Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board: Buchner, Johannes / Lei, Ming / Ludwig, Stephan / Sies, Helmut / Thomas, Douglas D. / Turk, Boris / Wittinghofer, Alfred

12 Issues per year

IMPACT FACTOR 2017: 3.022

CiteScore 2017: 2.81

SCImago Journal Rank (SJR) 2017: 1.562
Source Normalized Impact per Paper (SNIP) 2017: 0.705

See all formats and pricing
More options …
Volume 396, Issue 6-7


The effect of altered sphingolipid acyl chain length on various disease models

Woo-Jae Park
  • Department of Biochemistry, School of Medicine, Gachon University, Incheon 406-799, South Korea
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Joo-Won Park
  • Corresponding author
  • Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul 158-710, South Korea
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2015-01-24 | DOI: https://doi.org/10.1515/hsz-2014-0310


Sphingolipids have emerged as an important lipid mediator in intracellular signalling and metabolism. Ceramide, which is central to sphingolipid metabolism, is generated either via a de novo pathway, by attaching fatty acyl CoA to a long-chain base, or via a salvage pathway, by degrading pre-existing sphingolipids. As a ‘sphingolipid rheostat’ has been proposed, the balance between ceramide and sphingosine-1-phosphate has been the object of considerable attention. Ceramide has recently been reported to have a different function depending on its acyl chain length: six ceramide synthases (CerS) determine the specific ceramide acyl chain length in mammals. All CerS-deficient mice generated to date show that sphingolipids with defined acyl chain lengths play distinct pathophysiological roles in disease models. This review describes recent advances in understanding the associations of CerS with various diseases and includes clinical case reports.

Keywords: acyl chain length; ceramide synthase; disease; sphingolipid


  • Abe, K., Ohno, Y., Sassa, T., Taguchi, R., Caliskan, M., Ober, C., and Kihara, A. (2013). Mutation for nonsyndromic mental retardation in the trans-2-enoyl-CoA reductase TER gene involved in fatty acid elongation impairs the enzyme activity and stability, leading to change in sphingolipid profile. J. Biol. Chem. 288, 36741–36749.Google Scholar

  • Ali, M., Fritsch, J., Zigdon, H., Pewzner-Jung, Y., Schutze, S., and Futerman, A.H. (2013). Altering the sphingolipid acyl chain composition prevents LPS/GLN-mediated hepatic failure in mice by disrupting TNFR1 internalization. Cell Death Dis. 4, e929.Google Scholar

  • Aronova, S., Wedaman, K., Aronov, P.A., Fontes, K., Ramos, K., Hammock, B.D., and Powers, T. (2008). Regulation of ceramide biosynthesis by TOR complex 2. Cell Metab. 7, 148–158.Google Scholar

  • Becker, I., Wang-Eckhardt, L., Yaghootfam, A., Gieselmann, V., and Eckhardt, M. (2008). Differential expression of (dihydro)ceramide synthases in mouse brain: oligodendrocyte-specific expression of CerS2/Lass2. Histochem. Cell Biol. 129, 233–241.Google Scholar

  • Ben-David, O., Pewzner-Jung, Y., Brenner, O., Laviad, E.L., Kogot-Levin, A., Weissberg, I., Biton, I.E., Pienik, R., Wang, E., Kelly, S., et al. (2011). Encephalopathy caused by ablation of very long acyl chain ceramide synthesis may be largely due to reduced galactosylceramide levels. J. Biol. Chem. 286, 30022–30033.Google Scholar

  • Blank, N., Schiller, M., Krienke, S., Wabnitz, G., Ho, A.D., and Lorenz, H.M. (2007). Cholera toxin binds to lipid rafts but has a limited specificity for ganglioside GM1. Immunol. Cell Biol. 85, 378–382.Google Scholar

  • Blumenfeld, H.J., Tohn, R., Haeryfar, S.M., Liu, Y., Savage, P.B., and Delovitch, T.L. (2011). Structure-guided design of an invariant natural killer T cell agonist for optimum protection from type 1 diabetes in non-obese diabetic mice. Clin. Exp. Immunol. 166, 121–133.Google Scholar

  • Cinar, R., Godlewski, G., Liu, J., Tam, J., Jourdan, T., Mukhopadhyay, B., Harvey-White, J., and Kunos, G. (2014). Hepatic cannabinoid-1 receptors mediate diet-induced insulin resistance by increasing de novo synthesis of long-chain ceramides. Hepatology 59, 143–153.Google Scholar

