Skip to main content
SpringerLink
Log in

De Novo Sphingolipid Biosynthesis in Atherosclerosis

  • Chapter
  • First Online:
Sphingolipid Metabolism and Metabolic Disease

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1372))

Abstract

Atherosclerosis is the formation of fibrofatty lesions in the arterial wall, and this inflammatory state of the artery is the main cause of advanced pathological processes, including myocardial infarction and stroke. Dyslipidemic conditions with excess cholesterol accumulate within the arterial vessel wall and initiate atherogenic processes. Following vascular reaction and lipid accumulation, the vascular wall gradually thickens. Together with the occurrence of local inflammation, early atherosclerotic lesions lead to advanced pathophysiological events, plaque rupture, and thrombosis. Ceramide and sphingomyelin have emerged as major risk factors for atherosclerosis and coronary artery disease. Currently, the clinical association between de novo sphingolipid biosynthesis and coronary artery disease has been established. Furthermore, therapeutic strategies to modulate this pathway, especially those involving serine palmitoyltransferase and sphingomyelin synthase, against atherosclerosis, cancer, type 2 diabetes, and non-alcoholic fatty liver disease are actively under development. In this chapter, we focus on the relationship between de novo sphingolipid biosynthesis and coronary artery disease.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 179.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 179.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

CAD:

Coronary artery disease

SPT:

Serine palmitoyltransferase

SM:

Sphingomyelin

SMS:

Sphingomyelin synthase

MTP:

Microsomal triglyceride transfer protein

SMase:

Sphingomyelinase

References

  1. Ding, M., & Rexrode, K. M. (2020). A review of lipidomics of cardiovascular disease highlights the importance of isolating lipoproteins. Metabolites, 10, 163.

    Article  CAS  PubMed Central  Google Scholar 

  2. Saleem, M., Herrmann, N., Dinoff, A., Marzolini, S., Mielke, M. M., Andreazza, A., et al. (2020). Association between sphingolipids and cardiopulmonary fitness in coronary artery disease patients undertaking cardiac rehabilitation. The Journals of Gerontology: Series A, 75, 671–679.

    Article  CAS  Google Scholar 

  3. Mozaffarian, D., Benjamin, E. J., Go, A. S., Arnett, D. K., Blaha, M. J., Cushman, M., et al. (2015). Heart disease and stroke statistics—2015 update: A report from the American Heart Association. Circulation, 131, e29–e32.

    PubMed  Google Scholar 

  4. Jame, S., & Barnes, G. (2020). Stroke and thromboembolism prevention in atrial fibrillation. Heart, 106, 10–17.

    Article  CAS  PubMed  Google Scholar 

  5. Skagen, K., Skjelland, M., Zamani, M., & Russell, D. (2016). Unstable carotid artery plaque: New insights and controversies in diagnostics and treatment. Croatian Medical Journal, 57, 311–320.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Berry, C. (2017). Stable coronary syndromes: The case for consolidating the nomenclature of stable ischemic heart disease. Circulation, 136, 437–439.

    Article  PubMed  Google Scholar 

  7. Sakakura, K., Nakano, M., Otsuka, F., Ladich, E., Kolodgie, F. D., & Virmani, R. (2013). Pathophysiology of atherosclerosis plaque progression. Heart, Lung & Circulation, 22, 399–411.

    Article  Google Scholar 

  8. Visscher, M., Moerman, A. M., Burgers, P. C., Van Beusekom, H. M., Luider, T. M., Verhagen, H. J., et al. (2019). Data processing pipeline for lipid profiling of carotid atherosclerotic plaque with mass spectrometry imaging. Journal of the American Society for Mass Spectrometry, 30, 1790–1800.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Libby, P. (2021). The changing landscape of atherosclerosis. Nature, 592, 524–533.

