DOI QR코드

DOI QR Code

Ceramide and Sphingosine 1-Phosphate in Liver Diseases

  • Received : 2020.03.01
  • Accepted : 2020.04.19
  • Published : 2020.05.31

Abstract

The liver is an important organ in the regulation of glucose and lipid metabolism. It is responsible for systemic energy homeostasis. When energy need exceeds the storage capacity in the liver, fatty acids are shunted into nonoxidative sphingolipid biosynthesis, which increases the level of cellular ceramides. Accumulation of ceramides alters substrate utilization from glucose to lipids, activates triglyceride storage, and results in the development of both insulin resistance and hepatosteatosis, increasing the likelihood of major metabolic diseases. Another sphingolipid metabolite, sphingosine 1-phosphate (S1P) is a bioactive signaling molecule that acts via S1P-specific G protein coupled receptors. It regulates many cellular and physiological events. Since an increase in plasma S1P is associated with obesity, it seems reasonable that recent studies have provided evidence that S1P is linked to lipid pathophysiology, including hepatosteatosis and fibrosis. Herein, we review recent findings on ceramides and S1P in obesity-mediated liver diseases and the therapeutic potential of these sphingolipid metabolites.

Keywords

References

  1. Aerts, J.M., Ottenhoff, R., Powlson, A.S., Grefhorst, A., van Eijk, M., Dubbelhuis, P.F., Aten, J., Kuipers, F., Serlie, M.J., Wennekes, T., et al. (2007). Pharmacological inhibition of glucosylceramide synthase enhances insulin sensitivity. Diabetes 56, 1341-1349. https://doi.org/10.2337/db06-1619
  2. Al Fadel, F., Fayyaz, S., Japtok, L., and Kleuser, B. (2016). Involvement of sphingosine 1-phosphate in palmitate-induced non-alcoholic fatty liver disease. Cell. Physiol. Biochem. 40, 1637-1645. https://doi.org/10.1159/000453213
  3. Barr, E.L., Cameron, A.J., Balkau, B., Zimmet, P.Z., Welborn, T.A., Tonkin, A.M., and Shaw, J.E. (2010). HOMA insulin sensitivity index and the risk of all-cause mortality and cardiovascular disease events in the general population: the Australian Diabetes, Obesity and Lifestyle Study (AusDiab) study. Diabetologia 53, 79-88. https://doi.org/10.1007/s00125-009-1588-0
  4. Bashiardes, S., Shapiro, H., Rozin, S., Shibolet, O., and Elinav, E. (2016). Nonalcoholic fatty liver and the gut microbiota. Mol. Metab. 5, 782-794. https://doi.org/10.1016/j.molmet.2016.06.003
  5. Bataller, R. and Brenner, D.A. (2005). Liver fibrosis. J. Clin. Invest. 115, 209-218. https://doi.org/10.1172/JCI24282
  6. Becker, S., Kinny-Koster, B., Bartels, M., Scholz, M., Seehofer, D., Berg, T., Engelmann, C., Thiery, J., Ceglarek, U., and Kaiser, T. (2017). Low sphingosine-1-phosphate plasma levels are predictive for increased mortality in patients with liver cirrhosis. PLoS One 12, e0174424. https://doi.org/10.1371/journal.pone.0174424
  7. Bissell, D.M. (1998). Hepatic fibrosis as wound repair: a progress report. J. Gastroenterol. 33, 295-302. https://doi.org/10.1007/s005350050087
  8. Bradbury, M.W. (2006). Lipid metabolism and liver inflammation. I. Hepatic fatty acid uptake: possible role in steatosis. Am. J. Physiol. Gastrointest. Liver Physiol. 290, G194-G198. https://doi.org/10.1152/ajpgi.00413.2005
  9. Brinkmann, V., Billich, A., Baumruker, T., Heining, P., Schmouder, R., Francis, G., Aradhye, S., and Burtin, P. (2010). Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nat. Rev. Drug Discov. 9, 883-897. https://doi.org/10.1038/nrd3248
  10. Brunati, A.M., Tibaldi, E., Carraro, A., Gringeri, E., D'Amico, F., Jr, Toninello, A., Massimino, M.L., Pagano, M.A., Nalesso, G., and Cillo, U. (2008). Crosstalk between PDGF and S1P signalling elucidates the inhibitory effect and potential antifibrotic action of the immunomodulator FTY720 in activated HSC-cultures. Biochim. Biophys. Acta 1783, 347-359. https://doi.org/10.1016/j.bbamcr.2007.11.008
  11. Chang, N., Ge, J., Xiu, L., Zhao, Z., Duan, X., Tian, L., Xie, J., Yang, L., and Li, L. (2017). HuR mediates motility of human bone marrow-derived mesenchymal stem cells triggered by sphingosine 1-phosphate in liver fibrosis. J. Mol. Med. 95, 69-82. https://doi.org/10.1007/s00109-016-1460-x