  • Coetzee, T., Fujita, N., Dupree, J., Shi, R., Blight, A., Suzuki, K., and Popko, B. (1996). Myelination in the absence of galactocerebroside and sulfatide: normal structure with abnormal function and regional instability. Cell 86, 209–219.Google Scholar

  • de Jong, S., Timmer, T., Heijenbrok, F.J., and de Vries, E.G. (2001). Death receptor ligands, in particular TRAIL, to overcome drug resistance. Cancer Metastasis Rev. 20, 51–56.Google Scholar

  • Dewson, G. and Kluck, R.M. (2009). Mechanisms by which Bak and Bax permeabilise mitochondria during apoptosis. J. Cell Sci. 122, 2801–2808.Google Scholar

  • Ebel, P., Vom Dorp, K., Petrasch-Parwez, E., Zlomuzica, A., Kinugawa, K., Mariani, J., Minich, D., Ginkel, C., Welcker, J., Degen, J., et al. (2013). Inactivation of ceramide synthase 6 in mice results in an altered sphingolipid metabolism and behavioral abnormalities. J. Biol. Chem. 288, 21433–21447.Google Scholar

  • Ebel, P., Imgrund, S., Vom Dorp, K., Hofmann, K., Maier, H., Drake, H., Degen, J., Dormann, P., Eckhardt, M., Franz, T., et al. (2014). Ceramide synthase 4 deficiency in mice causes lipid alterations in sebum and results in alopecia. Biochem. J. 461, 147–158.Google Scholar

  • Eberle, M., Ebel, P., Wegner, M.S., Mannich, J., Tafferner, N., Ferreiros, N., Birod, K., Schreiber, Y., Krishnamoorthy, G., Willecke, K., et al. (2014). Regulation of ceramide synthase 6 in a spontaneous experimental autoimmune encephalomyelitis model is sex dependent. Biochem. Pharmacol. 92, 326–335.Google Scholar

  • Eckl, K.M., Tidhar, R., Thiele, H., Oji, V., Hausser, I., Brodesser, S., Preil, M.L., Onal-Akan, A., Stock, F., Muller, D., et al. (2013). Impaired epidermal ceramide synthesis causes autosomal recessive congenital ichthyosis and reveals the importance of ceramide acyl chain length. J. Invest. Dermatol. 133, 2202–2011.Google Scholar

  • Erez-Roman, R., Pienik, R., and Futerman, A.H. (2010). Increased ceramide synthase 2 and 6 mRNA levels in breast cancer tissues and correlation with sphingosine kinase expression. Biochem. Biophys. Res. Commun. 391, 219–223.Google Scholar

  • Fan, S., Niu, Y., Tan, N., Wu, Z., Wang, Y., You, H., Ke, R., Song, J., Shen, Q., Wang, W., et al. (2013). LASS2 enhances chemosensitivity of breast cancer by counteracting acidic tumor microenvironment through inhibiting activity of V-ATPase proton pump. Oncogene 32, 1682–1690.Google Scholar

  • Fan, S.H., Wang, Y.Y., Lu, J., Zheng, Y.L., Wu, D.M., Zhang, Z.F., Shan, Q., Hu, B., Li, M.Q., and Cheng, W. (2015). CERS2 suppresses tumor cell invasion and is associated with decreased V-ATPase and MMP-2/MMP-9 activities in breast cancer. J. Cell. Biochem. 116, 502–513.Google Scholar

  • Fox, L.M., Cox, D.G., Lockridge, J.L., Wang, X., Chen, X., Scharf, L., Trott, D.L., Ndonye, R.M., Veerapen, N., Besra, G.S., et al. (2009). Recognition of lyso-phospholipids by human natural killer T lymphocytes. PLoS Biol. 7, e1000228.CrossrefGoogle Scholar

  • Fox, T.E., Bewley, M.C., Unrath, K.A., Pedersen, M.M., Anderson, R.E., Jung, D.Y., Jefferson, L.S., Kim, J.K., Bronson, S.K., Flanagan, J.M., et al. (2011). Circulating sphingolipid biomarkers in models of type 1 diabetes. J. Lipid Res. 52, 509–517.Google Scholar

  • Fresques, T., Niles, B., Aronova, S., Mogri, H., Rakhshandehroo, T., and Powers, T. (2014). Regulation of ceramide synthase by casein kinase 2-dependent phosphorylation in S. cerevisiae. J. Biol. Chem. Nov 26. pii: jbc.M114.621086. [Epub ahead of print].Google Scholar

