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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

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


IMPACT FACTOR 2018: 3.014
5-year IMPACT FACTOR: 3.162

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Volume 396, Issue 6-7

Issues

Sphingolipids in liver injury, repair and regeneration

Hiroyuki Nojima
  • Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way, ML 0558, Cincinnati, OH 45267-0558, USA
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/ Christopher M. Freeman
  • Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way, ML 0558, Cincinnati, OH 45267-0558, USA
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/ Erich Gulbins
  • Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way, ML 0558, Cincinnati, OH 45267-0558, USA
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/ Alex B. Lentsch
  • Corresponding author
  • Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way, ML 0558, Cincinnati, OH 45267-0558, USA
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Published Online: 2015-03-12 | DOI: https://doi.org/10.1515/hsz-2014-0296

Abstract

Sphingolipids are not only essential components of cellular membranes but also function as intracellular and extracellular mediators that regulate important physiological cellular processes including cell survival, proliferation, apoptosis, differentiation, migration and immune responses. The liver possesses the unique ability to regenerate after injury in a complex manner that involves numerous mediators, including sphingolipids such as ceramide and sphingosine 1-phosphate. Here we present the current understanding of the involvement of the sphingolipid pathway and the role this pathway plays in regulating liver injury, repair and regeneration. The regulation of sphingolipids and their enzymes may have a great impact in the development of novel therapeutic modalities for a variety of liver injuries and diseases.

Keywords: ceramide; liver injury; liver regeneration; sphingolipids; sphingosine 1-phosphate

References

  • Abu-Amara, M., Yang, S.Y., Tapuria, N., Fuller, B., Davidson, B., and Seifalian, A. (2010). Liver ischemia/reperfusion injury: processes in inflammatory networks – a review. Liver Transpl. 16, 1016–1032.Google Scholar

  • Adachi, T., Nakashima, S., Saji, S., Nakamura, T., and Nozawa, Y. (1996). Mitogen-activated protein kinase activation in hepatocyte growth factor-stimulated rat hepatocytes: involvement of protein tyrosine kinase and protein kinase C. Hepatology 23, 1244–1253.PubMedCrossrefGoogle Scholar

  • Albi, E., Peloso, I., and Magni, M.V. (1999). Nuclear membrane sphingomyelin-cholesterol changes in rat liver after hepatectomy. Biochem. Biophys. Res. Commun. 262, 692–695.Google Scholar

  • Albi, E., Rossi, G., Maraldi, N.M., Magni, M.V., Cataldi, S., Solimando, L., and Zini, N. (2003). Involvement of nuclear phosphatidylinositol-dependent phospholipases C in cell cycle progression during rat liver regeneration. J. Cell. Physiol. 197, 181–188.Google Scholar

  • Albi, E., Lazzarini, A., Lazzarini, R., Floridi, A., Damaskopoulou, E., Curcio, F., and Cataldi, S. (2013). Nuclear lipid microdomain as place of interaction between sphingomyelin and DNA during liver regeneration. Int. J. Mol. Sci. 14, 6529–6541.PubMedCrossrefGoogle Scholar

  • Alessenko, A. and Chatterjee, S. (1995). Neutral sphingomyelinase: localization in rat liver nuclei and involvement in regeneration/proliferation. Mol. Cell. Biochem. 143, 169–174.Google Scholar

  • Alessenko, A.V., Platonova, L.V., Sakevarashvili, G.R., Khrenov, A.V., Shingarova, L.N., Shono, N.I., and Galperin, E.I. (1999). Role of endogenous TNF-α and sphingosine in induced DNA synthesis in regenerating rat liver after partial hepatectomy. Biochemistry (Moscow) 64, 890–895.Google Scholar

  • Alessenko, A.V., Galperin, E.I., Dudnik, L.B., Korobko, V.G., Mochalova, E.S., Platonova, L.V., Shingarova, L.N., Shono, N.I., and Shupik, M.A. (2002). Role of tumor necrosis factor α and sphingomyelin cycle activation in the induction of apoptosis by ischemia/reperfusion of the liver. Biochemistry (Moscow) 67, 1347–1355.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

  • Arora, A.S., Jones, B.J., Patel, T.C., Bronk, S.F., and Gores, G.J. (1997). Ceramide induces hepatocyte cell death through disruption of mitochondrial function in the rat. Hepatology 25, 958–963.PubMedCrossrefGoogle Scholar

  • Ballou, L.R., Chao, C.P., Holness, M.A., Barker, S.C., and Raghow, R. (1992). Interleukin–1-mediated PGE2 production and sphingomyelin metabolism. Evidence for the regulation of cyclooxygenase gene expression by sphingosine and ceramide. J. Biol. Chem. 267, 20044–20050.Google Scholar