  12. Chaurasia, B., Tippetts, T.S., Mayoral Monibas, R., Liu, J., Li, Y., Wang, L., Wilkerson, J.L., Sweeney, C.R., Pereira, R.F., et al. (2019). Targeting a ceramide double bond improves insulin resistance and hepatic steatosis. Science 365, 386-392. https://doi.org/10.1126/science.aav3722
  13. Chen, J., Wang, W., Qi, Y., Kaczorowski, D., McCaughan, G.W., Gamble, J.R., Don, A.S., Gao, X., Vadas, M.A., and Xia, P. (2016a). Deletion of sphingosine kinase 1 ameliorates hepatic steatosis in diet-induced obese mice: role of $PPAR\gamma$. Biochim. Biophys. Acta 1861, 138-147. https://doi.org/10.1016/j.bbalip.2015.11.006
  14. Chen, Q., Denard, B., Lee, C.E., Han, S., Ye, J.S., and Ye, J. (2016b). Inverting the topology of a transmembrane protein by regulating the translocation of the first transmembrane helix. Mol. Cell 63, 567-578. https://doi.org/10.1016/j.molcel.2016.06.032
  15. Chen, T.C., Lee, R.A., Tsai, S.L., Kanamaluru, D., Gray, N.E., Yiv, N., Cheang, R.T., Tan, J.H., Lee, J.Y., Fitch, M.D., et al. (2019). An ANGPTL4-ceramideprotein kinase Czeta axis mediates chronic glucocorticoid exposureinduced hepatic steatosis and hypertriglyceridemia in mice. J. Biol. Chem. 294, 9213-9224. https://doi.org/10.1074/jbc.RA118.006259
  16. Cohen, J.C., Horton, J.D., and Hobbs, H.H. (2011). Human fatty liver disease: old questions and new insights. Science 332, 1519-1523. https://doi.org/10.1126/science.1204265
  17. Deevska, G.M., Rozenova, K.A., Giltiay, N.V., Chambers, M.A., White, J., Boyanovsky, B.B., Wei, J., Daugherty, A., Smart, E.J., Reid, M.B., et al. (2009). Acid sphingomyelinase deficiency prevents diet-induced hepatic triacylglycerol accumulation and hyperglycemia in mice. J. Biol. Chem. 284, 8359-8368. https://doi.org/10.1074/jbc.M807800200
  18. Denard, B., Lee, C., and Ye, J. (2012). Doxorubicin blocks proliferation of cancer cells through proteolytic activation of CREB3L1. Elife 1, e00090. https://doi.org/10.7554/eLife.00090
  19. Ding, B.S., Liu, C.H., Sun, Y., Chen, Y., Swendeman, S.L., Jung, B., Chavez, D., Cao, Z., Christoffersen, C., Nielsen, L.B., et al. (2016). HDL activation of endothelial sphingosine-1-phosphate receptor-1 (S1P1) promotes regeneration and suppresses fibrosis in the liver. JCI Insight 1, e87058.
  20. Dyckman, A.J. (2017). Modulators of sphingosine-1-phosphate pathway biology: recent advances of sphingosine-1-phosphate receptor 1 (S1P1) agonists and future perspectives. J. Med. Chem. 60, 5267-5289. https://doi.org/10.1021/acs.jmedchem.6b01575
  21. Friedman, S.L. (2008). Mechanisms of hepatic fibrogenesis. Gastroenterology 134, 1655-1669. https://doi.org/10.1053/j.gastro.2008.03.003
  22. Fucho, R., Martinez, L., Baulies, A., Torres, S., Tarrats, N., Fernandez, A., Ribas, V., Astudillo, A.M., Balsinde, J., Garcia-Roves, P., et al. (2014). ASMase regulates autophagy and lysosomal membrane permeabilization and its inhibition prevents early stage non-alcoholic steatohepatitis. J. Hepatol. 61, 1126-1134. https://doi.org/10.1016/j.jhep.2014.06.009
  23. Gao, D., Pararasa, C., Dunston, C.R., Bailey, C.J., and Griffiths, H.R. (2012). Palmitate promotes monocyte atherogenicity via de novo ceramide synthesis. Free Radic. Biol. Med. 53, 796-806. https://doi.org/10.1016/j.freeradbiomed.2012.05.026
  24. Gao, W., Liu, H., Yuan, J., Wu, C., Huang, D., Ma, Y., Zhu, J., Ma, L., Guo, J., Shi, H., et al. (2016). Exosomes derived from mature dendritic cells increase endothelial inflammation and atherosclerosis via membrane TNF-$\alpha$ mediated NF-$\kappa$B pathway. J. Cell. Mol. Med. 20, 2318-2327. https://doi.org/10.1111/jcmm.12923
  25. Geng, T., Sutter, A., Harland, M.D., Law, B.A., Ross, J.S., Lewin, D., Palanisamy, A., Russo, S.B., Chavin, K.D., and Cowart, L.A. (2015). SphK1 mediates hepatic inflammation in a mouse model of NASH induced by high saturated fat feeding and initiates proinflammatory signaling in hepatocytes. J. Lipid Res. 56, 2359-2371. https://doi.org/10.1194/jlr.M063511