  • Ginkel, C., Hartmann, D., vom Dorp, K., Zlomuzica, A., Farwanah, H., Eckhardt, M., Sandhoff, R., Degen, J., Rabionet, M., Dere, E., et al. (2012). Ablation of neuronal ceramide synthase 1 in mice decreases ganglioside levels and expression of myelin-associated glycoprotein in oligodendrocytes. J. Biol. Chem. 287, 41888–41902.Google Scholar

  • Hartmann, D., Lucks, J., Fuchs, S., Schiffmann, S., Schreiber, Y., Ferreiros, N., Merkens, J., Marschalek, R., Geisslinger, G., and Grosch, S. (2012). Long chain ceramides and very long chain ceramides have opposite effects on human breast and colon cancer cell growth. Int. J. Biochem. Cell. Biol. 44, 620–628.Google Scholar

  • Imgrund, S., Hartmann, D., Farwanah, H., Eckhardt, M., Sandhoff, R., Degen, J., Gieselmann, V., Sandhoff, K., and Willecke, K. (2009). Adult ceramide synthase 2 (CERS2)-deficient mice exhibit myelin sheath defects, cerebellar degeneration, and hepatocarcinomas. J. Biol. Chem. 284, 33549–33560.Google Scholar

  • Imokawa, G., Abe, A., Jin, K., Higaki, Y., Kawashima, M., and Hidano, A. (1991). Decreased level of ceramides in stratum corneum of atopic dermatitis: an etiologic factor in atopic dry skin? J. Invest. Dermatol. 96, 523–526.Google Scholar

  • Jennemann, R., Rabionet, M., Gorgas, K., Epstein, S., Dalpke, A., Rothermel, U., Bayerle, A., van der Hoeven, F., Imgrund, S., Kirsch, J., et al. (2012). Loss of ceramide synthase 3 causes lethal skin barrier disruption. Hum. Mol. Genet. 21, 586–608.CrossrefGoogle Scholar

  • Jensen, S.A., Calvert, A.E., Volpert, G., Kouri, F.M., Hurley, L.A., Luciano, J.P., Wu, Y., Chalastanis, A., Futerman, A.H., and Stegh, A.H. (2014). Bcl2L13 is a ceramide synthase inhibitor in glioblastoma. Proc. Natl. Acad. Sci. USA 111, 5682–5687.Google Scholar

  • Jorizzo, J.L., Atherton, D.J., Crounse, R.G., and Wells, R.S. (1982). Ichthyosis, brittle hair, impaired intelligence, decreased fertility and short stature (IBIDS syndrome). Br. J. Dermatol. 106, 705–710.Google Scholar

  • Kageyama-Yahara, N., and Riezman, H. (2006). Transmembrane topology of ceramide synthase in yeast. Biochem. J. 398, 585–593.Google Scholar

  • Karahatay, S., Thomas, K., Koybasi, S., Senkal, C.E., Elojeimy, S., Liu, X., Bielawski, J., Day, T.A., Gillespie, M.B., Sinha, D., et al. (2007). Clinical relevance of ceramide metabolism in the pathogenesis of human head and neck squamous cell carcinoma (HNSCC): attenuation of C(18)-ceramide in HNSCC tumors correlates with lymphovascular invasion and nodal metastasis. Cancer Lett. 256, 101–111.Google Scholar

  • Kirin, M., Chandra, A., Charteris, D.G., Hayward, C., Campbell, S., Celap, I., Bencic, G., Vatavuk, Z., Kirac, I., Richards, A.J., et al. (2013). Genome-wide association study identifies genetic risk underlying primary rhegmatogenous retinal detachment. Hum. Mol. Genet. 22, 3174–3185.Google Scholar

  • Koch, M., Stronge, V.S., Shepherd, D., Gadola, S.D., Mathew, B., Ritter, G., Fersht, A.R., Besra, G.S., Schmidt, R.R., Jones, E.Y., et al. (2005). The crystal structure of human CD1d with and without alpha-galactosylceramide. Nat. Immunol. 6, 819–826.Google Scholar

  • Kremser, C., Klemm, A.L., van Uelft, M., Imgrund, S., Ginkel, C., Hartmann, D., and Willecke, K. (2013). Cell-type-specific expression pattern of ceramide synthase 2 protein in mouse tissues. Histochem. Cell Biol. 140, 533–547.Google Scholar

  • Lahiri, S., and Futerman, A.H. (2005). LASS5 is a bona fide dihydroceramide synthase that selectively utilizes palmitoyl-CoA as acyl donor. J. Biol. Chem. 280, 33735–33738.Google Scholar

