Sphingolipids and Hepatic Steatosis

  • Benjamin T. Bikman
  • Scott A. Summers
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 721)


The development of a fatty liver predisposes individuals to an array of health problems including diabetes, cardiovascular disease and certain forms of cancer. Inhibition or genetic ablation of genes controlling sphingolipid synthesis in rodents resolves hepatic steatosis and in many cases wards off the health complications associated with excessive hepatic triglyceride accumulation. Examples include the pharmacological inhibition of serine palmitoyltransferase or glucosylceramide synthase or the genetic depletion of acid sphingomyelinase, which dramatically reduce hepatic triglyceride levels in mice susceptible to the development of a fatty liver. The magnitude of the effects on triglyceride depletion in these models is impressive, but the relevance to humans and the mechanism of action is unclear. Herein we probe into the connections between sphingolipids and triglyceride synthesis in an attempt to identify causal relationships and opportunities for therapeutic intervention.


Hepatic STEATOSIS Ceramide Level Sphingolipid Synthesis Hepatic Triglyceride Level Lipid Peroxide Oxidation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Grundy SM, Brewer HB Jr, Cleeman JI et al. Definition of metabolic syndrome: report of the National Heart, Lung and Blood Institute/American Heart Association conference on scientific issues related to definition. Arterioscler Thromb Vasc Biol 2004; 24:e13–e18.PubMedCrossRefGoogle Scholar
  2. 2.
    Economic costs of diabetes in the U.S. In 2007. Diabetes Care 2008; 31:596–615.Google Scholar
  3. 3.
    Cardiovascular Disease Statistics 2009. American Heart Assocation. Available at:
  4. 4.
    Global Strategy on Diet and Physical activity 2009. World health organization. Available at:
  5. 5.
    Coleman RA, Lee DP. Enzymes of triacylglycerol synthesis and their regulation. Prog Lipid Res 2004; 43:134–176.PubMedCrossRefGoogle Scholar
  6. 6.
    Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology 2003; 37:1202–1219.PubMedCrossRefGoogle Scholar
  7. 7.
    Kim CH, Younossi ZM. Nonalcoholic fatty liver disease: a manifestation of the metabolic syndrome. Cleve Clin J Med 2008; 75:721–728.PubMedCrossRefGoogle Scholar
  8. 8.
    Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: fromsteatosis to cirrhosis. Hepatology 2006; 43:S99–S112.PubMedCrossRefGoogle Scholar
  9. 9.
    Machado M, Marques-Vidal P, Cortez-Pinto H. Hepatic histology in obese patients undergoing bariatric surgery. J Hepatol 2006; 45:600–606.PubMedCrossRefGoogle Scholar
  10. 10.
    Clark JM, Brancati FL, Diehl AM. The prevalence and etiology of elevated aminotransferase levels in the United States. Am J Gastroenterol 2003; 98:960–967.PubMedCrossRefGoogle Scholar
  11. 11.
    Turinsky J, Bayly BP, O’Sullivan DM. 1,2-Diacylglycerol and ceramide levels in rat liver and skeletal muscle in vivo. Am J Physiol 1991; 261:E620–E627.PubMedGoogle Scholar
  12. 12.
    Holland WL, Brozinick JT, Wang LP et al. Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-and obesity-induced insulin resistance. Cell Metab 2007; 5:167–179.PubMedCrossRefGoogle Scholar
  13. 13.
    Turinsky J, O’Sullivan DM, Bayly BP. 1,2-Diacylglycerol and ceramide levels in insulin-resistant tissues of the rat in vivo. J Biol Chem 1990; 265:16880–16885.PubMedGoogle Scholar
  14. 14.
    Aerts JM, Ottenhoff R, Powlson AS et al. Pharmacological inhibition of glucosylceramide synthase enhances insulin sensitivity. Diabetes 2007; 56:1341–1349.PubMedCrossRefGoogle Scholar
  15. 15.
    Yetukuri L, Katajamaa M, Medina-Gomez G et al. Bioinformatics strategies for lipidomics analysis: characterization of obesity related hepatic steatosis. BMC Syst Biol 2007; 1:12.PubMedCrossRefGoogle Scholar
  16. 16.
    Greco D, Kotronen A, Westerbacka J et al. Gene expression in human NAFLD. Am J Physiol Gastrointest Liver Physiol 2008; 294:G1281–G1287.PubMedCrossRefGoogle Scholar
  17. 17.