  26. Gonzalez-Fernandez, B., Sanchez, D.I., Crespo, I., San-Miguel, B., Alvarez, M., Tunon, M.J., and Gonzalez-Gallego, J. (2017). Inhibition of the SphK1/ S1P signaling pathway by melatonin in mice with liver fibrosis and human hepatic stellate cells. BioFactors 43, 272-282. https://doi.org/10.1002/biof.1342
  27. Gosejacob, D., Jäger, P.S., Vom Dorp, K., Frejno, M., Carstensen, A.C., Köhnke, M., Degen, J., Dörmann, P., and Hoch, M. (2016). Ceramide synthase 5 is essential to maintain C16:0-ceramide pools and contributes to the development of diet-induced obesity. J. Biol. Chem. 291, 6989-7003. https://doi.org/10.1074/jbc.M115.691212
  28. Hajduch, E., Balendran, A., Batty, I.H., Litherland, G.J., Blair, A.S., Downes, C.P., and Hundal, H.S. (2001). Ceramide impairs the insulin-dependent membrane recruitment of protein kinase B leading to a loss in downstream signalling in L6 skeletal muscle cells. Diabetologia 44, 173-183. https://doi.org/10.1007/s001250051596
  29. Hastie, C.E., Padmanabhan, S., Slack, R., Pell, A.C., Oldroyd, K.G., Flapan, A.D., Jennings, K.P., Irving, J., Eteiba, H., Dominiczak, A.F., et al. (2010). Obesity paradox in a cohort of 4880 consecutive patients undergoing percutaneous coronary intervention. Eur. Heart J. 31, 222-226. https://doi.org/10.1093/eurheartj/ehp317
  30. Higuchi, H. and Gores, G.J. (2003). Mechanisms of liver injury: an overview. Curr. Mol. Med. 3, 483-490. https://doi.org/10.2174/1566524033479528
  31. Holland, W.L., Brozinick, J.T., Wang, L.P., Hawkins, E.D., Sargent, K.M., Liu, Y., Narra, K., Hoehn, K.L., Knotts, T.A., Siesky, A., et al. (2007). Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell Metab. 5, 167-179. https://doi.org/10.1016/j.cmet.2007.01.002
  32. 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. 53, 53-56. https://doi.org/10.3177/jnsv.53.53
  33. 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. https://doi.org/10.1194/jlr.M800496-JLR200
  34. Jiang, C., Xie, C., Li, F., Zhang, L., Nichols, R.G., Krausz, K.W., Cai, J., Qi, Y., Fang, Z.Z., Takahashi, S., et al. (2015). Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease. J. Clin. Invest. 125, 386-402. https://doi.org/10.1172/JCI76738
  35. Jiang, M., Li, C., Liu, Q., Wang, A., and Lei, M. (2019). Inhibiting ceramide synthesis attenuates hepatic steatosis and fibrosis in rats with nonalcoholic fatty liver disease. Front. Endocrinol. 10, 665. https://doi.org/10.3389/fendo.2019.00665
  36. Jin, J., Zhang, X., Lu, Z., Perry, D.M., Li, Y., Russo, S.B., Cowart, L.A., Hannun, Y.A., and Huang, Y. (2013). Acid sphingomyelinase plays a key role in palmitic acid-amplified inflammatory signaling triggered by lipopolysaccharide at low concentrations in macrophages. Am. J. Physiol. Endocrinol. Metab. 305, E853-E867. https://doi.org/10.1152/ajpendo.00251.2013
  37. Kageyama, Y., Ikeda, H., Watanabe, N., Nagamine, M., Kusumoto, Y., Yashiro, M., Satoh, Y., Shimosawa, T., Shinozaki, K., Tomiya, T., et al. (2012). Antagonism of sphingosine 1-phosphate receptor 2 causes a selective reduction of portal vein pressure in bile duct-ligated rodents. Hepatology 56, 1427-1438. https://doi.org/10.1002/hep.25780
  38. Kaneko, T., Murakami, T., Kawana, H., Takahashi, M., Yasue, T., and Kobayashi, E. (2006). Sphingosine-1-phosphate receptor agonists suppress concanavalin A-induced hepatic injury in mice. Biochem. Biophys. Res. Commun. 345, 85-92. https://doi.org/10.1016/j.bbrc.2006.04.067
  39. Khattar, M., Deng, R., Kahan, B.D., Schroder, P.M., Phan, T., Rutzky, L.P., and Stepkowski, S.M. (2013). Novel sphingosine-1-phosphate receptor modulator KRP203 combined with locally delivered regulatory T cells induces permanent acceptance of pancreatic islet allografts. Transplantation 95, 919-927. https://doi.org/10.1097/TP.0b013e3182842396
  40. Kim, Y.R., Lee, E.J., Shin, K.O., Kim, M.H., Pewzner-Jung, Y., Lee, Y.M., Park, J.W., Futerman, A.H., and Park, W.J. (2019). Hepatic triglyceride accumulation via endoplasmic reticulum stress-induced SREBP-1 activation is regulated by ceramide synthases. Exp. Mol. Med. 51, 1-16.