  • Barth, B.M., Shanmugavelandy, S.S., Kaiser, J.M., McGovern, C., Altinoglu, E.I., Haakenson, J.K., Hengst, J.A., Gilius, E.L., Knupp, S.A., Fox, T.E., et al. (2013). PhotoImmunoNanoTherapy reveals an anticancer role for sphingosine kinase 2 and dihydrosphingosine-1-phosphate. ACS Nano. 7, 2132–2144.CrossrefPubMedGoogle Scholar

  • Bartke, N. and Hannun, Y.A. (2009). Bioactive sphingolipids: metabolism and function. J. Lipid Res. 50 (Suppl.), S91–S96.Google Scholar

  • Basnakian, A.G., Ueda, N., Hong, X., Galitovsky, V.E., Yin, X., and Shah, S.V. (2005). Ceramide synthase is essential for endonuclease-mediated death of renal tubular epithelial cells induced by hypoxia-reoxygenation. Am. J. Physiol. Renal Physiol. 288, F308–F314.Google Scholar

  • Bataller, R. and Brenner, D.A. (2005). Liver fibrosis. J. Clin. Invest. 115, 209–218.Google Scholar

  • Belghiti, J., Noun, R., Zante, E., Ballet, T., and Sauvanet, A. (1996). Portal triad clamping or hepatic vascular exclusion for major liver resection. A controlled study. Ann. Surg. 224, 155–161.Google Scholar

  • Bernal, W., Auzinger, G., Dhawan, A., and Wendon, J. (2010). Acute liver failure. Lancet 376, 190–201.Google Scholar

  • Bollinger, C.R., Teichgraber, V., and Gulbins, E. (2005). Ceramide-enriched membrane domains. Biochim. Biophys. Acta 1746, 284–294.Google Scholar

  • Bradham, C.A., Stachlewitz, R.F., Gao, W., Qian, T., Jayadev, S., Jenkins, G., Hannun, Y., Lemasters, J.J., Thurman, R.G., and Brenner, D.A. (1997). Reperfusion after liver transplantation in rats differentially activates the mitogen-activated protein kinases. Hepatology 25, 1128–1135.PubMedCrossrefGoogle Scholar

  • Brown, R.E. (1998). Sphingolipid organization in biomembranes: what physical studies of model membranes reveal. J. Cell. Sci. 111, 1–9.Google Scholar

  • Canbay, A., Friedman, S., and Gores, G.J. (2004). Apoptosis: the nexus of liver injury and fibrosis. Hepatology 39, 273–278.PubMedCrossrefGoogle Scholar

  • Chatzakos, V., Rundlof, A.K., Ahmed, D., de Verdier, P.J., and Flygare, J. (2012). Inhibition of sphingosine kinase 1 enhances cytotoxicity, ceramide levels and ROS formation in liver cancer cells treated with selenite. Biochem. Pharmacol. 84, 712–721.Google Scholar

  • Chen, J., Nikolova-Karakashian, M., Merrill, A.H., Jr., and Morgan, E.T. (1995). Regulation of cytochrome P450 2C11 (CYP2C11) gene expression by interleukin-1, sphingomyelin hydrolysis, and ceramides in rat hepatocytes. J. Biol. Chem. 270, 25233–25238.Google Scholar

  • Colletti, L.M., Remick, D.G., Burtch, G.D., Kunkel, S.L., Strieter, R.M., and Campbell, D.A., Jr. (1990). Role of tumor necrosis factor-α in the pathophysiologic alterations after hepatic ischemia/reperfusion injury in the rat. J. Clin. Invest. 85, 1936–1943.Google Scholar

  • Coutant, A., Rescan, C., Gilot, D., Loyer, P., Guguen-Guillouzo, C., and Baffet, G. (2002). PI3K-FRAP/mTOR pathway is critical for hepatocyte proliferation whereas MEK/ERK supports both proliferation and survival. Hepatology 36, 1079–1088.CrossrefGoogle Scholar

  • Cuvillier, O., Pirianov, G., Kleuser, B., Vanek, P.G., Coso, O.A., Gutkind, S., and Spiegel, S. (1996). Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate. Nature 381, 800–803.Google Scholar

  • Cuzzocrea, S., Di Paola, R., Genovese, T., Mazzon, E., Esposito, E., Crisafulli, C., Bramanti, P., and Salvemini, D. (2008). Anti-inflammatory and anti-apoptotic effects of fumonisin B1, an inhibitor of ceramide synthase, in a rodent model of splanchnic ischemia and reperfusion injury. J. Pharmacol. Exp. Ther 327, 45–57.Google Scholar

  • Davaille, J., Li, L., Mallat, A., and Lotersztajn, S. (2002). Sphingosine 1-phosphate triggers both apoptotic and survival signals for human hepatic myofibroblasts. J. Biol. Chem. 277, 37323–37330.Google Scholar