    Kotronen A, Seppänen-Laakso T, Westerbacka J et al. Hepatic stearoyl-CoA desaturase (SCD)-1 activity and diacylglycerol but not ceramide concentrations are increased in the nonalcoholic human fatty liver. Diabetes 2009; 58:203–208.PubMedCrossRefGoogle Scholar
  18. 18.
    Kolak M, Westerbacka J, Velagapudi VR et al. Adipose tissue inflammation and increased ceramide content characterize subjects with high liver fat content independent of obesity. Diabetes 2007; 56:1960–1968.PubMedCrossRefGoogle Scholar
  19. 19.
    Summers SA. Ceramides in insulin resistance and lipotoxicity. Prog Lipid Res 2006; 45:42–72.PubMedCrossRefGoogle Scholar
  20. 20.
    Memon RA, Holleran WM, Moser AH et al. Endotoxin and cytokines increase hepatic sphingolipid biosynthesis and produce lipoproteins enriched in ceramides and sphingomyelin. Arterioscler Thromb Vasc Biol 1998; 18:1257–1265.PubMedCrossRefGoogle Scholar
  21. 21.
    Yang G, Badeanlou L, Bielawski J et al. Central role of ceramide biosynthesis in body weight regulation, energy metabolism and the metabolic syndrome. Am J Physiol Endocrinol Metab 2009; 297:E211–E224.PubMedCrossRefGoogle Scholar
  22. 22.
    Bijl N, Sokolović M, Vrins C et al. Modulation of glycosphingolipid metabolism significantly improves hepatic insulin sensitivity and reverses hepatic steatosis in mice. Hepatology 2009.Google Scholar
  23. 23.
    Zhao H, Przybylska M, Wu IH et al. Inhibiting glycosphingolipid synthesis ameliorates hepatic steatosis in obese mice. Hepatology 2009; 50:85–93.PubMedCrossRefGoogle Scholar
  24. 24.
    Mathias S, Pena LA, Kolesnick RN. Signal transduction of stress via ceramide. Biochem J 1998; 335 (Pt 3):465–480.PubMedGoogle Scholar
  25. 25.
    Deevska GM, Rozenova KA, Giltiay NV et al. Acid Sphingomyelinase Deficiency Prevents Diet-induced hepatic triacylglycerol accumulation and hyperglycemia in Mice. J Biol Chem 2009; 284:8359–8368.PubMedCrossRefGoogle Scholar
  26. 26.
    Dressler KA, Mathias S, Kolesnick RN. Tumor necrosis factor-alpha activates the sphingomyelin signal transduction pathway in a cell-free system. Science 1992; 255:1715–1718.PubMedCrossRefGoogle Scholar
  27. 27.
    Andrieu-Abadie N, Levade T. Sphingomyelin hydrolysis during apoptosis. Biochim Biophys Acta 2002; 1585:126–134.PubMedGoogle Scholar
  28. 28.
    Schutze S, Wiegmann K, Machleidt T et al. TNF-induced activation of NF-kappa B. Immunobiology 1995; 193:193–203.PubMedGoogle Scholar
  29. 29.
    Wiegmann K, Schutze S, Machleidt T et al. Functional dichotomy of neutral and acidic sphingomyelinases in tumor necrosis factor signaling. Cell 1994; 78:1005–1015.PubMedCrossRefGoogle Scholar
  30. 30.
    Schütze S, Potthoff K, Machleidt T et al. TNF activates NF-kappa B by phosphatidylcholine-specific phospholipase C-induced “acidic” sphingomyelin breakdown. Cell 1992; 71:765–776.PubMedCrossRefGoogle Scholar
  31. 31.
    Mathias S, Dressler KA, Kolesnick RN. Characterization of aceramide-activatedproteinkinase: stimulation by tumor necrosis factor alpha. Proc Natl Acad Sci USA 1991; 88:10009–10013.PubMedCrossRefGoogle Scholar
  32. 32.
    Chatterjee S. Neutral sphingomyelinase action stimulates signal transduction of tumor necrosis factor-alpha in the synthesis of cholesteryl esters in human fibroblasts. J Biol Chem 1994; 269:879–882.PubMedGoogle Scholar
  33. 33.
    Liu B, Andrieu-Abadie N, Levade T et al. Glutathione regulation of neutral sphingomyelinase in tumor necrosis factor-alpha-induced cell death. J Biol Chem 1998; 273:11313–11320.PubMedCrossRefGoogle Scholar
  34. 34.
    Ségui B, Cuvillier O, Adam-Klages S, et al. Involvement of FAN in TNF-induced apoptosis. J Clin Invest 2001; 108:143–151.PubMedGoogle Scholar
  35. 35.