  • Laviad, E.L., Albee, L., Pankova-Kholmyansky, I., Epstein, S., Park, H., Merrill, A.H., Jr., and Futerman, A.H. (2008). Characterization of ceramide synthase 2: tissue distribution, substrate specificity, and inhibition by sphingosine 1-phosphate. J. Biol. Chem. 283, 5677–5684.Google Scholar

  • Laviad, E.L., Kelly, S., Merrill, A.H., Jr., and Futerman, A.H. (2012). Modulation of ceramide synthase activity via dimerization. J. Biol. Chem. 287, 21025–21033.Google Scholar

  • Lee, P.T., Putnam, A., Benlagha, K., Teyton, L., Gottlieb, P.A., and Bendelac, A. (2002). Testing the NKT cell hypothesis of human IDDM pathogenesis. J. Clin. Invest. 110, 793–800.Google Scholar

  • Lee, H., Rotolo, J.A., Mesicek, J., Penate-Medina, T., Rimner, A., Liao, W.C., Yin, X., Ragupathi, G., Ehleiter, D., Gulbins, E., et al. (2011). Mitochondrial ceramide-rich macrodomains functionalize Bax upon irradiation. PLoS One 6, e19783.Google Scholar

  • Lemaitre, R.N., King, I.B., Kabagambe, E.K., Wu, J.H., McKnight, B., Manichaikul, A., Guan, W., Sun, Q., Chasman, D.I., Foy, M., et al. (2015). Genetic loci associated with circulating levels of very long-chain saturated fatty acids. J. Lipid Res. 56, 176–184.Google Scholar

  • Levy, M. and Futerman, A.H. (2010). Mammalian ceramide synthases. IUBMB Life 62, 347–356.Google Scholar

  • Li, X., Fujio, M., Imamura, M., Wu, D., Vasan, S., Wong, C.H., Ho, D.D., and Tsuji, M. (2010). Design of a potent CD1d-binding NKT cell ligand as a vaccine adjuvant. Proc. Natl. Acad. Sci. USA 107, 13010–13015.Google Scholar

  • Lindsten, T., Ross, A.J., King, A., Zong, W.X., Rathmell, J.C., Shiels, H.A., Ulrich, E., Waymire, K.G., Mahar, P., Frauwirth, K., et al. (2000). The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues. Mol. Cell 6, 1389–1399.PubMedCrossrefGoogle Scholar

  • Liu, Y.Y., Han, T.Y., Giuliano, A.E., and Cabot, M.C. (1999). Expression of glucosylceramide synthase, converting ceramide to glucosylceramide, confers adriamycin resistance in human breast cancer cells. J. Biol. Chem. 274, 1140–1146.Google Scholar

  • McCarthy, C., Shepherd, D., Fleire, S., Stronge, V.S., Koch, M., Illarionov, P.A., Bossi, G., Salio, M., Denkberg, G., Reddington, F., et al. (2007). The length of lipids bound to human CD1d molecules modulates the affinity of NKT cell TCR and the threshold of NKT cell activation. J. Exp. Med. 204, 1131–1144.Google Scholar

  • Mesicek, J., Lee, H., Feldman, T., Jiang, X., Skobeleva, A., Berdyshev, E.V., Haimovitz-Friedman, A., Fuks, Z., and Kolesnick, R. (2010). Ceramide synthases 2, 5, and 6 confer distinct roles in radiation-induced apoptosis in HeLa cells. Cell Signal. 22, 1300–1307.Google Scholar

  • Mesika, A., Ben-Dor, S., Laviad, E.L., and Futerman, A.H. (2007). A new functional motif in Hox domain-containing ceramide synthases: identification of a novel region flanking the Hox and TLC domains essential for activity. J. Biol. Chem. 282, 27366–27373.Google Scholar

  • Mizutani, Y., Kihara, A., and Igarashi, Y. (2005). Mammalian Lass6 and its related family members regulate synthesis of specific ceramides. Biochem. J. 390, 263–271.Google Scholar

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

  • Mosbech, M.B., Olsen, A.S., Neess, D., Ben-David, O., Klitten, L.L., Larsen, J., Sabers, A., Vissing, J., Nielsen, J.E., Hasholt, L., et al. (2014). Reduced ceramide synthase 2 activity causes progressive myoclonic epilepsy. Ann. Clin. Transl. Neurol. 1, 88–98.Google Scholar