  • Dawson, T.C., Lentsch, A.B., Wang, Z., Cowhig, J.E., Rot, A., Maeda, N., and Peiper, S.C. (2000). Exaggerated response to endotoxin in mice lacking the Duffy antigen/receptor for chemokines (DARC). Blood 96, 1681–1684.PubMedGoogle Scholar

  • Dbaibo, G.S., Obeid, L.M., and Hannun, Y.A. (1993). Tumor necrosis factor-α (TNF-α) signal transduction through ceramide. Dissociation of growth inhibitory effects of TNF-α from activation of nuclear factor-κB. J. Biol. Chem. 268, 17762–17766.Google Scholar

  • Donati, C., Cencetti, F., Nincheri, P., Bernacchioni, C., Brunelli, S., Clementi, E., Cossu, G., and Bruni, P. (2007). Sphingosine 1-phosphate mediates proliferation and survival of mesoangioblasts. Stem Cells 25, 1713–1719.PubMedCrossrefGoogle Scholar

  • Fausto, N., Campbell, J.S., and Riehle, K.J. (2006). Liver regeneration. Hepatology 43, S45–53.CrossrefGoogle Scholar

  • Frago, L.M., Paneda, C., Fabregat, I., and Varela-Nieto, I. (2001). Short-chain ceramide regulates hepatic methionine adenosyltransferase expression. J. Hepatol. 34, 192–201.Google Scholar

  • Futerman, A.H. and Riezman, H. (2005). The ins and outs of sphingolipid synthesis. Trends Cell. Biol. 15, 312–318.Google Scholar

  • Garcia-Ruiz, C., Colell, A., Mari, M., Morales, A., Calvo, M., Enrich, C., and Fernandez-Checa, J.C. (2003). Defective TNF-α-mediated hepatocellular apoptosis and liver damage in acidic sphingomyelinase knockout mice. J. Clin. Invest. 111, 197–208.Google Scholar

  • Grassme, H., Jekle, A., Riehle, A., Schwarz, H., Berger, J., Sandhoff, K., Kolesnick, R., and Gulbins, E. (2001). CD95 signaling via ceramide-rich membrane rafts. J. Biol. Chem. 276, 20589–20596.Google Scholar

  • Gulbins, E. and Kolesnick, R. (2003). Raft ceramide in molecular medicine. Oncogene 22, 7070–7077.CrossrefPubMedGoogle Scholar

  • Gulbins, E., Bissonnette, R., Mahboubi, A., Martin, S., Nishioka, W., Brunner, T., Baier, G., Baier-Bitterlich, G., Byrd, C., Lang, F., et al. (1995). FAS-induced apoptosis is mediated via a ceramide-initiated RAS signaling pathway. Immunity 2, 341–351.CrossrefGoogle Scholar

  • Hannun, Y.A. and Bell, R.M. (1989). Functions of sphingolipids and sphingolipid breakdown products in cellular regulation. Science 243, 500–507.Google Scholar

  • Hannun, Y.A. and Obeid, L.M. (2008). Principles of bioactive lipid signalling: lessons from sphingolipids. Nat. Rev. Mol. Cell. Biol. 9, 139–150.CrossrefPubMedGoogle Scholar

  • Hines, I.N., Harada, H., Flores, S., Gao, B., McCord, J.M., and Grisham, M.B. (2005). Endothelial nitric oxide synthase protects the post-ischemic liver: potential interactions with superoxide. Biomed. Pharmacother. 59, 183–189.Google Scholar

  • Hinson, J.A., Roberts, D.W., and James, L.P. (2010). Mechanisms of acetaminophen-induced liver necrosis. Handb. Exp. Pharmacol. 369–405.PubMedGoogle Scholar

  • Houmard, B.S., Guan, Z., Kim-Lee, M., Stokes, B.T., and Ottobre, J.S. (1991). The effects of elevation and depletion of intracellular free calcium on progesterone and prostaglandin production by the primate corpus luteum. Biol. Reprod. 45, 560–565.Google Scholar

  • Husted, T.L., Blanchard, J., Schuster, R., Shen, H., and Lentsch, A.B. (2006). Potential role for IL-23 in hepatic ischemia/reperfusion injury. Inflamm. Res. 55, 177–178.Google Scholar

  • Ichi, I., Nakahara, K., Fujii, K., Iida, C., Miyashita, Y., and Kojo, S. (2007). Increase of ceramide in the liver and plasma after carbon tetrachloride intoxication in the rat. J. Nutr. Sci. Vitaminol. (Tokyo) 53, 53–56.CrossrefGoogle Scholar

  • Ikeda, H., Satoh, H., Yanase, M., Inoue, Y., Tomiya, T., Arai, M., Tejima, K., Nagashima, K., Maekawa, H., Yahagi, N., et al. (2003). Antiproliferative property of sphingosine 1-phosphate in rat hepatocytes involves activation of Rho via Edg-5. Gastroenterology 124, 459–469.Google Scholar

