Glucosylceramide in Humans

  • Maria C. Messner
  • Myles C. Cabot
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 688)


Glucosylceramide has a unique and often ambiguous role in mammalian cells. Activation of glucosylceramide synthase, the enzyme that places a glucosyl moiety onto ceramide, is the first pathway-committed step to the production of more complex glycosphingolipids such as lactosylceramide and gangliosides. Alterations in the level of glucosylceramide are noted in cells and tissues in response to cardiovascular disease, diabetes, skin disorders and cancer. Overall, upregulation of glucosylceramide offers cellular protection and primes certain cells for proliferation. However, prolonged overabundance of glucosylceramide is detrimental, as seen in Gaucher disease in humans.


Atopic Eczema Gauche Disease Follicular Thyroid Carcinoma Nonlesional Skin Ulatory Molecule 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Yamashita T, Wada R, Sasaki T et al. A vital role for glycosphingolipid synthesis during development and differentiation. Proc Natl Acad Sci USA 1999; 96:9142–9147.CrossRefPubMedGoogle Scholar
  2. 2.
    Hanada K, Kumagai K, Yasuda S et al. Molecular machinery for nonvesicular trafficking of ceramide. Nature 2003; 426:803–809.CrossRefPubMedGoogle Scholar
  3. 3.
    D’Angelo G, Polishchuk E, Di Tullio G et al. Glycosphingolipid synthesis requires FAPP2 transfer of glucosylceramide. Nature 2007; 449:62–67.CrossRefPubMedGoogle Scholar
  4. 4.
    Halter D, Neumann S, van Dijk SM et al. Pre-and postGolgi translocation of glucosylceramide in glycosphingolipid synthesis. J Cell Biol 2007; 179:101–115.CrossRefPubMedGoogle Scholar
  5. 5.
    Lavie Y, Cao H, Volner A et al. Agents that reverse multidrug resistance, tamoxifen, verapamil and cyclosporin A, block glycosphingolipid metabolism by inhibiting ceramide glycosylation in human cancer cells. J Biol Chem 1997; 272:1682–1687.CrossRefPubMedGoogle Scholar
  6. 6.
    Lannert H, Gorgas K, Meissner I et al. Functional organization of the Golgi apparatus in glycosphingolipid biosynthesis. Lactosylceramide and subsequent glycosphingolipids are formed in the lumen of the late Golgi. J Biol Chem 1998; 273:2939–2946.CrossRefPubMedGoogle Scholar
  7. 7.
    Maxzud MK, Maccioni HJ. Glucosylceramide synthesized in vitro from endogenous ceramide is uncoupled from synthesis of lactosylceramide in Golgi membranes from chicken embryo neural retina cells. Neurochem Res 2000; 25:145–152.CrossRefPubMedGoogle Scholar
  8. 8.
    Veldman RJ, Klappe K, Hinrichs J et al. Altered sphingolipid metabolism in multidrug-resistant ovarian cancer cells is due to uncoupling of glycolipid biosynthesis in the Golgi apparatus. Faseb J 2002; 16:1111–1113.PubMedGoogle Scholar
  9. 9.
    Fuller M, Rozaklis T, Lovejoy M et al. Glucosylceramide accumulation is not confined to the lysosome in fibroblasts from patients with Gaucher disease. Mol Genet Metab 2008; 93:437–443.CrossRefPubMedGoogle Scholar
  10. 10.
    Cox TM. Gaucher disease: understanding the molecular pathogenesis of sphingolipidoses. J Inherit Metab Dis 2001; 24 Suppl 2:106–121; discussion 187–108.PubMedGoogle Scholar
  11. 11.
    Gil GA, Bussolino DF, Portal MM et al. c-Fos activated phospholipid synthesis is required for neurite elongation in differentiating PC12 cells. Mol Biol Cell 2004; 15:1881–1894.CrossRefPubMedGoogle Scholar
  12. 12.
    Crespo PM, Silvestre DC, Gil GA et al. c-Fos activates glucosylceramide synthase and glycolipid synthesis in PC12 cells. J Biol Chem 2008; 283:31163–31171.CrossRefPubMedGoogle Scholar
  13. 13.