  41. King, A., Houlihan, D.D., Kavanagh, D., Haldar, D., Luu, N., Owen, A., Suresh, S., Than, N.N., Reynolds, G., Penny, J., et al. (2017). Sphingosine-1-phosphate prevents egress of hematopoietic stem cells from liver to reduce fibrosis. Gastroenterology 153, 233-248.e16. https://doi.org/10.1053/j.gastro.2017.03.022
  42. Kisseleva, T., Cong, M., Paik, Y., Scholten, D., Jiang, C., Benner, C., Iwaisako, K., Moore-Morris, T., Scott, B., Tsukamoto, H., et al. (2012). Myofibroblasts revert to an inactive phenotype during regression of liver fibrosis. Proc. Natl. Acad. Sci. U. S. A. 109, 9448-9453. https://doi.org/10.1073/pnas.1201840109
  43. Kitatani, K., Taniguchi, M., and Okazaki, T. (2015). Role of sphingolipids and metabolizing enzymes in hematological malignancies. Mol. Cells 38, 482-495. https://doi.org/10.14348/molcells.2015.0118
  44. Kong, Y., Wang, H., Wang, S., and Tang, N. (2014). FTY720, a sphingosine-1 phosphate receptor modulator, improves liver fibrosis in a mouse model by impairing the motility of bone marrow-derived mesenchymal stem cells. Inflammation 37, 1326-1336. https://doi.org/10.1007/s10753-014-9877-2
  45. Kowalski, G.M., Kloehn, J., Burch, M.L., Selathurai, A., Hamley, S., Bayol, S.A.M., Lamon, S., Watt, M.J., Lee-Young, R.S., McConville, M.J., et al. (2015). Overexpression of sphingosine kinase 1 in liver reduces triglyceride content in mice fed a low but not high-fat diet. Biochim. Biophys. Acta 1851, 210-219. https://doi.org/10.1016/j.bbalip.2014.12.002
  46. Kurek, K., Piotrowska, D.M., Wiesiolek, P., Lukaszuk, B., Chabowski, A., Gorski, J., and Zendzian-Piotrowska, M. (2013). Inhibition of ceramide de novo synthesis reduces liver lipid accumulation in rats with nonalcoholic fatty liver disease. Liver Int. 34, 1074-1083. https://doi.org/10.1111/liv.12331
  47. Lallemand, T., Rouahi, M., Swiader, A., Grazide, M.H., Geoffre, N., Alayrac, P., Recazens, E., Coste, A., Salvayre, R., Negre-Salvayre, A., et al. (2018). nSMase2 (type 2-neutral sphingomyelinase) deficiency or inhibition by GW4869 reduces inflammation and atherosclerosis in Apoe-/- mice. Arterioscler. Thromb. Vasc. Biol. 38, 1479-1492. https://doi.org/10.1161/ATVBAHA.118.311208
  48. Lee, S.Y., Hong, I.K., Kim, B.R., Shim, S.M., Lee, J.S., Lee, H.Y., Choi, C.S., Kim, B.K., and Park, T.S. (2015). Activation of sphingosine kinase 2 by endoplasmic reticulum stress ameliorates hepatic steatosis and insulin resistance in mice. Hepatology 62, 135-146. https://doi.org/10.1002/hep.27804
  49. 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. https://doi.org/10.2353/ajpath.2009.090037
  50. 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. https://doi.org/10.1016/j.jhep.2009.01.028
  51. 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. https://doi.org/10.1016/j.jhep.2010.08.028
  52. Li, Y., Dong, J., Ding, T., Kuo, M.S., Cao, G., Jiang, X.C., and Li, Z. (2013). Sphingomyelin synthase 2 activity and liver steatosis: an effect of ceramide-mediated peroxisome proliferator-activated receptor $\gamma$2 suppression. Arterioscler. Thromb. Vasc. Biol. 33, 1513-1520. https://doi.org/10.1161/ATVBAHA.113.301498
  53. Liangpunsakul, S., Rahmini, Y., Ross, R.A., Zhao, Z., Xu, Y., and Crabb, D.W. (2012). Imipramine blocks ethanol-induced ASMase activation, ceramide generation, and PP2A activation, and ameliorates hepatic steatosis in ethanol-fed mice. Am. J. Physiol. Gastrointest. Liver Physiol. 302, G515-G523. https://doi.org/10.1152/ajpgi.00455.2011
  54. Lindenmeyer, C.C. and McCullough, A.J. (2018). The natural history of nonalcoholic fatty liver disease-an evolving view. Clin. Liver Dis. 22, 11-21. https://doi.org/10.1016/j.cld.2017.08.003
  55. Liu, X., Yue, S., Li, C., Yang, L., You, H., and Li, L. (2011). Essential roles of sphingosine 1-phosphate receptor types 1 and 3 in human hepatic stellate cells motility and activation. J. Cell. Physiol. 226, 2370-2377. https://doi.org/10.1002/jcp.22572
  56. Longato, L., Tong, M., Wands, J.R., and de la Monte, S.M. (2012). High fat diet induced hepatic steatosis and insulin resistance: role of dysregulated ceramide metabolism. Hepatol. Res. 42, 412-427. https://doi.org/10.1111/j.1872-034X.2011.00934.x