  • Ikeda, H., Watanabe, N., Ishii, I., Shimosawa, T., Kume, Y., Tomiya, T., Inoue, Y., Nishikawa, T., Ohtomo, N., Tanoue, Y., et al. (2009). Sphingosine 1-phosphate regulates regeneration and fibrosis after liver injury via sphingosine 1-phosphate receptor 2. J. Lipid Res. 50, 556–564.Google Scholar

  • Iwaisako, K., Jiang, C., Zhang, M., Cong, M., Moore-Morris, T.J., Park, T.J., Liu, X., Xu, J., Wang, P., Paik, Y.H., et al. (2014). Origin of myofibroblasts in the fibrotic liver in mice. Proc. Natl. Acad. Sci. USA 111, E3297–3305.Google Scholar

  • Jaeschke, H., Williams, C.D., Ramachandran, A., and Bajt, M.L. (2012). Acetaminophen hepatotoxicity and repair: the role of sterile inflammation and innate immunity. Liver Int. 32, 8–20.PubMedCrossrefGoogle Scholar

  • Jenkins, G.M., Richards, A., Wahl, T., Mao, C., Obeid, L., and Hannun, Y. (1997). Involvement of yeast sphingolipids in the heat stress response of Saccharomyces cerevisiae. J. Biol. Chem. 272, 32566–32572.Google Scholar

  • Jin, J., Hou, Q., Mullen, T.D., Zeidan, Y.H., Bielawski, J., Kraveka, J.M., Bielawska, A., Obeid, L.M., Hannun, Y.A., and Hsu, Y.T. (2008). Ceramide generated by sphingomyelin hydrolysis and the salvage pathway is involved in hypoxia/reoxygenation-induced Bax redistribution to mitochondria in NT-2 cells. J. Biol. Chem. 283, 26509–26517.Google Scholar

  • Jones, B.E., Lo, C.R., Srinivasan, A., Valentino, K.L., and Czaja, M.J. (1999). Ceramide induces caspase-independent apoptosis in rat hepatocytes sensitized by inhibition of RNA synthesis. Hepatology 30, 215–222.CrossrefPubMedGoogle Scholar

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

  • Khashab, M., Tector, A.J., and Kwo, P.Y. (2007). Epidemiology of acute liver failure. Curr. Gastroenterol. Rep. 9, 66–73.CrossrefPubMedGoogle Scholar

  • Kim, M.Y., Linardic, C., Obeid, L., and Hannun, Y. (1991). Identification of sphingomyelin turnover as an effector mechanism for the action of tumor necrosis factor α and γ-interferon. Specific role in cell differentiation. J. Biol. Chem. 266, 484–489.Google Scholar

  • Kolesnick, R. (1994). Signal transduction through the sphingomyelin pathway. Mol. Chem. Neuropathol. 21, 287–297.PubMedCrossrefGoogle Scholar

  • Kolesnick, R.N. and Clegg, S. (1988). 1,2-Diacylglycerols, but not phorbol esters, activate a potential inhibitory pathway for protein kinase C in GH3 pituitary cells. Evidence for involvement of a sphingomyelinase. J. Biol. Chem. 263, 6534–6537.Google Scholar

  • Kuboki, S., Okaya, T., Schuster, R., Blanchard, J., Denenberg, A., Wong, H.R., and Lentsch, A.B. (2007). Hepatocyte NF-κB activation is hepatoprotective during ischemia-reperfusion injury and is augmented by ischemic hypothermia. Am. J. Physiol. Gastrointest. Liver Physiol. 292, G201–G207.Google Scholar

  • Kuboki, S., Sakai, N., Tschop, J., Edwards, M.J., Lentsch, A.B., and Caldwell, C.C. (2009). Distinct contributions of CD4+ T cell subsets in hepatic ischemia/reperfusion injury. Am. J. Physiol. Gastrointest. Liver Physiol. 296, G1054–1059.Google Scholar

  • Lahiri, S. and Futerman, A.H. (2007). The metabolism and function of sphingolipids and glycosphingolipids. Cell. Mol. Life Sci. 64, 2270–2284.Google Scholar

  • Lang, P.A., Schenck, M., Nicolay, J.P., Becker, J.U., Kempe, D.S., Lupescu, A., Koka, S., Eisele, K., Klarl, B.A., Rubben, H., et al. (2007). Liver cell death and anemia in Wilson disease involve acid sphingomyelinase and ceramide. Nat. Med. 13, 164–170.CrossrefPubMedGoogle Scholar