    Liu YY, Yu JY, Yin D et al. A role for ceramide in driving cancer cell resistance to doxorubicin. Faseb J 2008; 22:2541–2551.CrossRefPubMedGoogle Scholar
  14. 14.
    Uchida Y, Itoh M, Taguchi Y et al. Ceramide reduction and transcriptional up-regulation of glucosylceramide synthase through doxorubicin-activated Sp1 in drug-resistant HL-60/ADR cells. Cancer Res 2004; 64:6271–6279.CrossRefPubMedGoogle Scholar
  15. 15.
    Di Sano F, Fazi B, Citro G et al. Glucosylceramide synthase and its functional interaction with RTN-1C regulate chemotherapeutic-induced apoptosis in neuroepithelioma cells. Cancer Res 2003; 63:3860–3865.PubMedGoogle Scholar
  16. 16.
    Tagami S, Eguchi Y, Kinoshita M et al. A novel protein, RTN-XS, interacts with both Bcl-XL and Bcl-2 on endoplasmic reticulum and reduces their anti-apoptotic activity. Oncogene 2000; 19:5736–5746.CrossRefPubMedGoogle Scholar
  17. 17.
    Taguchi Y, Kondo T, Watanabe M et al. Interleukin-2-induced survival of natural killer (NK) cells involving phosphatidylinositol-3 kinase-dependent reduction of ceramide through acid sphingomyelinase, sphingomyelin synthase and glucosylceramide synthase. Blood 2004; 104:3285–3293.CrossRefPubMedGoogle Scholar
  18. 18.
    Abe A, Wild SR, Lee WL et al. Agents for the treatment of glycosphingolipid storage disorders. Curr Drug Metab 2001; 2:331–338.CrossRefPubMedGoogle Scholar
  19. 19.
    Shu L, Lee L, Shayman JA. Regulation of phospholipase C-gamma activity by glycosphingolipids. J Biol Chem 2002; 277:18447–18453.CrossRefPubMedGoogle Scholar
  20. 20.
    Ahmed SN, Brown DA, London E. On the origin of sphingolipid/cholesterol-rich detergent-insoluble cell membranes: physiological concentrations of cholesterol and sphingolipid induce formation of a detergent-insoluble, liquid-ordered lipid phase in model membranes. Biochemistry 1997; 36:10944–10953.CrossRefPubMedGoogle Scholar
  21. 21.
    Hein LK, Meikle PJ, Hopwood JJ et al. Secondary sphingolipid accumulation in a macrophage model of Gaucher disease. Mol Genet Metab 2007; 92:336–345.CrossRefPubMedGoogle Scholar
  22. 22.
    Sprong H, Degroote S, Claessens T et al. Glycosphingolipids are required for sorting melanosomal proteins in the Golgi complex. J Cell Biol 2001; 155:369–380.CrossRefPubMedGoogle Scholar
  23. 23.
    Sheets ED, Lee GM, Simson R et al. Transient confinement of a glycosylphosphatidylinositol-anchored protein in the plasma membrane. Biochemistry 1997; 36:12449–12458.CrossRefPubMedGoogle Scholar
  24. 24.
    Wojtal KA, de Vries E, Hoekstra D et al. Efficient trafficking of MDR1/P-glycoprotein to apical canalicular plasma membranes in HepG2 cells requires PKA-RIIalpha anchoring and glucosylceramide. Mol Biol Cell 2006; 17:3638–3650.CrossRefPubMedGoogle Scholar
  25. 25.
    Dijkhuis AJ, Klappe K, Kamps W et al. Gangliosides do not affect ABC transporter function in human neuroblastoma cells. J Lipid Res 2006; 47:1187–1195.CrossRefPubMedGoogle Scholar
  26. 26.
    van ISC, Hoekstra D. (Glyco)sphingolipids are sorted in sub-apical compartments in HepG2 cells: a role for nonGolgi-related intracellular sites in the polarized distribution of (glyco)sphingolipids. J Cell Biol 1998; 142:683–696.CrossRefGoogle Scholar
  27. 27.
    van der Bijl P, Lopes-Cardozo M, van Meer G. Sorting of newly synthesized galactosphingolipids to the two surface domains of epithelial cells. J Cell Biol 1996; 132:813–821.CrossRefPubMedGoogle Scholar
  28. 28.
