Google Scholar 

  83. Takuwa Y, Okamoto Y, Yoshioka K et al. Sphingosine-1-phosphate signaling and biological activities in the cardiovascular system. Biochim Biophys Acta 2008; 1781:483–488.

    PubMed  CAS  Google Scholar 

  84. Marggraf WD, Anderer FA, Kanfer JN. The formation of sphingomyelin fromphosphatidylcholine in plasma membrane preparations from mouse fibroblasts. Biochim Biophys Acta 1981; 664:61–73.

    PubMed  CAS  Google Scholar 

  85. Villani M, Subathra M, Im YB et al. Sphingomyelin synthases regulate production of diacylglycerol at the Golgi. Biochem J 2008; 414:31–41.

    PubMed  CAS  Google Scholar 

  86. Tafesse FG, Huitema K, Hermansson M et al. Both sphingomyelin synthases SMS1 and SMS2 are required for sphingomyelin homeostasis and growth in human HeLa cells. J Biol Chem 2007; 282:17537–17547.

    PubMed  CAS  Google Scholar 

  87. Marinetti GV, Cattieu K. Composition and metabolism of phospholipids of human leukocytes. Chem Phys Lipids 1982; 31:169–177.

    PubMed  CAS  Google Scholar 

  88. Ichikawa S, Hirabayashi Y. Glucosylceramide synthase and glycosphingolipid synthesis. Trends Cell Biol 1998; 8:198–202.

    PubMed  CAS  Google Scholar 

  89. Yip Mc, Dain JA. Frog brain uridine diphosphate galactose-N-acetylgalactosaminyl-N-acetylneuraminyl galactosylglucosylceramide galactosyltransferase. Biochem J 1970; 118:247–252.

    PubMed  CAS  Google Scholar 

  90. Sadhu DP. Influence of lactose on the transglycosidation of sphingosine base in the rat brain. Am J Physiol 1953; 175:283–284.

    PubMed  CAS  Google Scholar 

  91. Fleischer B. Localization of some glycolipid glycosylating enzymes in the Golgi apparatus of rat kidney. J Supramol Struct 1977; 7:79–89.

    PubMed  CAS  Google Scholar 

  92. Merrill AH Jr. Cell regulation by sphingosine and more complex sphingolipids. J Bioenerg Biomembr 1991; 23:83–104.

    PubMed  CAS  Google Scholar 

  93. Pettus BJ, Bielawska A, Spiegel S et al. Ceramide kinase mediates cytokine-and calcium ionophore-induced arachidonic acid release. J Biol Chem 2003; 278:38206–38213.

    PubMed  CAS  Google Scholar 

  94. Pettus BJ, Kitatani K, Chalfant CE et al. The coordination of prostaglandin E2 production by sphingosine-1-phosphate and ceramide-1-phosphate. Mol Pharmacol 2005; 68:330–335.

    PubMed  CAS  Google Scholar 

  95. Sugiura M, Kono K, Liu H et al. Ceramide kinase, a novel lipid kinase. Molecular cloning and functional characterization. J Biol Chem 2002; 277:23294–23300.

    PubMed  CAS  Google Scholar 

  96. Hinkovska-Galcheva V, Boxer LA, Kindzelskii A et al. Ceramide 1-phosphate, a mediator of phagocytosis. J Biol Chem 2005; 280:26612–26621.

    PubMed  CAS  Google Scholar 

  97. Lamour NF, Subramanian P, Wijesinghe DS et al. Ceramide 1-phosphate is required for the translocation of group IVA cytosolic phospholipase A2 and prostaglandin synthesis. J Biol Chem 2009; 284:26897–26907.

    PubMed  CAS  Google Scholar 

  98. Le Stunff H, Giussani P, Maceyka M et al. Recycling of sphingosine is regulated by the concerted actions of sphingosine-1-phosphate phosphohydrolase 1 and sphingosine kinase 2. J Biol Chem 2007; 282:34372–34380.