  • Muir, A., Ramachandran, S., Roelants, F.M., Timmons, G., and Thorner, J. (2014). TORC2-dependent protein kinase Ypk1 phosphorylates ceramide synthase to stimulate synthesis of complex sphingolipids. Elife 3, doi: 10.7554/eLife.03779.CrossrefGoogle Scholar

  • Mullen, T.D., Spassieva, S., Jenkins, R.W., Kitatani, K., Bielawski, J., Hannun, Y.A., and Obeid, L.M. (2011). Selective knockdown of ceramide synthases reveals complex interregulation of sphingolipid metabolism. J. Lipid Res. 52, 68–77.Google Scholar

  • Pappas, A. (2009). Epidermal surface lipids. Dermatoendocrinol 1, 72–76.Google Scholar

  • Park, J.W. and Pewzner-Jung, Y. (2013). Ceramide synthases: reexamining longevity. Handb. Exp. Pharmacol. 215, 89–107.Google Scholar

  • Park, J.W., Park, W.J., Kuperman, Y., Boura-Halfon, S., Pewzner-Jung, Y., and Futerman, A.H. (2013a). Ablation of very long acyl chain sphingolipids causes hepatic insulin resistance in mice due to altered detergent-resistant membranes. Hepatology 57, 525–532.Google Scholar

  • Park, W.J., Park, J.W., Erez-Roman, R., Kogot-Levin, A., Bame, J.R., Tirosh, B., Saada, A., Merrill, A.H., Jr., Pewzner-Jung, Y., and Futerman, A.H. (2013b). Protection of a ceramide synthase 2 null mouse from drug-induced liver injury: role of gap junction dysfunction and connexin 32 mislocalization. J. Biol. Chem. 288, 30904–30916.Google Scholar

  • Park, J.W., Park, W.J., and Futerman, A.H. (2014a). Ceramide synthases as potential targets for therapeutic intervention in human diseases. Biochim. Biophys. Acta 1841, 671–681.Google Scholar

  • Park, W.J., Park, J.W., Merrill, A.H., Jr., Storch, J., Pewzner-Jung, Y., and Futerman, A.H. (2014b). Hepatic fatty acid uptake is regulated by the sphingolipid acyl chain length. Biochim. Biophys. Acta 1841, 1754–1766.Google Scholar

  • Patel, S.J., Milwid, J.M., King, K.R., Bohr, S., Iracheta-Velle, A., Li, M., Vitalo, A., Parekkadan, B., Jindal, R., and Yarmush, M.L. (2012). Gap junction inhibition prevents drug-induced liver toxicity and fulminant hepatic failure. Nat. Biotechnol. 30, 179–183.Google Scholar

  • Petrache, I., Kamocki, K., Poirier, C., Pewzner-Jung, Y., Laviad, E.L., Schweitzer, K.S., Van Demark, M., Justice, M.J., Hubbard, W.C., and Futerman, A.H. (2013). Ceramide synthases expression and role of ceramide synthase-2 in the lung: insight from human lung cells and mouse models. PLoS One 8, e62968.Google Scholar

  • Pewzner-Jung, Y., Brenner, O., Braun, S., Laviad, E.L., Ben-Dor, S., Feldmesser, E., Horn-Saban, S., Amann-Zalcenstein, D., Raanan, C., Berkutzki, T., et al. (2010a). A critical role for ceramide synthase 2 in liver homeostasis: II. Insights into molecular changes leading to hepatopathy. J. Biol. Chem. 285, 10911–10923.Google Scholar

  • Pewzner-Jung, Y., Park, H., Laviad, E.L., Silva, L.C., Lahiri, S., Stiban, J., Erez-Roman, R., Brugger, B., Sachsenheimer, T., Wieland, F., et al. (2010b). A critical role for ceramide synthase 2 in liver homeostasis: I. alterations in lipid metabolic pathways. J. Biol. Chem. 285, 10902–10910.Google Scholar

  • Pewzner-Jung, Y., Tavakoli Tabazavareh, S., Grassme, H., Becker, K.A., Japtok, L., Steinmann, J., Joseph, T., Lang, S., Tuemmler, B., Schuchman, E.H., et al. (2014). Sphingoid long chain bases prevent lung infection by Pseudomonas aeruginosa. EMBO Mol. Med. 6, 1205–1214.CrossrefGoogle Scholar

  • Rabionet, M., van der Spoel, A.C., Chuang, C.C., von Tumpling-Radosta, B., Litjens, M., Bouwmeester, D., Hellbusch, C.C., Korner, C., Wiegandt, H., Gorgas, K., et al. (2008). Male germ cells require polyenoic sphingolipids with complex glycosylation for completion of meiosis: a link to ceramide synthase-3. J. Biol. Chem. 283, 13357–13369.Google Scholar