  • Larson, A.M., Polson, J., Fontana, R.J., Davern, T.J., Lalani, E., Hynan, L.S., Reisch, J.S., Schiodt, F.V., Ostapowicz, G., Shakil, A.O., et al. (2005). Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology 42, 1364–1372.Google Scholar

  • Le Stunff, H., Milstien, S., and Spiegel, S. (2004). Generation and metabolism of bioactive sphingosine-1-phosphate. J. Cell. Biochem. 92, 882–899.Google Scholar

  • Lentsch, A.B., Yoshidome, H., Cheadle, W.G., Miller, F.N., and Edwards, M.J. (1998a). Chemokine involvement in hepatic ischemia/reperfusion injury in mice: roles for macrophage inflammatory protein-2 and KC. Hepatology 27, 1172–1177.PubMedGoogle Scholar

  • Lentsch, A.B., Yoshidome, H., Cheadle, W.G., Miller, F.N., and Edwards, M.J. (1998b). Chemokine involvement in hepatic ischemia/reperfusion injury in mice: roles for macrophage inflammatory protein-2 and Kupffer cells. Hepatology 27, 507–512.PubMedGoogle Scholar

  • Lentsch, A.B., Yoshidome, H., Kato, A., Warner, R.L., Cheadle, W.G., Ward, P.A., and Edwards, M.J. (1999). Requirement for interleukin-12 in the pathogenesis of warm hepatic ischemia/reperfusion injury in mice. Hepatology 30, 1448–1453.CrossrefGoogle Scholar

  • Levade, T. and Jaffrezou, J.P. (1999). Signalling sphingomyelinases: which, where, how and why? Biochim. Biophys. Acta 1438, 1–17.Google Scholar

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

  • Li, C., Jiang, X., Yang, L., Liu, X., Yue, S., and Li, L. (2009a). Involvement of sphingosine 1-phosphate (SIP)/S1P3 signaling in cholestasis-induced liver fibrosis. Am. J. Pathol. 175, 1464–1472.Google Scholar

  • Li, C., Kong, Y., Wang, H., Wang, S., Yu, H., Liu, X., Yang, L., Jiang, X., Li, L., and Li, L. (2009b). Homing of bone marrow mesenchymal stem cells mediated by sphingosine 1-phosphate contributes to liver fibrosis. J. Hepatol. 50, 1174–1183.Google Scholar

  • Li, C., Zheng, S., You, H., Liu, X., Lin, M., Yang, L., and Li, L. (2011). Sphingosine 1-phosphate (S1P)/S1P receptors are involved in human liver fibrosis by action on hepatic myofibroblasts motility. J. Hepatol. 54, 1205–1213.Google Scholar

  • Limaye, V., Vadas, M.A., Pitson, S.M., and Gamble, J.R. (2009). The effects of markedly raised intracellular sphingosine kinase-1 activity in endothelial cells. Cell. Mol. Biol. Lett. 14, 411–423.PubMedGoogle Scholar

  • Liu, H., Sugiura, M., Nava, V.E., Edsall, L.C., Kono, K., Poulton, S., Milstien, S., Kohama, T., and Spiegel, S. (2000). Molecular cloning and functional characterization of a novel mammalian sphingosine kinase type 2 isoform. J. Biol. Chem. 275, 19513–19520.Google Scholar

  • Liu, Q., Rehman, H., Shi, Y., Krishnasamy, Y., Lemasters, J.J., Smith, C.D., and Zhong, Z. (2012). Inhibition of sphingosine kinase-2 suppresses inflammation and attenuates graft injury after liver transplantation in rats. PLoS One 7, e41834.Google Scholar

  • Llacuna, L., Mari, M., Garcia-Ruiz, C., Fernandez-Checa, J.C., and Morales, A. (2006). Critical role of acidic sphingomyelinase in murine hepatic ischemia-reperfusion injury. Hepatology 44, 561–572.CrossrefPubMedGoogle Scholar

  • Luedde, T. and Trautwein, C. (2006). Intracellular survival pathways in the liver. Liver Int. 26, 1163–1174.CrossrefPubMedGoogle Scholar

  • Maggio, B., Fanani, M.L., Rosetti, C.M., and Wilke, N. (2006). Biophysics of sphingolipids II. Glycosphingolipids: an assortment of multiple structural information transducers at the membrane surface. Biochim. Biophys. Acta 1758, 1922–1944.Google Scholar

  • Mari, M., Colell, A., Morales, A., Paneda, C., Varela-Nieto, I., Garcia-Ruiz, C., and Fernandez-Checa, J.C. (2004). Acidic sphingomyelinase downregulates the liver-specific methionine adenosyltransferase 1A, contributing to tumor necrosis factor-induced lethal hepatitis. J. Clin. Invest. 113, 895–904.Google Scholar