    Singh I, Pahan K, Khan M et al. Cytokine-mediated induction of ceramide production is redox-sensitive. Implications to proinflammatory cytokine-mediated apoptosis in demyelinating diseases. J Biol Chem 1998; 273:20354–20362.PubMedCrossRefGoogle Scholar
  36. 36.
    Bettaieb A, Record M, Côme MG et al. Opposite effects of tumor necrosis factor alpha on the sphingomyelin-ceramide pathway in two myeloid leukemia cell lines: role of transverse sphingomyelin distribution in the plasma membrane. Blood 1996; 88:1465–1472.PubMedGoogle Scholar
  37. 37.
    Vandenabeele P, Declercq W, Beyaert R et al. Two tumour necrosis factor receptors: structure and function. Trends Cell Biol 1995; 5:392–399.PubMedCrossRefGoogle Scholar
  38. 38.
    Tomita K, Tamiya G, Ando S et al. Tumour necrosis factor alpha signalling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohepatitis in mice. Gut 2006; 55:415–424.PubMedCrossRefGoogle Scholar
  39. 39.
    Alessenko AV, Shupik MA, Bugrova AE et al. The relation between sphingomyelinase activity, lipid peroxide oxidation and NO-releasing in mice liver and brain. FEBS Lett 2005; 579:5571–5576.PubMedCrossRefGoogle Scholar
  40. 40.
    Reinehr R, Becker S, Keitel V et al. Bile salt-induced apoptosis involves NADPH oxidase isoform activation. Gastroenterology 2005; 129:2009–2031.PubMedCrossRefGoogle Scholar
  41. 41.
    Day CP, James OF. Steatohepatitis: a tale of two “hits”? Gastroenterology 1998; 114:842–845.PubMedCrossRefGoogle Scholar
  42. 42.
    Day CP, James OF. Hepatic steatosis: innocent bystander or guilty party? Hepatology 1998; 27:1463–1466.PubMedCrossRefGoogle Scholar
  43. 43.
    Day CP, Saksena S. Non-alcoholic steatohepatitis: definitions and pathogenesis. J Gastroenterol Hepatol 2002; 17(Suppl 3):S377–S384.PubMedCrossRefGoogle Scholar
  44. 44.
    Donnelly KL, Smith CI, Schwarzenberg SJ et al. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest 2005; 115:1343–1351.PubMedGoogle Scholar
  45. 45.
    Utzschneider KM, Kahn SE. Review: The role of insulin resistance in nonalcoholic fatty liver disease. J Clin Endocrinol Metab 2006; 91:4753–4761.PubMedCrossRefGoogle Scholar
  46. 46.
    Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 1993; 259:87–91.PubMedCrossRefGoogle Scholar
  47. 47.
    Baranova A, Gowder SJ, Schlauch K et al. Gene expression of leptin, resistin and adiponectin in the white adipose tissue of obese patients with non-alcoholic fatty liver disease and insulin resistance. Obes Surg 2006; 16:1118–1125.PubMedCrossRefGoogle Scholar
  48. 48.
    Lutchman G, Promrat K, Kleiner DE et al. Changes in serum adipokine levels during pioglitazone treatment for nonalcoholic steatohepatitis: relationship to histological improvement. Clin Gastroenterol Hepatol 2006; 4:1048–1052.PubMedCrossRefGoogle Scholar
  49. 49.
    Li Z, Yang S, Lin H et al. Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. Hepatology 2003; 37:343–350.PubMedCrossRefGoogle Scholar
  50. 50.
    Lin HZ, Yang SQ, Chuckaree C et al. Metformin reverses fatty liver disease in obese, leptin-deficient mice. Nat Med 2000; 6:998–1003.PubMedCrossRefGoogle Scholar
  51. 51.
    Xu A, Wang Y, Keshaw H et al. The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J Clin Invest 2003; 112:91–100.PubMedGoogle Scholar
  52. 52.
    Hui JM, Hodge A, Farrell GC et al. Beyond insulin resistance in NaSh: TNf-alpha or adiponectin? Hepatology 2004; 40:46–54.PubMedCrossRefGoogle Scholar
  53. 53.
    Louthan MV, Barve S, McClain CJ et al. Decreased serum adiponectin: an early event in pediatric nonalcoholic fatty liver disease. J Pediatr 2005; 147:835–838.PubMedCrossRefGoogle Scholar
  54. 54.