  57. Ma, M.M., Chen, J.L., Wang, G.G., Wang, H., Lu, Y., Li, J.F., Yi, J., Yuan, Y.J., Zhang, Q.W., Mi, J., et al. (2007). Sphingosine kinase 1 participates in insulin signalling and regulates glucose metabolism and homeostasis in KK/Ay diabetic mice. Diabetologia 50, 891-900. https://doi.org/10.1007/s00125-006-0589-5
  58. Maceyka, M., Harikumar, K.B., Milstien, S., and Spiegel, S. (2012). Sphingosine-1-phosphate signaling and its role in disease. Trends Cell Biol. 22, 50-60. https://doi.org/10.1016/j.tcb.2011.09.003
  59. Maceyka, M. and Spiegel, S. (2014). Sphingolipid metabolites in inflammatory disease. Nature 510, 58-67. https://doi.org/10.1038/nature13475
  60. Mari, M., Colell, A., Morales, A., Caballero, F., Moles, A., Fernandez, A., Terrones, O., Basanez, G., Antonsson, B., Garcia-Ruiz, C., et al. (2008). Mechanism of mitochondrial glutathione-dependent hepatocellular susceptibility to TNF despite NF-kappaB activation. Gastroenterology 134, 1507-1520. https://doi.org/10.1053/j.gastro.2008.01.073
  61. Mauer, A.S., Hirsova, P., Maiers, J.L., Shah, V.H., and Malhi, H. (2017). Inhibition of sphingosine 1-phosphate signaling ameliorates murine nonalcoholic steatohepatitis. Am. J. Physiol. Gastrointest. Liver Physiol. 312, G300-G313. https://doi.org/10.1152/ajpgi.00222.2016
  62. Merrill, A.H., Jr. (2002). De novo sphingolipid biosynthesis: a necessary, but dangerous, pathway. J. Biol. Chem. 277, 25843-25846. https://doi.org/10.1074/jbc.R200009200
  63. Mitsutake, S., Zama, K., Yokota, H., Yoshida, T., Tanaka, M., Mitsui, M., Ikawa, M., Okabe, M., Tanaka, Y., Yamashita, T., et al. (2011). Dynamic modification of sphingomyelin in lipid microdomains controls development of obesity, fatty liver, and type 2 diabetes. J. Biol. Chem. 286, 28544-28555. https://doi.org/10.1074/jbc.M111.255646
  64. 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. https://doi.org/10.2353/ajpath.2010.091257
  65. Nagahashi, M., Takabe, K., Liu, R., Peng, K., Wang, X., Wang, Y., Hait, N.C., Wang, X., Allegood, J.C., Yamada, A., et al. (2015). Conjugated bile acidactivated S1P receptor 2 is a key regulator of sphingosine kinase 2 and hepatic gene expression. Hepatology 61, 1216-1226. https://doi.org/10.1002/hep.27592
  66. Nishi, T., Kobayashi, N., Hisano, Y., Kawahara, A., and Yamaguchi, A. (2014). Molecular and physiological functions of sphingosine 1-phosphate transporters. Biochim. Biophys. Acta 1841, 759-765. https://doi.org/10.1016/j.bbalip.2013.07.012
  67. Park, S.J. and Im, D.S. (2017). Sphingosine 1-phosphate receptor modulators and drug discovery. Biomol. Ther. 25, 80-90. https://doi.org/10.4062/biomolther.2016.160
  68. Park, W.J., Park, J.W., Merrill, A.H., Storch, J., Pewzner-Jung, Y., and Futerman, A.H. (2014). Hepatic fatty acid uptake is regulated by the sphingolipid acyl chain length. Biochim. Biophys. Acta 1841, 1754-1766. https://doi.org/10.1016/j.bbalip.2014.09.009
  69. Pessayre, D., Mansouri, A., and Fromenty, B. (2002). Nonalcoholic steatosis and steatohepatitis. V. Mitochondrial dysfunction in steatohepatitis. Am. J. Physiol. Gastrointest. Liver Physiol. 282, G193-G199. https://doi.org/10.1152/ajpgi.00426.2001
  70. Postic, C. and Girard, J. (2008). Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. J. Clin. Invest. 118, 829-838. https://doi.org/10.1172/JCI34275
  71. Powell, D.J., Hajduch, E., Kular, G., and Hundal, H.S. (2003). Ceramide disables 3-phosphoinositide binding to the pleckstrin homology domain of protein kinase B (PKB)/Akt by a PKCzeta-dependent mechanism. Mol. Cell. Biol. 23, 7794-7808. https://doi.org/10.1128/MCB.23.21.7794-7808.2003
  72. Pyne, N.J. and Pyne, S. (2010). Sphingosine 1-phosphate and cancer. Nat. Rev. Cancer 10, 489-503. https://doi.org/10.1038/nrc2875
  73. Qi, Y., Chen, J., Lay, A., Don, A., Vadas, M., and Xia, P. (2013). Loss of sphingosine kinase 1 predisposes to the onset of diabetes via promoting pancreatic $\beta$-cell death in diet-induced obese mice. FASEB J. 27, 4294-4304. https://doi.org/10.1096/fj.13-230052
  74. 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. https://doi.org/10.1016/j.cmet.2014.09.015
  75. Rinella, M.E. and Sanyal, A.J. (2016). Management of NAFLD: a stagebased approach. Nat. Rev. Gastroenterol. Hepatol. 13, 196-205. https://doi.org/10.1038/nrgastro.2016.3