  • McGill, M.R., Sharpe, M.R., Williams, C.D., Taha, M., Curry, S.C., and Jaeschke, H. (2012). The mechanism underlying acetaminophen-induced hepatotoxicity in humans and mice involves mitochondrial damage and nuclear DNA fragmentation. J. Clin. Invest. 122, 1574–1583.Google Scholar

  • Meyer, S.G. and de Groot, H. (2003). Cycloserine and threo-dihydrosphingosine inhibit TNF-alpha-induced cytotoxicity: evidence for the importance of de novo ceramide synthesis in TNF-α signaling. Biochim. Biophys. Acta 1643, 1–4.Google Scholar

  • Meyer zu Heringdorf, D., Lass, H., Kuchar, I., Lipinski, M., Alemany, R., Rumenapp, U., and Jakobs, K.H. (2001). Stimulation of intracellular sphingosine-1-phosphate production by G-protein-coupled sphingosine-1-phosphate receptors. Eur. J. Pharmacol. 414, 145–154.Google Scholar

  • Michalopoulos, G., Houck, K.A., Dolan, M.L., and Leutteke, N.C. (1984). Control of hepatocyte replication by two serum factors. Cancer Res. 44, 4414–4419.PubMedGoogle Scholar

  • Michalopoulos, G.K. (2007). Liver regeneration. J. Cell. Physiol. 213, 286–300.Google Scholar

  • Moles, A., Tarrats, N., Morales, A., Dominguez, M., Bataller, R., Caballeria, J., Garcia-Ruiz, C., Fernandez-Checa, J.C., and Mari, M. (2010). Acidic sphingomyelinase controls hepatic stellate cell activation and in vivo liver fibrogenesis. Am. J. Pathol. 177, 1214–1224.Google Scholar

  • Mullen, T.D., Hannun, Y.A., Obeid, L.M., (2012). Ceramide synthases at the centre of sphingolipid metabolism and biology. Biochem. J. 441, 789–802.Google Scholar

  • Nakamura, T., Nawa, K., and Ichihara, A. (1984). Partial purification and characterization of hepatocyte growth factor from serum of hepatectomized rats. Biochem. Biophys. Res. Commun. 122, 1450–1459.Google Scholar

  • Nebigil, C.G. (1997). Suppression of phospholipase C β, γ, and δ families alters cell growth and phosphatidylinositol 4,5-bisphosphate levels. Biochemistry 36, 15949–15958.Google Scholar

  • Nikolova-Karakashian, M., Morgan, E.T., Alexander, C., Liotta, D.C., and Merrill, A.H., Jr. (1997). Bimodal regulation of ceramidase by interleukin-1β. Implications for the regulation of cytochrome p450 2C11. J. Biol. Chem. 272, 18718–18724.Google Scholar

  • Nixon, G.F. (2009). Sphingolipids in inflammation: pathological implications and potential therapeutic targets. Br. J. Pharmacol. 158, 982–993.Google Scholar

  • Novgorodov, S.A. and Gudz, T.I. (2009). Ceramide and mitochondria in ischemia/reperfusion. J. Cardiovasc. Pharmacol. 53, 198–208.Google Scholar

  • Obinata, H. and Hla, T. (2012). Sphingosine 1-phosphate in coagulation and inflammation. Semin. Immunopathol. 34, 73–91.Google Scholar

  • Ogretmen, B. and Hannun, Y.A. (2004). Biologically active sphingolipids in cancer pathogenesis and treatment. Nat. Rev. Cancer 4, 604–616.CrossrefPubMedGoogle Scholar

  • Olivera, A., Kohama, T., Edsall, L., Nava, V., Cuvillier, O., Poulton, S., and Spiegel, S. (1999). Sphingosine kinase expression increases intracellular sphingosine-1-phosphate and promotes cell growth and survival. J. Cell. Biol. 147, 545–558.Google Scholar

  • Osawa, Y., Banno, Y., Nagaki, M., Brenner, D.A., Naiki, T., Nozawa, Y., Nakashima, S., and Moriwaki, H. (2001). TNF-α-induced sphingosine 1-phosphate inhibits apoptosis through a phosphatidylinositol 3-kinase/Akt pathway in human hepatocytes. J. Immunol. 167, 173–180.Google Scholar

  • Osawa, Y., Uchinami, H., Bielawski, J., Schwabe, R.F., Hannun, Y.A., and Brenner, D.A. (2005). Roles for C16-ceramide and sphingosine 1-phosphate in regulating hepatocyte apoptosis in response to tumor necrosis factor-α. J. Biol. Chem. 280, 27879–27887.Google Scholar

  • Ostapowicz, G., Fontana, R.J., Schiodt, F.V., Larson, A., Davern, T.J., Han, S.H., McCashland, T.M., Shakil, A.O., Hay, J.E., Hynan, L., et al. (2002). Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann. Intern. Med. 137, 947–954.Google Scholar