    Musso G, Gambino R, Biroli G et al. Hypoadiponectinemia predicts the severity of hepatic fibrosis and pancreatic Beta-cell dysfunction in nondiabetic nonobese patients with nonalcoholic steatohepatitis. Am J Gastroenterol 2005; 100:2438–2446.PubMedCrossRefGoogle Scholar
  55. 55.
    Musso G, Gambino R, Durazzo M et al. Adipokines in NASH: postprandial lipid metabolism as a link between adiponectin and liver disease. Hepatology 2005; 42:1175–1183.PubMedCrossRefGoogle Scholar
  56. 56.
    Kaser S, Moschen A, Cayon A et al. Adiponectin and its receptors in non-alcoholic steatohepatitis. Gut 2005; 54:117–121.PubMedCrossRefGoogle Scholar
  57. 57.
    Lemoine M, Ratziu V, Kim M et al. Serum adipokine levels predictive of liver injury in non-alcoholic fatty liver disease. Liver Int 2009.Google Scholar
  58. 58.
    Jarrar MH, Baranova A, Collantes R et al. Adipokines and cytokines in non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2008; 27:412–421.PubMedCrossRefGoogle Scholar
  59. 59.
    Feldstein AE, Werneburg NW, Canbay A et al. Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway. Hepatology 2004; 40:185–194.PubMedCrossRefGoogle Scholar
  60. 60.
    Crespo J et al. Gene expression of tumor necrosis factor alpha and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. Hepatology 2001; 34:1158–1163.PubMedCrossRefGoogle Scholar
  61. 61.
    Abiru S et al. Serum cytokine and soluble cytokine receptor levels inpatients withnon-alcoholic steatohepatitis. Liver Int 2006; 26:39–45.PubMedCrossRefGoogle Scholar
  62. 62.
    Hannun YA, Bell RM. The sphingomyelin cycle: a prototypic sphingolipid signaling pathway. Adv Lipid Res 1993; 25:27–41.PubMedGoogle Scholar
  63. 63.
    Kolesnick R, Golde DW. The sphingomyelin pathway in tumor necrosis factor and interleukin-1 signaling. Cell 1994; 77:325–328.PubMedCrossRefGoogle Scholar
  64. 64.
    Messmer TO, Wang E, Stevens VL et al. Sphingolipid biosynthesis by rat liver cells: effects of serine, fatty acids and lipoproteins. J Nutr 1989; 119:534–538.PubMedGoogle Scholar
  65. 65.
    Gill JM, Sattar N. Ceramides: A new player in the inflammation-insulin resistance paradigm? Diabetologia 2009.Google Scholar
  66. 66.
    Samad F, Hester KD, Yang G et al. Altered adipose and plasma sphingolipid metabolism in obesity: a potential mechanism for cardiovascular and metabolic risk. Diabetes 2006; 55:2579–2587.PubMedCrossRefGoogle Scholar
  67. 67.
    Shah C, Yang G, Lee I et al. Protection from high fat diet-induced increase in ceramide in mice lacking plasminogen activator inhibitor 1. J Biol Chem 2008; 283:13538–13548.PubMedCrossRefGoogle Scholar
  68. 68.
    de Mello VD, Lankinen M, Schwab U et al. Link between plasma ceramides, inflammation and insulin resistance: association with serum IL-6 concentration inpatients with coronary heart disease. Diabetologia 2009; 52:2612–2615.PubMedCrossRefGoogle Scholar
  69. 69.
    de Mello VD, Lankinen M, Schwab U et al. Link between plasma ceramides, inflammation and insulin resistance: association with serum IL-6 concentration in patients with coronary heart disease. Diabetologia 2009.Google Scholar
  70. 70.
    Li Z, Soloski MJ, Diehl AM. Dietary factors alter hepatic innate immune system in mice with nonalcoholic fatty liver disease. Hepatology 2005; 42:880–885.PubMedCrossRefGoogle Scholar
  71. 71.
    Bouwens L, Baekeland M, De Zanger R et al. Quantitation, tissue distribution and proliferation kinetics of Kupffer cells in normal rat liver. Hepatology 1986; 6:718–722.PubMedCrossRefGoogle Scholar
  72. 72.
    Racanelli V, Rehermann B. The liver as an immunological organ. Hepatology 2006; 43:S54–S62.PubMedCrossRefGoogle Scholar
  73. 73.
    Bouwens L, Knook DL, Wisse E. Local proliferation and extrahepatic recruitment of liver macrophages (Kupffer cells) in partial-body irradiated rats. J Leukoc Biol 1986; 39:687–697.PubMedGoogle Scholar
  74. 74.