  76. Rippe, R.A. and Brenner, D.A. (2004). From quiescence to activation: gene regulation in hepatic stellate cells. Gastroenterology 127, 1260-1262. https://doi.org/10.1053/j.gastro.2004.08.028
  77. Rohrbach, T., Maceyka, M., and Spiegel, S. (2017). Sphingosine kinase and sphingosine-1-phosphate in liver pathobiology. Crit. Rev. Biochem. Mol. Biol. 52, 543-553. https://doi.org/10.1080/10409238.2017.1337706
  78. Rohrbach, T.D., Asgharpour, A., Maczis, M.A., Montefusco, D., Cowart, L.A., Bedossa, P., Sanyal, A.J., and Spiegel, S. (2019). FTY720/fingolimod decreases hepatic steatosis and expression of fatty acid synthase in dietinduced nonalcoholic fatty liver disease in mice. J. Lipid Res. 60, 1311-1322. https://doi.org/10.1194/jlr.M093799
  79. Rutkute, K., Asmis, R.H., and Nikolova-Karakashian, M.N. (2007a). Regulation of neutral sphingomyelinase-2 by GSH: a new insight to the role of oxidative stress in aging-associated inflammation. J. Lipid Res. 48, 2443-2452. https://doi.org/10.1194/jlr.M700227-JLR200
  80. Rutkute, K., Karakashian, A.A., Giltiay, N.V., Dobierzewska, A., and Nikolova-Karakashian, M.N. (2007b). Aging in rat causes hepatic hyperresposiveness to interleukin-1beta which is mediated by neutral sphingomyelinase-2. Hepatology 46, 1166-1176. https://doi.org/10.1002/hep.21777
  81. Samad, F., Hester, K.D., Yang, G., Hannun, Y.A., and Bielawski, J. (2006). Altered adipose and plasma sphingolipid metabolism in obesity: a potential mechanism for cardiovascular and metabolic risk. Diabetes 55, 2579-2587. https://doi.org/10.2337/db06-0330
  82. Sanyal, A.J. and Pacana, T. (2015). A lipidomic readout of disease progression in a diet-induced mouse model of nonalcoholic fatty liver disease. Trans. Am. Clin. Climatol. Assoc. 126, 271-288.
  83. Sato, M., Ikeda, H., Uranbileg, B., Kurano, M., Saigusa, D., Aoki, J., Maki, H., Kudo, H., Hasegawa, K., Kokudo, N., et al. (2016). Sphingosine kinase-1, S1P transporter spinster homolog 2 and S1P2 mRNA expressions are increased in liver with advanced fibrosis in human. Sci. Rep. 6, 32119. https://doi.org/10.1038/srep32119
  84. Sattar, N., Forrest, E., and Preiss, D. (2014). Non-alcoholic fatty liver disease. BMJ 349, g4596. https://doi.org/10.1136/bmj.g4596
  85. Schilling, J.D., Machkovech, H.M., He, L., Sidhu, R., Fujiwara, H., Weber, K., Ory, D.S., and Schaffer, J.E. (2013). Palmitate and lipopolysaccharide trigger synergistic ceramide production in primary macrophages. J. Biol. Chem. 288, 2923-2932. https://doi.org/10.1074/jbc.M112.419978
  86. Schuppan, D. and Afdhal, N.H. (2008). Liver cirrhosis. Lancet 371, 838-851. https://doi.org/10.1016/S0140-6736(08)60383-9
  87. Schwalm, S., Pfeilschifter, J., and Huwiler, A. (2013). Sphingosine-1-phosphate: a Janus-faced mediator of fibrotic diseases. Biochim. Biophys. Acta 1831, 239-250. https://doi.org/10.1016/j.bbalip.2012.07.022
  88. Shea, B.S. and Tager, A.M. (2012). Sphingolipid regulation of tissue fibrosis. Open Rheumatol. J. 6, 123-129. https://doi.org/10.2174/1874312901206010123
  89. Stoffel, W., Jenke, B., Holz, B., Binczek, E., Gunter, R.H., Knifka, J., Koebke, J., and Niehoff, A. (2007). Neutral sphingomyelinase (SMPD3) deficiency causes a novel form of chondrodysplasia and dwarfism that is rescued by Col2A1-driven smpd3 transgene expression. Am. J. Pathol. 171, 153-161. https://doi.org/10.2353/ajpath.2007.061285
  90. Summers, S.A., Garza, L.A., Zhou, H., and Birnbaum, M.J. (1998). Regulation of insulin-stimulated glucose transporter GLUT4 translocation and Akt kinase activity by ceramide. Mol. Cell. Biol. 18, 5457-5464. https://doi.org/10.1128/MCB.18.9.5457
  91. Tagami, S., Inokuchi Ji, J., Kabayama, K., Yoshimura, H., Kitamura, F., Uemura, S., Ogawa, C., Ishii, A., Saito, M., Ohtsuka, Y., et al. (2002). Ganglioside GM3 participates in the pathological conditions of insulin resistance. J. Biol. Chem. 277, 3085-3092. https://doi.org/10.1074/jbc.M103705200
  92. Takabe, K. and Spiegel, S. (2014). Export of sphingosine-1-phosphate and cancer progression. J. Lipid Res. 55, 1839-1846. https://doi.org/10.1194/jlr.R046656