    PubMed  Google Scholar 

  99. Jasinska R, Zhang QX, Pilquil C et al. Biochem J 1999; 340 (Pt 3):677–686.

    PubMed  CAS  Google Scholar 

  100. Stoffel W, Bauer E, Stahl J. The metabolism of sphingosine bases in Tetrahymena pyriformis. Sphingosine kinase and sphingosine-1-phosphate lyase. Hoppe Seylers Z Physiol Chem 1974; 355:61–74.

    PubMed  CAS  Google Scholar 

  101. Ichi I, Kamikawa C, Nakagawa T et al. Neutral sphingomyelinase-induced ceramide accumulation by oxidative stress during carbon tetrachloride intoxication. Toxicology 2009; 261:33–40.

    PubMed  CAS  Google Scholar 

  102. Santana P, Pena LA, Haimovitz-Friedman A et al. Cell 1996; 86:189–199.

    PubMed  CAS  Google Scholar 

  103. Chigorno V, Riva C, Valsecchi M et al. Acid sphingomyelinase-deficient human lymphoblasts and mice are defective in radiation-induced apoptosis. Eur J Biochem 1997; 250:661–669.

    PubMed  CAS  Google Scholar 

  104. Wilkening G, Linke T, Uhlhorn-Dierks G et al. Degradation of membrane-bound ganglioside GM1. Stimulation by bis(monoacylglycero)phosphate and the activator proteins SaP-B and GM2-aP. J Biol Chem 2000; 275:35814–35819.

    PubMed  CAS  Google Scholar 

  105. Modrak DE, Leon E, Goldenberg DM et al. Ceramide regulates gemcitabine-induced senescence and apoptosis in human pancreatic cancer cell lines. Mol Cancer Res 2009; 7:890–896.

    PubMed  CAS  Google Scholar 

  106. Jenkins GM, Cowart LA, Signorelli P et al. J Biol Chem 2002; 277:42572–45578.

    PubMed  CAS  Google Scholar 

  107. Chalfant CE, Rathman K, Pinkerman RL 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 2002; 277:12587–12595.

    PubMed  CAS  Google Scholar 

  108. Kitatani K, Nemoto M, Akiba S et al. Stimulation by de novo-synthesized ceramide of phospholipase A(2)-dependent cholesterol esterification promoted by the uptake of oxidized low-density lipoprotein in macrophages. Cell Signal 2002; 14:695–701.

    PubMed  CAS  Google Scholar 

  109. Cowart LA, Hannun YA. Selective substrate supply in the regulation of yeast de novo sphingolipid synthesis. J Biol Chem 2007; 282:12330–12340.

    PubMed  CAS  Google Scholar 

  110. Srivastava S, Chan C. Application of metabolic flux analysis to identify the mechanisms of free fatty acid toxicity to human hepatoma cell line. Biotechnol Bioeng 2008; 99:399–410.

    PubMed  CAS  Google Scholar 

  111. Jaffrezou JP, Levade T, Bettaieb A et al. Daunorubicin-induced apoptosis: triggering of ceramide generation through sphingomyelin hydrolysis. EMBO J 1996; 15:2417–2424.

    PubMed  CAS  Google Scholar 

  112. Castillo SS, Levy M, Thaikoottathil JV et al. Reactive nitrogen and oxygen species activate different sphingomyelinases to induce apoptosis in airway epithelial cells. Exp Cell Res 2007; 313:2680–2686.

    PubMed  CAS  Google Scholar 

  113. Zager RA, Conrad DS, Burkhart K. Ceramide accumulation during oxidant renal tubular injury: mechanisms and potential consequences. J Am Soc Nephrol 1998; 9:1670–1680.