    Tewes BJ, Galla HJ. Lipid polarity in brain capillary endothelial cells. Endothelium 2001; 8:207–220.CrossRefPubMedGoogle Scholar
  29. 29.
    Grayson S, Johnson-Winegar AG, Wintroub BU et al. Lamellar body-enriched fractions from neonatal mice: preparative techniques and partial characterization. J Invest Dermatol 1985; 85:289–294.CrossRefPubMedGoogle Scholar
  30. 30.
    Hamanaka S, Nakazawa S, Yamanaka M et al. Glucosylceramide accumulates preferentially in lamellar bodies in differentiated keratinocytes. Br J Dermatol 2005; 152:426–434.CrossRefPubMedGoogle Scholar
  31. 31.
    Hamanaka S, Hara M, Nishio H et al. Human epidermal glucosylceramides are major precursors of stratum corneum ceramides. J Invest Dermatol 2002; 119:416–423.CrossRefPubMedGoogle Scholar
  32. 32.
    Jennemann R, Sandhoff R, Langbein L et al. Integrity and barrier function of the epidermis critically depend on glucosylceramide synthesis. J Biol Chem 2007; 282:3083–3094.CrossRefPubMedGoogle Scholar
  33. 33.
    Uchida Y, Murata S, Schmuth M et al. Glucosylceramide synthesis and synthase expression protect against ceramide-induced stress. J Lipid Res 2002; 43:1293–1302.PubMedGoogle Scholar
  34. 34.
    Segre JA. Epidermal barrier formation and recovery in skin disorders. J Clin Invest 2006; 116:1150–1158.CrossRefPubMedGoogle Scholar
  35. 35.
    Alessandrini F, Pfister S, Kremmer E et al. Alterations of glucosylceramide-beta-glucosidase levels in the skin of patients with psoriasis vulgaris. J Invest Dermatol 2004; 123:1030–1036.CrossRefPubMedGoogle Scholar
  36. 36.
    Miyanishi K, Shiono N, Shirai H et al. Reduction of transepidermal water loss by oral intake of glucosylceramides in patients with atopic eczema. Allergy 2005; 60:1454–1455.CrossRefPubMedGoogle Scholar
  37. 37.
    Tsuji K, Mitsutake S, Ishikawa J et al. Dietary glucosylceramide improves skin barrier function in hairless mice. J Dermatol Sci 2006; 44:101–107.CrossRefPubMedGoogle Scholar
  38. 38.
    Deguchi H, Fernandez JA, Pabinger I et al. Plasma glucosylceramide deficiency as potential risk factor for venous thrombosis and modulator of anticoagulant protein C pathway. Blood 2001; 97:1907–1914.CrossRefPubMedGoogle Scholar
  39. 39.
    Yegneswaran S, Deguchi H, Griffin JH. Glucosylceramide, a neutral glycosphingolipid anticoagulant cofactor, enhances the interaction of human-and bovine-activated protein C with negatively charged phospholipid vesicles. J Biol Chem 2003; 278:14614–14621.CrossRefPubMedGoogle Scholar
  40. 40.
    Mukhin DN, Chao FF, Kruth HS. Glycosphingolipid accumulation in the aortic wall is another feature of human atherosclerosis. Arterioscler Thromb Vasc Biol 1995; 15:1607–1615.PubMedGoogle Scholar
  41. 41.
    Chatterjee SB, Dey S, Shi WY et al. Accumulation of glycosphingolipids in human atherosclerotic plaque and unaffected aorta tissues. Glycobiology 1997; 7:57–65.CrossRefPubMedGoogle Scholar
  42. 42.
    Marks N, Berg MJ, Saito M et al. Glucosylceramide synthase decrease in frontal cortex of Alzheimer brain correlates with abnormal increase in endogenous ceramides: consequences to morphology and viability on enzyme suppression in cultured primary neurons. Brain Res 2008; 1191:136–147.CrossRefPubMedGoogle Scholar
  43. 43.
    Satoi H, Tomimoto H, Ohtani R et al. Astroglial expression of ceramide in Alzheimer’s disease brains: a role during neuronal apoptosis. Neuroscience 2005; 130:657–666.CrossRefPubMedGoogle Scholar
  44. 44.