  93. Taniguchi, C.M., Kondo, T., Sajan, M., Luo, J., Bronson, R., Asano, T., Farese, R., Cantley, L.C., and Kahn, C.R. (2006). Divergent regulation of hepatic glucose and lipid metabolism by phosphoinositide 3-kinase via Akt and PKClambda/zeta. Cell Metab. 3, 343-353. https://doi.org/10.1016/j.cmet.2006.04.005
  94. Turner, N., Kowalski, G.M., Leslie, S.J., Risis, S., Yang, C., Lee-Young, R.S., Babb, J.R., Meikle, P.J., Lancaster, G.I., Henstridge, D.C., et al. (2013). Distinct patterns of tissue-specific lipid accumulation during the induction of insulin resistance in mice by high-fat feeding. Diabetologia 56, 1638-1648. https://doi.org/10.1007/s00125-013-2913-1
  95. Turpin, S.M., Nicholls, H.T., Willmes, D.M., Mourier, A., Brodesser, S., Wunderlich, C.M., Mauer, J., Xu, E., Hammerschmidt, P., Brönneke, H.S., et al. (2014). Obesity-induced CerS6-dependent C16:0 ceramide production promotes weight gain and glucose intolerance. Cell Metab. 20, 678-686. https://doi.org/10.1016/j.cmet.2014.08.002
  96. Unger, R.H. (2003). Lipid overload and overflow: metabolic trauma and the metabolic syndrome. Trends Endocrinol. Metab. 14, 398-403. https://doi.org/10.1016/j.tem.2003.09.008
  97. Ussher, J.R., Koves, T.R., Cadete, V.J.J., Zhang, L., Jaswal, J.S., Swyrd, S.J., Lopaschuk, D.G., Proctor, S.D., Keung, W., Muoio, D.M., et al. (2010). Inhibition of de novo ceramide synthesis reverses diet-induced insulin resistance and enhances whole-body oxygen consumption. Diabetes 59, 2453-2464. https://doi.org/10.2337/db09-1293
  98. Verma, M.K., Yateesh, A.N., Neelima, K., Pawar, N., Sandhya, K., Poornima, J., Lakshmi, M.N., Yogeshwari, S., Pallavi, P.M., Oommen, A.M., et al. (2014). Inhibition of neutral sphingomyelinases in skeletal muscle attenuates fatty-acid induced defects in metabolism and stress. SpringerPlus 3, 255-212. https://doi.org/10.1186/2193-1801-3-255
  99. Wang, C.N., O'Brien, L., and Brindley, D.N. (1998). Effects of cell-permeable ceramides and tumor necrosis factor-alpha on insulin signaling and glucose uptake in 3T3-L1 adipocytes. Diabetes 47, 24-31. https://doi.org/10.2337/diab.47.1.24
  100. Wang, R., Ding, Q., De Assuncao, T.M., Mounajjed, T., Maiers, J.L., Dou, C., Cao, S., Yaqoob, U., Huebert, R.C., and Shah, V.H. (2017a). Hepatic stellate cell selective disruption of dynamin-2 GTPase increases murine fibrogenesis through up-regulation of sphingosine-1 phosphate-induced cell migration. Am. J. Pathol. 187, 134-145. https://doi.org/10.1016/j.ajpath.2016.09.001
  101. Wang, Y., Harashima, S.I., Liu, Y., Usui, R., and Inagaki, N. (2017b). Sphingosine kinase 1-interacting protein is a novel regulator of glucosestimulated insulin secretion. Sci. Rep. 7, 779. https://doi.org/10.1038/s41598-017-00900-7
  102. Watt, M.J., Barnett, A.C., Bruce, C.R., Schenk, S., Horowitz, J.F., and Hoy, A.J. (2012). Regulation of plasma ceramide levels with fatty acid oversupply: evidence that the liver detects and secretes de novo synthesised ceramide. Diabetologia 55, 2741-2746. https://doi.org/10.1007/s00125-012-2649-3
  103. Xia, J.Y., Holland, W.L., Kusminski, C.M., Sun, K., Sharma, A.X., Pearson, M.J., Sifuentes, A.J., McDonald, J.G., Gordillo, R., and Scherer, P.E. (2015). Targeted induction of ceramide degradation leads to improved systemic metabolism and reduced hepatic steatosis. Cell Metab. 22, 266-278. https://doi.org/10.1016/j.cmet.2015.06.007
  104. Xiu, L., Chang, N., Yang, L., Liu, X., Yang, L., Ge, J., and Li, L. (2015). Intracellular sphingosine 1-phosphate contributes to collagen expression of hepatic myofibroblasts in human liver fibrosis independent of its receptors. Am. J. Pathol. 185, 387-398. https://doi.org/10.1016/j.ajpath.2014.09.023
  105. Xu, W., Lu, C., Zhang, F., Shao, J., and Zheng, S. (2016). Dihydroartemisinin restricts hepatic stellate cell contraction via an FXR-S1PR2-dependent mechanism. IUBMB Life 68, 376-387. https://doi.org/10.1002/iub.1492
  106. Yamashita, T., Hashiramoto, A., Haluzik, M., Mizukami, H., Beck, S., Norton, A., Kono, M., Tsuji, S., Daniotti, J.L., Werth, N., et al. (2003). Enhanced insulin sensitivity in mice lacking ganglioside GM3. Proc. Natl. Acad. Sci. U. S. A. 100, 3445-3449. https://doi.org/10.1073/pnas.0635898100