  • Radner, F.P., Marrakchi, S., Kirchmeier, P., Kim, G.J., Ribierre, F., Kamoun, B., Abid, L., Leipoldt, M., Turki, H., Schempp, W., et al. (2013). Mutations in CERS3 cause autosomal recessive congenital ichthyosis in humans. PLoS Genet. 9, e1003536.CrossrefGoogle Scholar

  • Raichur, S., Wang, S.T., Chan, P.W., Li, Y., Ching, J., Chaurasia, B., Dogra, S., Ohman, M.K., Takeda, K., Sugii, S., et al. (2014). CerS2 haploinsufficiency inhibits b-oxidation and confers susceptibility to diet-induced steatohepatitis and insulin resistance. Cell Metab. 20, 687–695.Google Scholar

  • Riebeling, C., Allegood, J.C., Wang, E., Merrill, A.H., Jr., and Futerman, A.H. (2003). Two mammalian longevity assurance gene (LAG1) family members, trh1 and trh4, regulate dihydroceramide synthesis using different fatty acyl-CoA donors. J. Biol. Chem. 278, 43452–43459.Google Scholar

  • Russo, S.B., Baicu, C.F., Van Laer, A., Geng, T., Kasiganesan, H., Zile, M.R., and Cowart, L.A. (2012). Ceramide synthase 5 mediates lipid-induced autophagy and hypertrophy in cardiomyocytes. J. Clin. Invest. 122, 3919–3930.Google Scholar

  • Samanta, S., Stiban, J., Maugel, T.K., and Colombini, M. (2011). Visualization of ceramide channels by transmission electron microscopy. Biochim. Biophys. Acta 1808, 1196–1201.Google Scholar

  • Sassa, T., Suto, S., Okayasu, Y., and Kihara, A. (2012). A shift in sphingolipid composition from C24 to C16 increases susceptibility to apoptosis in HeLa cells. Biochim. Biophys. Acta 1821, 1031–1037.Google Scholar

  • Schiffmann, S., Sandner, J., Birod, K., Wobst, I., Angioni, C., Ruckhaberle, E., Kaufmann, M., Ackermann, H., Lotsch, J., Schmidt, H., et al. (2009). Ceramide synthases and ceramide levels are increased in breast cancer tissue. Carcinogenesis 30, 745–752.Google Scholar

  • Senkal, C.E., Ponnusamy, S., Rossi, M.J., Bialewski, J., Sinha, D., Jiang, J.C., Jazwinski, S.M., Hannun, Y.A., and Ogretmen, B. (2007). 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. 6, 712–722.CrossrefGoogle Scholar

  • Separovic, D., Breen, P., Joseph, N., Bielawski, J., Pierce, J.S., Van Buren, E., and Gudz, T.I. (2012). siRNA-mediated down-regulation of ceramide synthase 1 leads to apoptotic resistance in human head and neck squamous carcinoma cells after photodynamic therapy. Anticancer Res. 32, 2479–2485.Google Scholar

  • Shiffman, D., Pare, G., Oberbauer, R., Louie, J.Z., Rowland, C.M., Devlin, J.J., Mann, J.F., and McQueen, M.J. (2014). A gene variant in CERS2 is associated with rate of increase in albuminuria in patients with diabetes from ONTARGET and TRANSCEND. PLoS One 9, e106631.Google Scholar

  • Siskind, L.J. and Colombini, M. (2000). The lipids C2- and C16-ceramide form large stable channels. Implications for apoptosis. J. Biol. Chem. 275, 38640–38644.Google Scholar

  • Siskind, L.J., Mullen, T.D., Romero Rosales, K., Clarke, C.J., Hernandez-Corbacho, M.J., Edinger, A.L., and Obeid, L.M. (2010). The BCL-2 protein BAK is required for long-chain ceramide generation during apoptosis. J. Biol. Chem. 285, 11818–11826.Google Scholar

  • Spassieva, S., Seo, J.G., Jiang, J.C., Bielawski, J., Alvarez-Vasquez, F., Jazwinski, S.M., Hannun, Y.A., and Obeid, L.M. (2006). Necessary role for the Lag1p motif in (dihydro)ceramide synthase activity. J. Biol. Chem. 281, 33931–33938.Google Scholar