    PubMed  CAS  Google Scholar 

  114. Huwiler A, Pfeilschifter J, van den Bosch H. J Biol Chem 1999; 274:7190–7195.

    PubMed  CAS  Google Scholar 

  115. Cacicedo JM, Benjachareowong S, Chou E et al. Palmitate-induced apoptosis in cultured bovine retinal pericytes: roles of NAD(P)H oxidase, oxidant stress, and ceramide. Diabetes 2005; 54:1838–1845.

    PubMed  CAS  Google Scholar 

  116. Osawa Y, Uchinami H, Bielawski J et al. Roles for C16-ceramideandsphingosine 1-phosphate in regulating hepatocyte apoptosis in response to tumor necrosis factor-alpha. J Biol Chem 2005; 280:27879–27887.

    PubMed  CAS  Google Scholar 

  117. Pru JK, Hendry IR, Davis JS et al. Soluble Fas ligand activates the sphingomyelin pathway and induces apoptosis in luteal steroidogenic cells independently of stress-activated p38(MAPK). Endocrinology 2002; 143:4350–4357.

    PubMed  CAS  Google Scholar 

  118. Long SD, Pekala PH. Lipid mediators of insulin resistance: ceramide signalling down-regulates GLUT4 gene transcription in 3T3-L1 adipocytes. Biochem J 1996; 319(Pt 1):179–184.

    PubMed  CAS  Google Scholar 

  119. Brindley DN, Wang CN, Mei J et al. Lipids 1999; 34 Suppl:S85–S88.

    PubMed  CAS  Google Scholar 

  120. Schmitz-Peiffer C, Craig DL, Biden TJ. Ceramide generation is sufficient to account for the inhibition of the insulin-stimulated PKB pathway in C2C12 skeletal muscle cells pretreated with palmitate. J Biol Chem 1999; 274:24202–24210.

    PubMed  CAS  Google Scholar 

  121. Teruel T, Hernandez R, Lorenzo M. Ceramide mediates insulin resistance by tumor necrosis factor-alpha in brown adipocytes by maintaining Akt in an inactive dephosphorylated state. Diabetes 2001; 50:2563–2571.

    PubMed  CAS  Google Scholar 

  122. Dobrowsky RT, Kamibayashi C, Mumby MC et al. Ceramide activates heterotrimeric protein phosphatase 2A. J Biol Chem 1993; 268:15523–15530.

    PubMed  CAS  Google Scholar 

  123. Wu Y, Song P, Xu J et al. Activation of protein phosphatase 2A by palmitate inhibits AMP-activated protein kinase. J Biol Chem 2007; 282:9777–9788.

    PubMed  CAS  Google Scholar 

  124. Cazzolli R, Carpenter L, Biden TJ et al. A role for protein phosphatase 2A-like activity, but not atypical protein kinase Czeta, in the inhibition of protein kinase B/Akt and glycogen synthesis by palmitate. Diabetes 2001; 50:2210–2218.

    PubMed  CAS  Google Scholar 

  125. Stratford S, Hoehn KL, Liu F et al. Regulation of insulin action by ceramide: dual mechanisms linking ceramide accumulation to the inhibition of Akt/protein kinase B. J Biol Chem 2004; 279:36608–36615.

    PubMed  CAS  Google Scholar 

  126. Fox TE, Houck KL, O’Neill SM et al. Ceramide recruits and activates protein kinase C zeta (PKC zeta) within structured membrane microdomains. J Biol Chem 2007; 282:12450–12457.

    PubMed  CAS  Google Scholar 

  127. Holland WL, Brozinick JT, Wang LP et al. Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell Metab 2007; 5:167–179.

    PubMed  CAS  Google Scholar 

  128. Chavez JA, Summers SA. 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 2003; 419:101–109.

    PubMed  CAS  Google Scholar 

  129. Chavez JA, Knotts TA, Wang LP et al. A role for ceramide, but not diacylglycerol, in the antagonism of insulin signal transduction by saturated fatty acids. J Biol Chem 2003; 278:10297–10303.