  107. Yang, G., Badeanlou, L., Bielawski, J., Roberts, A.J., Hannun, Y.A., and Samad, F. (2009). Central role of ceramide biosynthesis in body weight regulation, energy metabolism, and the metabolic syndrome. Am. J. Physiol. Endocrinol. Metab. 297, E211-E224. https://doi.org/10.1152/ajpendo.91014.2008
  108. 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-beta1 via sphingosine kinase/sphingosine 1-phosphate (S1P)/S1P receptor axis. Am. J. Pathol. 181, 85-97. https://doi.org/10.1016/j.ajpath.2012.03.014
  109. Yang, L., Han, Z., Tian, L., Mai, P., Zhang, Y., Wang, L., and Li, L. (2015). Sphingosine 1-phosphate receptor 2 and 3 mediate bone marrowderived monocyte/macrophage motility in cholestatic liver injury in mice. Sci. Rep. 5, 13423. https://doi.org/10.1038/srep13423
  110. Yang, L., Yue, S., Yang, L., Liu, X., Han, Z., Zhang, Y., and Li, L. (2013). Sphingosine kinase/sphingosine 1-phosphate (S1P)/S1P receptor axis is involved in liver fibrosis-associated angiogenesis. J. Hepatol. 59, 114-123. https://doi.org/10.1016/j.jhep.2013.02.021
  111. Yano, M., Watanabe, K., Yamamoto, T., Ikeda, K., Senokuchi, T., Lu, M., Kadomatsu, T., Tsukano, H., Ikawa, M., Okabe, M., et al. (2011). Mitochondrial dysfunction and increased reactive oxygen species impair insulin secretion in sphingomyelin synthase 1-null mice. J. Biol. Chem. 286, 3992-4002. https://doi.org/10.1074/jbc.M110.179176
  112. Ying, W., Riopel, M., Bandyopadhyay, G., Dong, Y., Birmingham, A., Seo, J.B., Ofrecio, J.M., Wollam, J., Hernandez-Carretero, A., Fu, W., et al. (2017). Adipose tissue macrophage-derived exosomal miRNAs can modulate in vivo and in vitro insulin sensitivity. Cell 171, 372-384.e12. https://doi.org/10.1016/j.cell.2017.08.035
  113. Younossi, Z.M., Koenig, A.B., Abdelatif, D., Fazel, Y., Henry, L., and Wymer, M. (2016). Global epidemiology of nonalcoholic fatty liver disease-Metaanalytic assessment of prevalence, incidence, and outcomes. Hepatology 64, 73-84. https://doi.org/10.1002/hep.28431
  114. Zhao, H., Przybylska, M., Wu, I.H., Zhang, J., Maniatis, P., Pacheco, J., Piepenhagen, P., Copeland, D., Arbeeny, C., Shayman, J.A., et al. (2009). Inhibiting glycosphingolipid synthesis ameliorates hepatic steatosis in obese mice. Hepatology 50, 85-93. https://doi.org/10.1002/hep.22970
  115. Zhao, H., Przybylska, M., Wu, I.H., Zhang, J., Siegel, C., Komarnitsky, S., Yew, N.S., and Cheng, S.H. (2007). Inhibiting glycosphingolipid synthesis improves glycemic control and insulin sensitivity in animal models of type 2 diabetes. Diabetes 56, 1210-1218. https://doi.org/10.2337/db06-0719
  116. Zigdon, H., Kogot-Levin, A., Park, J.W., Goldschmidt, R., Kelly, S., Merrill, A.H., 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. https://doi.org/10.1074/jbc.M112.402719
  117. Zinda, M.J., Vlahos, C.J., and Lai, M.T. (2001). Ceramide induces the dephosphorylation and inhibition of constitutively activated Akt in PTEN negative U87mg cells. Biochem. Biophys. Res. Commun. 280, 1107-1115. https://doi.org/10.1006/bbrc.2000.4248

Cited by

  1. Modulation of sphingosine 1‐phosphate by hepatobiliary cholesterol handling vol.34, pp.11, 2020, https://doi.org/10.1096/fj.202001397r
  2. Ca2+ Sensitivity of Anoctamin 6/TMEM16F Is Regulated by the Putative Ca2+-Binding Reservoir at the N-Terminal Domain vol.44, pp.2, 2020, https://doi.org/10.14348/molcells.2021.2203
  3. Lipid metabolism in cancer progression and therapeutic strategies vol.2, pp.1, 2020, https://doi.org/10.1002/mco2.27
  4. Deletion or inhibition of SphK1 mitigates fulminant hepatic failure by suppressing TNFα‐dependent inflammation and apoptosis vol.35, pp.3, 2021, https://doi.org/10.1096/fj.202002540r
  5. Advances in paediatric nonalcoholic fatty liver disease: Role of lipidomics vol.27, pp.25, 2020, https://doi.org/10.3748/wjg.v27.i25.3815
  6. Involvement of Ceramides in Non-Alcoholic Fatty Liver Disease (NAFLD) Atherosclerosis (ATS) Development: Mechanisms and Therapeutic Targets vol.11, pp.11, 2020, https://doi.org/10.3390/diagnostics11112053
  7. Time-Dependent Changes in Hepatic Sphingolipid Accumulation and PI3K/Akt/mTOR Signaling Pathway in a Rat Model of NAFLD vol.22, pp.22, 2021, https://doi.org/10.3390/ijms222212478