  • Park, S.W., Kim, M., Chen, S.W., Brown, K.M., D’Agati, V.D., and Lee, H.T. (2010). Sphinganine-1-phosphate protects kidney and liver after hepatic ischemia and reperfusion in mice through S1P1 receptor activation. Lab. Invest. 90, 1209–1224.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.PubMedCrossrefGoogle 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. (2014). Ceramide synthases as potential targets for therapeutic intervention in human diseases. Biochim. Biophys. Acta 1841, 671–681.Google Scholar

  • Pettus, B.J., Kroesen, B.J., Szulc, Z.M., Bielawska, A., Bielawski, J., Hannun, Y.A., and Busman, M. (2004). Quantitative measurement of different ceramide species from crude cellular extracts by normal-phase high-performance liquid chromatography coupled to atmospheric pressure ionization mass spectrometry. Rapid Commun. Mass Spectrom. 18, 577–583.PubMedGoogle 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. (2010). 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

  • Polson, J. and Lee, W.M. (2007). Etiologies of acute liver failure: location, location, location! Liver Transpl. 13, 1362–1363.Google Scholar

  • Quillin, R.C., 3rd, Wilson, G.C., Nojima, H., Freeman, C.M., Wang, J., Schuster, R.M., Blanchard, J.A., Edwards, M.J., Gandhi, C.R., Gulbins, E., et al. (2015). Inhibition of acidic sphingomyelinase reduces established hepatic fibrosis in mice. Hepatol. Res. 45, 305–314.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 beta-oxidation and confers susceptibility to diet-induced steatohepatitis and insulin resistance. Cell Metab. 20, 687–695.Google Scholar

  • Refsnes, M., Dajani, O.F., Sandnes, D., Thoresen, G.H., Rottingen, J.A., Iversen, J.G., and Christoffersen, T. (1995). On the mechanisms of the growth-promoting effect of prostaglandins in hepatocytes: the relationship between stimulation of DNA synthesis and signaling mediated by adenylyl cyclase and phosphoinositide-specific phospholipase C. J. Cell Physiol. 164, 465–473.Google Scholar

  • Rutkute, K., Karakashian, A.A., Giltiay, N.V., Dobierzewska, A., and Nikolova-Karakashian, M.N. (2007). Aging in rat causes hepatic hyperresposiveness to interleukin-1β which is mediated by neutral sphingomyelinase-2. Hepatology 46, 1166–1176.PubMedCrossrefGoogle Scholar

  • Shi, Y., Rehman, H., Ramshesh, V.K., Schwartz, J., Liu, Q., Krishnasamy, Y., Zhang, X., Lemasters, J.J., Smith, C.D., and Zhong, Z. (2012). Sphingosine kinase-2 inhibition improves mitochondrial function and survival after hepatic ischemia-reperfusion. J. Hepatol. 56, 137–145.CrossrefGoogle Scholar

  • Snider, A.J., Orr Gandy, K.A., and Obeid, L.M. (2010). Sphingosine kinase: role in regulation of bioactive sphingolipid mediators in inflammation. Biochimie 92, 707–715.CrossrefGoogle Scholar

  • Spiegel, S. and Milstien, S. (2000a). Functions of a new family of sphingosine-1-phosphate receptors. Biochim. Biophys. Acta 1484, 107–116.Google Scholar

  • Spiegel, S. and Milstien, S. (2000b). Sphingosine-1-phosphate: signaling inside and out. FEBS Lett. 476, 55–57.Google Scholar

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

  • Suzuki, S. and Toledo-Pereyra, L.H. (1994). Interleukin 1 and tumor necrosis factor production as the initial stimulants of liver ischemia and reperfusion injury. J. Surg. Res. 57, 253–258.Google Scholar

  • Tagaram, H.R., Divittore, N.A., Barth, B.M., Kaiser, J.M., Avella, D., Kimchi, E.T., Jiang, Y., Isom, H.C., Kester, M., and Staveley-O’Carroll, K.F. (2011). Nanoliposomal ceramide prevents in vivo growth of hepatocellular carcinoma. Gut 60, 695–701.CrossrefGoogle Scholar

  • Tsuchihashi, S., Ke, B., Kaldas, F., Flynn, E., Busuttil, R.W., Briscoe, D.M., and Kupiec-Weglinski, J.W. (2006). Vascular endothelial growth factor antagonist modulates leukocyte trafficking and protects mouse livers against ischemia/reperfusion injury. Am. J. Pathol. 168, 695–705.Google Scholar

  • Tsung, A., Sahai, R., Tanaka, H., Nakao, A., Fink, M.P., Lotze, M.T., Yang, H., Li, J., Tracey, K.J., Geller, D.A., et al. (2005). The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion. J. Exp. Med. 201, 1135–1143.Google Scholar