    PubMed  CAS  Google Scholar 

  130. Park TS, Hu Y, Noh HL et al. Ceramide is a cardiotoxin in lipotoxic cardiomyopathy. J Lipid Res 2008; 49:2101–2112.

    PubMed  CAS  Google Scholar 

  131. Soltys CL, Buchholz L, Gandhi M et al. Am J Physiol Heart Circ Physiol 2002; 283:H1056–H1064.

    PubMed  CAS  Google Scholar 

  132. Lin CF, Chen CL, Chiang CW et al. GSK-3beta acts downstream of PP2A and the PI3-kinase-Akt pathway, and upstream of caspase-2 in ceramide-induced mitochondrial apoptosis. J Cell Sci 2007; 120:2935–2943.

    PubMed  CAS  Google Scholar 

  133. Zhou YT, Grayburn P, Karim A et al. Lipotoxic heart disease in obese rats: implications for human obesity. Proc Natl Acad Sci USA 2000; 97:1784–1789.

    PubMed  CAS  Google Scholar 

  134. Hernandez OM, Discher DJ, Bishopric NH et al. Rapid activation of neutral sphingomyelinase by hypoxia-reoxygenation of cardiac myocytes. Circ Res 2000; 86:198–204.

    PubMed  CAS  Google Scholar 

  135. Hreniuk D, Garay M, Gaarde W et al. Inhibition of c-Jun N-terminal kinase 1, but not c-Jun N-terminal kinase 2, suppresses apoptosis induced by ischemia/reoxygenation in rat cardiac myocytes. Mol Pharmacol 2001; 59:867–874.

    PubMed  CAS  Google Scholar 

  136. Ruvolo PP. Ceramide regulates cellular homeostasis via diverse stress signaling pathways. Leukemia 2001; 15:1153–1160.

    PubMed  CAS  Google Scholar 

  137. Pickersgill L, Litherland GJ, Greenberg AS et al. Key role for ceramides in mediating insulin resistance in human muscle cells. J Biol Chem 2007; 282:12583–12589.

    PubMed  CAS  Google Scholar 

  138. Todd MK, Watt MJ, Le J et al. Thiazolidinediones enhance skeletal muscle triacylglycerol synthesis while protecting against fatty acid-induced inflammation and insulin resistance. Am J Physiol Endocrinol Metab 2007; 292:E485–E493.

    PubMed  CAS  Google Scholar 

  139. Okere IC, Chandler MP, McElfresh TA et al. Am J Physiol Heart Circ Physiol 2006; 291:H38–H44.

    PubMed  CAS  Google Scholar 

  140. Blazquez C, Geelen MJ, Velasco G et al. The AMP-activated protein kinase prevents ceramide synthesis de novo and apoptosis in astrocytes. FEBS Lett 2001; 489:149–153.

    PubMed  CAS  Google Scholar 

  141. Hu W, Bielawski J, Samad F et al. Palmitate increases sphingosine-1-phosphate in C2C12 myotubes via upregulation of sphingosine kinase message and activity. J Lipid Res 2009; 50:1852–1862.

    PubMed  CAS  Google Scholar 

  142. Thrush AB, Brindley DN, Chabowski A et al. Skeletal muscle lipogenic protein expression is not different between lean and obese individuals: a potential factor in ceramide accumulation. J Clin Endocrinol Metab 2009; 94:5053–5061.

    PubMed  CAS  Google Scholar 

  143. Coen PM, Dube JJ, Amati F et al. Insulin resistance is associated with higher intramyocellular triglycerides in type I but not type II myocytes concomitant with higher ceramide content. Diabetes 2010; 59:80–88.

    PubMed  CAS  Google Scholar 

  144. Moro C, Galgani JE, Luu L et al. Influence of gender, obesity, and muscle lipase activity on intramyocellular lipids in sedentary individuals. J Clin Endocrinol Metab 2009; 94:3440–3447.