    Takahashi K, Ginis I, Nishioka R et al. Glucosylceramide synthase activity and ceramide levels are modulated during cerebral ischemia after ischemic preconditioning. J Cereb Blood Flow Metab 2004; 24:623–627.CrossRefPubMedGoogle Scholar
  45. 45.
    Inokuchi J, Kuroda Y, Kosaka S et al. L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol stimulates ganglioside biosynthesis, neurite outgrowth and synapse formation in cultured cortical neurons and ameliorates memory deficits in ischemic rats. Acta Biochim Pol 1998; 45:479–492.PubMedGoogle Scholar
  46. 46.
    Hisaki H, Okazaki T, Kubota M et al. L-PDMP improves glucosylceramide synthesis and behavior in rats with focal ischemia. Neurol Res 2008; 30:979–984.CrossRefPubMedGoogle Scholar
  47. 47.
    Butters TD, Dwek RA, Platt FM. Imino sugar inhibitors for treating the lysosomal glycosphingolipidoses. Glycobiology 2005; 15:43R–52R.CrossRefPubMedGoogle Scholar
  48. 48.
    Yohe HC, Kitzmiller TJ, Bement WJ et al. Reduced inflammatory potential of peritoneal macrophages recruited in mice pretreated with a glycolipid synthesis inhibitor. Inflammopharmacology 2006; 14:170–175.CrossRefPubMedGoogle Scholar
  49. 49.
    Thornton MV, Kudo D, Rayman P et al. Degradation of NF-kappa B in T-cells by gangliosides expressed on renal cell carcinomas. J Immunol 2004; 172:3480–3490.PubMedGoogle Scholar
  50. 50.
    Aerts JM, Ottenhoff R, Powlson AS et al. Pharmacological inhibition of glucosylceramide synthase enhances insulin sensitivity. Diabetes 2007; 56:1341–1349.CrossRefPubMedGoogle Scholar
  51. 51.
    Fox TE, Han X, Kelly S et al. Diabetes alters sphingolipid metabolism in the retina: a potential mechanism of cell death in diabetic retinopathy. Diabetes 2006; 55:3573–3580.CrossRefPubMedGoogle Scholar
  52. 52.
    Zigmond E, Zangen S, Pappo O et al. Beta-glycosphingolipids improved glucose intolerance and hepatic steatosis of the Cohen diabetic rat. Am J Physiol Endocrinol Metab 2008.Google Scholar
  53. 53.
    Margalit M, Shalev Z, Pappo O et al. Glucocerebroside ameliorates the metabolic syndrome in OB/ OB mice. J Pharmacol Exp Ther 2006; 319:105–110.CrossRefPubMedGoogle Scholar
  54. 54.
    Safadi R, Zigmond E, Pappo O et al. Amelioration of hepatic fibrosis via beta-glucosylceramide-mediated immune modulation is associated with altered CD8 and NKT-lymphocyte distribution. Int Immunol 2007; 19:1021–1029.CrossRefPubMedGoogle Scholar
  55. 55.
    Krivan HC, Roberts DD, Ginsburg V. Many pulmonary pathogenic bacteria bind specifically to the carbohydrate sequence GalNAc beta 1–4Gal found in some glycolipids. Proc Natl Acad Sci USA 1988; 85:6157–6161.CrossRefPubMedGoogle Scholar
  56. 56.
    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.CrossRefPubMedGoogle Scholar
  57. 57.
    Langeveld M, Ghauharali KJ, Sauerwein HP et al. Type I Gaucher disease, a glycosphingolipid storage disorder, is associated with insulin resistance. J Clin Endocrinol Metab 2008; 93:845–851.CrossRefPubMedGoogle Scholar
  58. 58.
    Saito M, Rosenberg A. The fate of glucosylceramide (glucocerebroside) in genetically impaired (lysosomal beta-glucosidase deficient) Gaucher disease diploid human fibroblasts. J Biol Chem 1985; 260:2295–2300.PubMedGoogle Scholar
  59. 59.
    Tagami S, Inokuchi Ji J, Kabayama K et al. Ganglioside GM3 participates in the pathological conditions of insulin resistance. J Biol Chem 2002; 277:3085–3092.CrossRefPubMedGoogle Scholar
  60. 60.