    Kawai T, Akira S. Innate immune recognition of viral infection. Nat Immunol 2006; 7:131–137.PubMedCrossRefGoogle Scholar
  75. 75.
    Szabo G, Dolganiuc A, Mandrekar P. Pattern recognition receptors: a contemporary view on liver diseases. Hepatology 2006; 44:287–298.PubMedCrossRefGoogle Scholar
  76. 76.
    Fessler MB, Rudel LL, Brown JM. Toll-like receptor signaling links dietary fatty acids to the metabolic syndrome. Curr Opin Lipidol 2009; 20:379–385.PubMedCrossRefGoogle Scholar
  77. 77.
    Seki E, Brenner DA. Toll-like receptors and adaptor molecules in liver disease: update. Hepatology 2008; 48:322–335.PubMedCrossRefGoogle Scholar
  78. 78.
    Treffkorn L, Scheibe R, Maruyama T et al. PGE2 exerts its effect on the LPS-induced release of TNF-alpha, ET-1, IL-1alpha, IL-6 and IL-10 via the EP2 and EP4 receptor in rat liver macrophages. Prostaglandins Other Lipid Mediat 2004; 74:113–123.PubMedCrossRefGoogle Scholar
  79. 79.
    Szabo G, Velayudham A, Romics L Jr et al. Modulation of non-alcoholic steatohepatitis by pattern recognition receptors in mice: the role of toll-like receptors 2 and 4. Alcohol Clin Exp Res 2005; 29:140S–145S.PubMedCrossRefGoogle Scholar
  80. 80.
    Seki E et al. Lipopolysaccharide-induced IL-18 secretion from murine Kupffer cells independently of myeloid differentiation factor 88 that is critically involved in induction of production of IL-12 and IL-1beta. J Immunol 2001; 166:2651–2657.PubMedGoogle Scholar
  81. 81.
    Su GL. Lipopolysaccharides in liver injury: molecular mechanisms of Kupffer cell activation. Am J Physiol Gastrointest liver Physiol 2002; 283:G256–G265.PubMedGoogle Scholar
  82. 82.
    Nakao A, Taki S, Yasui M et al. The fate of intravenously injected endotoxin in normal rats and in rats with liver failure. Hepatology 1994; 19:1251–1256.PubMedCrossRefGoogle Scholar
  83. 83.
    Memon RA, Holleran WM, Uchida Y et al. Regulation of sphingolipid and glycosphingolipid metabolism in extrahepatic tissues by endotoxin. J Lipid Res 2001; 42:452–459.PubMedGoogle Scholar
  84. 84.
    Peng Y, Rideout D, Rakita S et al. Downregulation of Adiponectin/AdipoR2 is Associated with Steatohepatitis in obese Mice. J Gastrointest Surg 2009.Google Scholar
  85. 85.
    Ma H, Gomez V, Lu L et al. Expression of adiponectin and its receptors in livers of morbidly obese patients with non-alcoholic fatty liver disease. J Gastroenterol Hepatol 2009; 24:233–237.PubMedCrossRefGoogle Scholar
  86. 86.
    Yamauchi T, Kamon J, Waki H et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 2001; 7:941–946.PubMedCrossRefGoogle Scholar
  87. 87.
    Stefan N, Machicao F, Staiger H et al. Polymorphisms in the gene encoding adiponectin receptor 1 are associated with insulin resistance and high liver fat. Diabetologia 2005; 48:2282–2291.PubMedCrossRefGoogle Scholar
  88. 88.
    Villa NY, Kupchak BR, Garitaonandia I et al. Sphingolipids function as downstream effectors of a fungal PAQR. Mol Pharmacol 2009; 75:866–875.PubMedCrossRefGoogle Scholar
  89. 89.
    Blazquez C, Geelen MJ, Velasco G et al. The AMP-activated protein kinase prevents ceramide synthesis de novo and apoptosis in astrocytes. FEBS Lett 2001; 489:149–153.PubMedCrossRefGoogle Scholar
  90. 90.
    Holland WL, Scherer PE. PAQRs: a counteracting force to ceramides? Mol Pharmacol 2009; 75:740–743.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Benjamin T. Bikman
    • 1
  • Scott A. Summers
    • 1
    • 2
  1. 1.Program in Cardiovascular and Metabolic DisordersDuke-NUS Graduate Medical SchoolSingapore
  2. 2.The Stedman Center for Nutrition and Metabolism ResearchDuke University Medical CenterDurhamUSA

Personalised recommendations