    PubMed  CAS  Google Scholar 

  145. Straczkowski M, Kowalska I, Baranowski M et al. Increased skeletal muscle ceramide level in men at risk of developing type 2 diabetes. Diabetologia 2007; 50:2366–2373.

    PubMed  CAS  Google Scholar 

  146. Baranowski M, Blachnio-Zabielska A, Hirnle T et al. Myocardium of type 2 diabetic and obese patients is characterized by alterations in sphingolipid metabolic enzymes but not by accumulation of ceramide. J Lipid Res 2010; 51:74–80.

    PubMed  Google Scholar 

  147. Liu L, Shi X, Bharadwaj KG et al. DGAT1 expression increases heart triglyceride content but ameliorates lipotoxicity. J Biol Chem 2009; 284:36312–36323.

    PubMed  CAS  Google Scholar 

  148. Guber A, Barcelo-Torns M, Casas J et al. Lipid droplet biogenesis induced by stress involves triacylglycerol synthesis that depends on group VIA phospholipase A2. J Biol Chem 2009; 284:5697–5708.

    Google Scholar 

  149. Shimabukuro M, Wang MY, Zhou YT et al. Protection against lipoapoptosis of beta cells through leptin-dependent maintenance of Bcl-2 expression. Proc Natl Acad Sci USA 1998; 95:9558–9561.

    PubMed  CAS  Google Scholar 

  150. Watt MJ, van Denderen BJ, Castelli LA et al. Adipose triglyceride lipase regulation of skeletal muscle lipid metabolism and insulin responsiveness. Mol Endocrinol 2008; 22:1200–1212.

    PubMed  CAS  Google Scholar 

  151. Hickson-Bick DL, Buja LM, McMillin JB. Palmitate-mediated alterations in the fatty acid metabolism of rat neonatal cardiac myocytes. J Mol Cell Cardiol 2000; 32:511–519.

    PubMed  CAS  Google Scholar 

  152. Lee JS, Pinnamaneni SK, Eo SJ et al. Saturated, but not n-6 polyunsaturated, fatty acids induce insulin resistance: role of intramuscular accumulation of lipid metabolites. J Appl Physiol 2006; 100:1467–1474.

    PubMed  CAS  Google Scholar 

  153. Haynes CA, Allegood JC, Park H et al. Sphingolipidomics: methods for the comprehensive analysis of sphingolipids. J Chromatogr B Analyt Technol Biomed Life Sci 2009; 877:2696–2708.

    PubMed  CAS  Google Scholar 

  154. Brice SE, Alford CW, Cowart LA. Modulation of sphingolipid metabolism by the phosphatidylinositol-4-phosphate phosphatase Sac1p through regulation of phosphatidylinositol in Saccharomyces cerevisiae. J Biol Chem 2009; 284:7588–7596.

    PubMed  CAS  Google Scholar 

  155. Nemoto S, Nakamura M, Osawa Y et al. Sphingosine kinase isoforms regulate oxaliplatin sensitivity of human colon cancer cells through ceramide accumulation and Akt activation. J Biol Chem 2009; 284:10422–10432.

    PubMed  CAS  Google Scholar 

  156. Li Z, Hailemariam TK, Zhou H et al. Inhibition of sphingomyelin synthase (SMS) affects intracellular sphingomyelin accumulation and plasma membrane lipid organization. Biochim Biophys Acta 2007; 1771:1186–1194.

    PubMed  CAS  Google Scholar 

  157. Senkal CE, Ponnusamy S, Bielawski J et al. Antiapoptotic roles of ceramide-synthase-6-generated C16-ceramide via selective regulation of the ATF6/CHOP arm of ER-stress-response pathways. FASEB J 2010; 24:296–308.

    PubMed  Google Scholar 

  158. Senkal CE, Ponnusamy S, Rossi MJ et al. Role of human longevity assurance gene 1 and C18-ceramide in chemotherapy-induced cell death in human head and neck squamous cell carcinomas. Mol cancer ther 2007; 6:712–722.