    Article  CAS  PubMed  Google Scholar 

  10. Zhou, Y. T., Grayburn, P., Karim, A., Shimabukuro, M., Higa, M., Baetens, D., et al. (2000). Lipotoxic heart disease in obese rats: Implications for human obesity. Proceedings of the National Academy of Sciences of the United States of America, 97, 1784–1789.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Chaurasia, B., Tippetts, T. S., Monibas, R. M., Liu, J., Li, Y., Wang, L., et al. (2019). Targeting a ceramide double bond improves insulin resistance and hepatic steatosis. Science, 365, 386–392.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ruangsiriluk, W., Grosskurth, S. E., Ziemek, D., Kuhn, M., des Etages, S. G., & Francone, O. L. (2012). Silencing of enzymes involved in ceramide biosynthesis causes distinct global alterations of lipid homeostasis and gene expression. Journal of Lipid Research, 53, 1459–1471.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Raichur, S., Wang, S. T., Chan, P. W., Li, Y., Ching, J., Chaurasia, B., et al. (2014). CerS2 haploinsufficiency inhibits β-oxidation and confers susceptibility to diet-induced steatohepatitis and insulin resistance. Cell Metabolism, 20, 687–695.

    Article  CAS  PubMed  Google Scholar 

  14. Turpin, S. M., Nicholls, H. T., Willmes, D. M., Mourier, A., Brodesser, S., Wunderlich, C. M., et al. (2014). Obesity-induced CerS6-dependent C16: 0 ceramide production promotes weight gain and glucose intolerance. Cell Metabolism, 20, 678–686.

    Article  CAS  PubMed  Google Scholar 

  15. Seah, J. Y. H., Chew, W. S., Torta, F., Khoo, C. M., Wenk, M. R., Herr, D. R., et al. (2020). Plasma sphingolipids and risk of cardiovascular diseases: A large-scale lipidomic analysis. Metabolomics, 16, 1–12.

    Article  CAS  Google Scholar 

  16. Jiang, X. C., Paultre, F., Pearson, T. A., Reed, R. G., Francis, C. K., Lin, M., et al. (2000). Plasma sphingomyelin level as a risk factor for coronary artery disease. Arteriosclerosis, Thrombosis, and Vascular Biology, 20, 2614–2618.

    Article  CAS  PubMed  Google Scholar 

  17. Ichi, I., Nakahara, K., Miyashita, Y., Hidaka, A., Kutsukake, S., Inoue, K., et al. (2006). Association of ceramides in human plasma with risk factors of atherosclerosis. Lipids, 41, 859–863.

    Article  CAS  PubMed  Google Scholar 

  18. Lowther, J., Naismith, J. H., Dunn, T. M., & Campopiano, D. J. (2012). Structural, mechanistic and regulatory studies of serine palmitoyltransferase. Biochemical Society Transactions, 40, 547–554.

    Article  CAS  PubMed  Google Scholar 

  19. Tidhar, R., & Futerman, A. H. (2013). The complexity of sphingolipid biosynthesis in the endoplasmic reticulum. Biochimica et Biophysica Acta (BBA), 1833, 2511–2518.

    Article  CAS  Google Scholar 

  20. Iqbal, J., Walsh, M. T., Hammad, S. M., Cuchel, M., Tarugi, P., Hegele, R. A., et al. (2015). Microsomal triglyceride transfer protein transfers and determines plasma concentrations of ceramide and sphingomyelin but not glycosylceramide. Journal of Biological Chemistry, 290, 25863–25875.

    Article  CAS  Google Scholar 

  21. Clarke, B. A., Majumder, S., Zhu, H., Lee, Y. T., Kono, M., Li, C., et al. (2019). The Ormdl genes regulate the sphingolipid synthesis pathway to ensure proper myelination and neurologic function in mice. eLife, 8, e51067.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Deng, Y., Rivera-Molina, F. E., Toomre, D. K., & Burd, C. G. (2016). Sphingomyelin is sorted at the trans Golgi network into a distinct class of secretory vesicle. Proceedings of the National Academy of Sciences, 113, 6677–6682.

    Article  CAS  Google Scholar 

  23. Weiss, B., & Stoffel, W. (1997). Human and murine serine-palmitoyl-CoA transferase--cloning, expression and characterization of the key enzyme in sphingolipid synthesis. European Journal of Biochemistry, 249, 239–247.

    Article  CAS  PubMed  Google Scholar 

  24. Hanada, K., Hara, T., Nishijima, M., Kuge, O., Dickson, R. C., & Nagiec, M. M. (1997). A mammalian homolog of the yeast LCB1 encodes a component of serine palmitoyltransferase, the enzyme catalyzing the first step in sphingolipid synthesis. The Journal of Biological Chemistry, 272, 32108–32114.