  • Turnbull, K.J., Brown, B.L., and Dobson, P.R. (1999). Caspase-3-like activity is necessary but not sufficient for daunorubicin-induced apoptosis in Jurkat human lymphoblastic leukemia cells. Leukemia 13, 1056–1061.CrossrefPubMedGoogle Scholar

  • Uchida, Y., Nardo, A.D., Collins, V., Elias, P.M., and Holleran, W.M. (2003). De novo ceramide synthesis participates in the ultraviolet B irradiation-induced apoptosis in undifferentiated cultured human keratinocytes. J. Invest. Dermatol. 120, 662–669.Google Scholar

  • Uehara, T., Bennett, B., Sakata, S.T., Satoh, Y., Bilter, G.K., Westwick, J.K., and Brenner, D.A. (2005). JNK mediates hepatic ischemia reperfusion injury. J. Hepatol. 42, 850–859.Google Scholar

  • Vessey, D.A., Li, L., Jin, Z.Q., Kelley, M., Honbo, N., Zhang, J., and Karliner, J.S. (2011). A sphingosine kinase form 2 knockout sensitizes mouse myocardium to ischemia/reoxygenation injury and diminishes responsiveness to ischemic preconditioning. Oxidat. Med. Cell. Longevity 2011, 961059.Google Scholar

  • Wanner, G.A., Ertel, W., Muller, P., Hofer, Y., Leiderer, R., Menger, M.D., and Messmer, K. (1996). Liver ischemia and reperfusion induces a systemic inflammatory response through Kupffer cell activation. Shock 5, 34–40.CrossrefPubMedGoogle Scholar

  • Watanabe, A., Nakashima, S., Adachi, T., Saji, S., and Nozawa, Y. (2000). Changes in the expression of lipid-mediated signal-transducing enzymes in the rat liver after partial hepatectomy. Surg. Today 30, 622–630.CrossrefPubMedGoogle Scholar

  • Webber, E.M., Bruix, J., Pierce, R.H., and Fausto, N. (1998). Tumor necrosis factor primes hepatocytes for DNA replication in the rat. Hepatology 28, 1226–1234.PubMedCrossrefGoogle Scholar

  • Wiegmann, K., Schutze, S., Machleidt, T., Witte, D., and Kronke, M. (1994). Functional dichotomy of neutral and acidic sphingomyelinases in tumor necrosis factor signaling. Cell 78, 1005–1015.Google Scholar

  • Xiong, Y., Lee, H.J., Mariko, B., Lu, Y.C., Dannenberg, A.J., Haka, A.S., Maxfield, F.R., Camerer, E., Proia, R.L., and Hla, T. (2013). Sphingosine kinases are not required for inflammatory responses in macrophages. J. Biol. Chem. 288, 32563–32573.Google Scholar

  • Yang, L., Chang, N., Liu, X., Han, Z., Zhu, T., Li, C., Yang, L., and Li, L. (2012). Bone marrow-derived mesenchymal stem cells differentiate to hepatic myofibroblasts by transforming growth factor-β1 via sphingosine kinase/sphingosine 1-phosphate (S1P)/S1P receptor axis. Am. J. Pathol. 181, 85–97.Google Scholar

  • Yu, J., Novgorodov, S.A., Chudakova, D., Zhu, H., Bielawska, A., Bielawski, J., Obeid, L.M., Kindy, M.S., and Gudz, T.I. (2007). JNK3 signaling pathway activates ceramide synthase leading to mitochondrial dysfunction. J. Biol. Chem. 282, 25940–25949.Google Scholar

  • Zabielski, P., Baranowski, M., Zendzian-Piotrowska, M., Blachnio, A., and Gorski, J. (2007). Partial hepatectomy activates production of the pro-mitotic intermediates of the sphingomyelin signal transduction pathway in the rat liver. Prostaglandins Other Lipid Mediat. 83, 277–284.Google Scholar

  • Zimmermann, A. (2004). Regulation of liver regeneration. Nephrol. Dial. Transplant. 19 (Suppl. 4), iv6–10.Google Scholar

  • Zwacka, R.M., Zhang, Y., Halldorson, J., Schlossberg, H., Dudus, L., and Engelhardt, J.F. (1997). CD4+ T-lymphocytes mediate ischemia/reperfusion-induced inflammatory responses in mouse liver. J. Clin. Invest. 100, 279–289.Google Scholar

About the article

Corresponding author: Alex B. Lentsch, Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way, ML 0558, Cincinnati, OH 45267-0558, USA, e-mail:


Received: 2014-12-04

Accepted: 2015-03-09

Published Online: 2015-03-12

Published in Print: 2015-06-01


Citation Information: Biological Chemistry, Volume 396, Issue 6-7, Pages 633–643, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/hsz-2014-0296.

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