  • Spiegel, S. and Milstien, S. (2003). Sphingosine-1-phosphate: an enigmatic signalling lipid. Nat. Rev. Mol. Cell. Biol. 4, 397–407.Google Scholar

  • Sridevi, P., Alexander, H., Laviad, E.L., Pewzner-Jung, Y., Hannink, M., Futerman, A.H., and Alexander, S. (2009). Ceramide synthase 1 is regulated by proteasomal mediated turnover. Biochim. Biophys. Acta 1793, 1218–1227.Google Scholar

  • Sridevi, P., Alexander, H., Laviad, E.L., Min, J., Mesika, A., Hannink, M., Futerman, A.H., and Alexander, S. (2010). Stress-induced ER to Golgi translocation of ceramide synthase 1 is dependent on proteasomal processing. Exp. Cell Res. 316, 78–91.Google Scholar

  • Stiban, J., Tidhar, R., and Futerman, A.H. (2010). Ceramide synthases: roles in cell physiology and signaling. Adv. Exp. Med. Biol. 688, 60–71.Google Scholar

  • Tait, S.W., and Green, D.R. (2010). Mitochondria and cell death: outer membrane permeabilization and beyond. Nat. Rev. Mol. Cell. Biol. 11, 621–632.Google Scholar

  • Tawada, C., Kanoh, H., Nakamura, M., Mizutani, Y., Fujisawa, T., Banno, Y., and Seishima, M. (2014). Interferon-g decreases ceramides with long-chain fatty acids: possible involvement in atopic dermatitis and psoriasis. J. Invest. Dermatol. 134, 712–718.Google Scholar

  • Tidhar, R. and Futerman, A.H. (2013). The complexity of sphingolipid biosynthesis in the endoplasmic reticulum. Biochim. Biophys. Acta 1833, 2511–2518.Google Scholar

  • Tidhar, R., Ben-Dor, S., Wang, E., Kelly, S., Merrill, A.H. Jr., and Futerman, A.H. (2012). Acyl chain specificity of ceramide synthases is determined within a region of 150 residues in the Tram-Lag-CLN8 (TLC) domain. J. Biol. Chem. 287, 3197–3206.Google Scholar

  • Turpin, S.M., Nicholls, H.T., Willmes, D.M., Mourier, A., Brodesser, S., Wunderlich, C.M., Mauer, J., Xu, E., Hammerschmidt, P., Bronneke, H.S., et al. (2014). Obesity-induced CerS6-dependent C16:0 ceramide production promotes weight gain and glucose intolerance. Cell Metab. 20, 678–686.Google Scholar

  • Venkataraman, K., Riebeling, C., Bodennec, J., Riezman, H., Allegood, J.C., Sullards, M.C., Merrill, A.H. Jr., and Futerman, A.H. (2002). Upstream of growth and differentiation factor 1 (uog1), a mammalian homolog of the yeast longevity assurance gene 1 (LAG1), regulates N-stearoyl-sphinganine (C18-(dihydro)ceramide) synthesis in a fumonisin B1-independent manner in mammalian cells. J. Biol. Chem. 277, 35642–35649.Google Scholar

  • Voelkel-Johnson, C., Hannun, Y.A., and El-Zawahry, A. (2005). Resistance to TRAIL is associated with defects in ceramide signaling that can be overcome by exogenous C6-ceramide without requiring down-regulation of cellular FLICE inhibitory protein. Mol. Cancer Ther. 4, 1320–1327.Google Scholar

  • White-Gilbertson, S., Mullen, T., Senkal, C., Lu, P., Ogretmen, B., Obeid, L., and Voelkel-Johnson, C. (2009). Ceramide synthase 6 modulates TRAIL sensitivity and nuclear translocation of active caspase-3 in colon cancer cells. Oncogene 28, 1132–1141.Google Scholar

  • Wilson, S.B. and Delovitch, T.L. (2003). Janus-like role of regulatory iNKT cells in autoimmune disease and tumour immunity. Nat. Rev. Immunol. 3, 211–222.Google Scholar

  • Wilson, S.B., Kent, S.C., Patton, K.T., Orban, T., Jackson, R.A., Exley, M., Porcelli, S., Schatz, D.A., Atkinson, M.A., Balk, S.P., et al. (1998). Extreme Th1 bias of invariant Va24JaQ T cells in type 1 diabetes. Nature 391, 177–181.Google Scholar

  • Zhao, L., Spassieva, S.D., Jucius, T.J., Shultz, L.D., Shick, H.E., Macklin, W.B., Hannun, Y.A., Obeid, L.M., and Ackerman, S.L. (2011). A deficiency of ceramide biosynthesis causes cerebellar purkinje cell neurodegeneration and lipofuscin accumulation. PLoS Genet. 7, e1002063.CrossrefGoogle Scholar