    PubMed  CAS  Google Scholar 

  159. van Meer G, Hoetzl S. Sphingolipid topology and the dynamic organization and function of membrane proteins. FEBS Lett 2010; 584:1800–1805.

    PubMed  Google Scholar 

  160. Westerlund B, Grandell PM, Isaksson YJ et al. Ceramide acyl chain length markedly influences miscibility with palmitoyl sphingomyelin in bilayer membranes. Eur Biophys J 2010; 39:1117–1128.

    PubMed  CAS  Google Scholar 

  161. Bielawski J, Pierce JS, Snider J et al. Comprehensive quantitative analysis of bioactive sphingolipids by high-performance liquid chromatography-tandem mass spectrometry. Methods Mol Biol 2009; 579:443–467.

    PubMed  CAS  Google Scholar 

  162. Levery SB. Glycosphingolipid structural analysis and glycosphingolipidomics. Methods Enzymol 2005; 405:300–369.

    PubMed  CAS  Google Scholar 

  163. Merrill AH Jr, Stokes TH, Momin A et al. Sphingolipidomics: a valuable tool for understanding the roles of sphingolipids in biology and disease. J Lipid Res 2009; 50 Suppl:S97–S102.

    PubMed  Google Scholar 

  164. Bielawska A, Perry DK, Hannun YA. Determination of ceramides and diglycerides by the diglyceride kinase assay. Anal Biochem 2001; 298:141–150.

    PubMed  CAS  Google Scholar 

  165. Van Veldhoven PP, Bishop WR, Yurivich DA et al. Ceramide quantitation: evaluation of a mixed micellar assay using E. coli diacylglycerol kinase. Biochem Mol Biol Int 1995; 36:21–30.

    PubMed  Google Scholar 

  166. van Echten-Deckert G. Sphingolipid extraction and analysis by thin-layer chromatography. Methods Enzymol 2000; 312:64–79.

    PubMed  Google Scholar 

  167. Schnaar RL, Needham LK. Thin-layer chromatography of glycosphingolipids. Methods Enzymol 1994; 230:371–389.

    PubMed  CAS  Google Scholar 

  168. Skipski VP. Thin-layer chromatography of neutral glycosphingolipids. Methods Enzymol 1975; 35:396–425.

    PubMed  CAS  Google Scholar 

  169. Cremesti AE, Fischl AS. Current methods for the identification and quantitation of ceramides: an overview. Lipids 2000; 35:937–945.

    PubMed  CAS  Google Scholar 

  170. Xu R, Jin J, Hu W et al. Golgi alkaline ceramidase regulates cell proliferation and survival by controlling levels of sphingosine and S1P. FASEB J 2006; 20:1813–1825.

    PubMed  CAS  Google Scholar 

  171. Milhas D, Clarke CJ, Hannun YA. Sphingomyelin metabolism at the plasma membrane: implications for bioactive sphingolipids. FEBS Lett 2010; 584:1887–1894.

    PubMed  CAS  Google Scholar 

  172. Pavoine C, Pecker F. Sphingomyelinases: their regulation and roles in cardiovascular pathophysiology. Cardiovasc Res 2009; 82:175–183.

    PubMed  CAS  Google Scholar 

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  1. Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, USA

    Sarah E. Brice & L. Ashley Cowart

  2. Ralph H. Johnson Veteran’s Administration, Charleston, South Carolina, USA

    L. Ashley Cowart

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  1. Sarah E. Brice
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  1. Department of Biochemistry and Molecular Biology, Medical University of South Carolina, and Ralph H. Johnson Veteran’s Administration, Charleston, South Carolina, USA

    L. Ashley Cowart PhD

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Brice, S.E., Cowart, L.A. (2011). Sphingolipid Metabolism and Analysis in Metabolic Disease. In: Cowart, L.A. (eds) Sphingolipids and Metabolic Disease. Advances in Experimental Medicine and Biology, vol 721. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-0650-1_1

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