    Lavie Y, Cao H, Bursten SL et al. Accumulation of glucosylceramides in multidrug-resistant cancer cells. J Biol Chem 1996; 271:19530–19536.CrossRefPubMedGoogle Scholar
  61. 61.
    Rath G, Schneider C, Langlois B et al. De novo ceramide synthesis is responsible for the anti-tumor properties of camptothecin and doxorubicin in follicular thyroid carcinoma. Int J Biochem Cell Biol 2008.Google Scholar
  62. 62.
    Xie P, Shen YF, Shi YP et al. Overexpression of glucosylceramide synthase in associated with multidrug resistance of leukemia cells. Leuk Res 2008; 32:475–480.CrossRefPubMedGoogle Scholar
  63. 63.
    Liu YY, Han TY, Yu JY et al. Oligonucleotides blocking glucosylceramide synthase expression selectively reverse drug resistance in cancer cells. J Lipid Res 2004; 45:933–940.CrossRefPubMedGoogle Scholar
  64. 64.
    Sun YL, Zhou GY, Li KN et al. Suppression of glucosylceramide synthase by RNA interference reverses multidrug resistance in human breast cancer cells. Neoplasma 2006; 53:1–8.PubMedGoogle Scholar
  65. 65.
    Liu YY, Han TY, Giuliano AE et al. Glycosylation of ceramide potentiates cellular resistance to tumor necrosis factor-alpha-induced apoptosis. Exp Cell Res 1999; 252:464–470.CrossRefPubMedGoogle Scholar
  66. 66.
    Liu YY, Cabot MC. Development of a mammalian Tet-on expression cell line: glucosylceramide synthase regulates TNF-alpha-induced apoptosis. Methods Mol Biol 2004; 249:177–192.PubMedGoogle Scholar
  67. 67.
    Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer 2002; 2:48–58.CrossRefPubMedGoogle Scholar
  68. 68.
    Gouaze V, Liu YY, Prickett CS et al. Glucosylceramide synthase blockade down-regulates P-glycoprotein and resensitizes multidrug-resistant breast cancer cells to anticancer drugs. Cancer Res 2005; 65:3861–3867.CrossRefPubMedGoogle Scholar
  69. 69.
    Gouaze-Andersson V, Yu JY, Kreitenberg AJ et al. Ceramide and glucosylceramide upregulate expression of the multidrug resistance gene MDR1 in cancer cells. Biochim Biophys Acta 2007; 1771:1407–1417.PubMedGoogle Scholar
  70. 70.
    Burstein Y, Zakuth V, Rechavi G et al. Abnormalities of cellular immunity and natural killer cells in Gaucher’s disease. J Clin Lab Immunol 1987; 23:149–151.PubMedGoogle Scholar
  71. 71.
    Lalazar G, Preston S, Zigmond E et al. Glycolipids as immune modulatory tools. Mini Rev Med Chem 2006; 6:1249–1253.CrossRefPubMedGoogle Scholar
  72. 72.
    Symolon H, Schmelz EM, Dillehay DL et al. Dietary soy sphingolipids suppress tumorigenesis and gene expression in 1,2-dimethylhydrazine-treated CF1 mice and ApcMin/+ mice. J Nutr 2004; 134:1157–1161.PubMedGoogle Scholar
  73. 73.
    Sullards MC, Lynch DV, Merrill AH Jr et al. Structure determination of soybean and wheat glucosylceramides by tandem mass spectrometry. J Mass Spectrom 2000; 35:347–353.CrossRefPubMedGoogle Scholar
  74. 74.
    Oku H, Wongtangtintharn S, Iwasaki H et al. Tumor specific cytotoxicity of glucosylceramide. Cancer Chemother Pharmacol 2007; 60:767–775.CrossRefPubMedGoogle Scholar
  75. 75.
    Sinclair GB, Jevon G, Colobong KE et al. Generation of a conditional knockout of murine glucocerebrosidase: utility for the study of Gaucher disease. Mol Genet Metab 2007; 90:148–156.CrossRefPubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2010

Authors and Affiliations

  1. 1.John Wayne Cancer InstituteSanta MonicaUSA

Personalised recommendations