  • Zigdon, H., Kogot-Levin, A., Park, J.W., Goldschmidt, R., Kelly, S., Merrill, A.H., Jr., Scherz, A., Pewzner-Jung, Y., Saada, A., and Futerman, A.H. (2013). Ablation of ceramide synthase 2 causes chronic oxidative stress due to disruption of the mitochondrial respiratory chain. J. Biol. Chem. 288, 4947–4956.Google Scholar

  • Zoller, I., Bussow, H., Gieselmann, V., and Eckhardt, M. (2005). Oligodendrocyte-specific ceramide galactosyltransferase (CGT) expression phenotypically rescues CGT-deficient mice and demonstrates that CGT activity does not limit brain galactosylceramide level. Glia 52, 190–198.Google Scholar

About the article

Corresponding author: Joo-Won Park, Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul 158-710, South Korea, e-mail:

Received: 2014-12-12

Accepted: 2015-01-21

Published Online: 2015-01-24

Published in Print: 2015-06-01

Citation Information: Biological Chemistry, Volume 396, Issue 6-7, Pages 693–705, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/hsz-2014-0310.

Export Citation

©2015 by De Gruyter.Get Permission

Citing Articles

Here you can find all Crossref-listed publications in which this article is cited. If you would like to receive automatic email messages as soon as this article is cited in other publications, simply activate the “Citation Alert” on the top of this page.

Michele Dei Cas and Riccardo Ghidoni
Nutrients, 2018, Volume 10, Number 7, Page 940
Francesca A. Ververs, Eric Kalkhoven, Belinda van’t Land, Marianne Boes, and Henk S. Schipper
Frontiers in Immunology, 2018, Volume 9
Sebastian Luger, Annette Schwebler, Rajkumar Vutukuri, Nerea Ferreiros Bouzas, Sandra Labocha, Yannick Schreiber, Robert Brunkhorst, Helmuth Steinmetz, Josef Pfeilschifter, and Waltraud Pfeilschifter
Therapeutic Advances in Neurological Disorders, 2018, Volume 11, Page 175628641876983
Kristi Helke, Peggi Angel, Ping Lu, Elizabeth Garrett-Mayer, Besim Ogretmen, Richard Drake, and Christina Voelkel-Johnson
Scientific Reports, 2018, Volume 8, Number 1
Matthew J. Scheffel, Kristi Helke, Ping Lu, Jacob S. Bowers, Besim Ogretmen, Elizabeth Garrett-Mayer, Chrystal M. Paulos, and Christina Voelkel-Johnson
Scientific Reports, 2017, Volume 7, Number 1
Min Hee Kim, Hee Kyung Ahn, Eun-Ji Lee, Su-Jeong Kim, Ye-Ryung Kim, Joo-Won Park, and Woo-Jae Park
International Journal of Molecular Medicine, 2017, Volume 39, Number 2, Page 453
Ye-Ryung Kim, Giora Volpert, Kyong-Oh Shin, So-Yeon Kim, Sun-Hye Shin, Younghay Lee, Sun Hee Sung, Yong-Moon Lee, Jung-Hyuck Ahn, Yael Pewzner-Jung, Woo-Jae Park, Anthony H. Futerman, and Joo-Won Park
Journal of Cellular and Molecular Medicine, 2017
Dominic Gosejacob, Philipp S. Jäger, Katharina vom Dorp, Martin Frejno, Anne C. Carstensen, Monika Köhnke, Joachim Degen, Peter Dörmann, and Michael Hoch
Journal of Biological Chemistry, 2016, Volume 291, Number 13, Page 6989
Mahmoudreza Doroudgar and Michel Lafleur
Biophysical Journal, 2017, Volume 112, Number 11, Page 2357
Rolando I. Castillo, Leonel E. Rojo, Marcela Henriquez-Henriquez, Hernán Silva, Alejandro Maturana, María J. Villar, Manuel Fuentes, and Pablo A. Gaspar
Frontiers in Neuroscience, 2016, Volume 10
Toshiyuki Yamaji, Aya Horie, Yuriko Tachida, Chisato Sakuma, Yusuke Suzuki, Yasunori Kushi, and Kentaro Hanada
International Journal of Molecular Sciences, 2016, Volume 17, Number 10, Page 1761

Comments (0)

Please log in or register to comment.
Log in