    Article  CAS  PubMed  Google Scholar 

  25. Parthibane, V., Lin, J., Acharya, D., Abimannan, T., Srideshikan, S. M., Klarmann, K., et al. (2021). SSSPTA is essential for serine palmitoyltransferase function during development and hematopoiesis. Journal of Biological Chemistry, 296, 100491.

    Article  CAS  Google Scholar 

  26. Hojjati, M. R., Li, Z., & Jiang, X. C. (2005). Serine palmitoyl-CoA transferase (SPT) deficiency and sphingolipid levels in mice. Biochimica et Biophysica Acta, 1737, 44–51.

    Article  CAS  PubMed  Google Scholar 

  27. Hornemann, T., Richard, S., Rutti, M. F., Wei, Y., & von Eckardstein, A. (2006). Cloning and initial characterization of a new subunit for mammalian serine-palmitoyltransferase. The Journal of Biological Chemistry, 281, 37275–37281.

    Article  CAS  PubMed  Google Scholar 

  28. Gable, K., Han, G., Monaghan, E., Bacikova, D., Natarajan, M., Williams, R., et al. (2002). Mutations in the yeast LCB1 and LCB2 genes, including those corresponding to the hereditary sensory neuropathy type I mutations, dominantly inactivate serine palmitoyltransferase. The Journal of Biological Chemistry, 277, 10194–10200.

    Article  CAS  PubMed  Google Scholar 

  29. Yard, B. A., Carter, L. G., Johnson, K. A., Overton, I. M., Dorward, M., Liu, H., et al. (2007). The structure of serine palmitoyltransferase; gateway to sphingolipid biosynthesis. Journal of Molecular Biology, 370, 870–886.

    Article  CAS  PubMed  Google Scholar 

  30. Hanada, K., Hara, T., & Nishijima, M. (2000). Purification of the serine palmitoyltransferase complex responsible for sphingoid base synthesis by using affinity peptide chromatography techniques. The Journal of Biological Chemistry, 275, 8409–8415.

    Article  CAS  PubMed  Google Scholar 

  31. Hornemann, T., Wei, Y., & von Eckardstein, A. (2007). Is the mammalian serine palmitoyltransferase a high-molecular-mass complex? The Biochemical Journal, 405, 157–164.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Gable, K., Slife, H., Bacikova, D., Monaghan, E., & Dunn, T. M. (2000). Tsc3p is an 80-amino acid protein associated with serine palmitoyltransferase and required for optimal enzyme activity. The Journal of Biological Chemistry, 275, 7597–7603.

    Article  CAS  PubMed  Google Scholar 

  33. Han, G., Gupta, S. D., Gable, K., Niranjanakumari, S., Moitra, P., Eichler, F., et al. (2009). Identification of small subunits of mammalian serine palmitoyltransferase that confer distinct acyl-CoA substrate specificities. Proceedings of the National Academy of Sciences of the United States of America, 106, 8186–8191.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Breslow, D. K., Collins, S. R., Bodenmiller, B., Aebersold, R., Simons, K., Shevchenko, A., et al. (2010). Orm family proteins mediate sphingolipid homeostasis. Nature, 463, 1048–1053.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Hjelmqvist, L., Tuson, M., Marfany, G., Herrero, E., Balcells, S., & Gonzalez-Duarte, R. (2002). ORMDL proteins are a conserved new family of endoplasmic reticulum membrane proteins. Genome Biology, 3, 27.

    Article  Google Scholar 

  36. Roelants, F. M., Breslow, D. K., Muir, A., Weissman, J. S., & Thorner, J. (2011). Protein kinase Ypk1 phosphorylates regulatory proteins Orm1 and Orm2 to control sphingolipid homeostasis in Saccharomyces cerevisiae. Proceedings of the National Academy of Sciences, 108, 19222–19227.

    Article  CAS  Google Scholar 

  37. Wadsworth, J. M., Clarke, D. J., McMahon, S. A., Lowther, J. P., Beattie, A. E., Langridge-Smith, P. R., et al. (2013). The chemical basis of serine palmitoyltransferase inhibition by myriocin. Journal of the American Chemical Society, 135, 14276–14285.

    Article  CAS  PubMed  Google Scholar 

  38. Roelants, F. M., Breslow, D. K., Muir, A., Weissman, J. S., & Thorner, J. (2011). Protein kinase Ypk1 phosphorylates regulatory proteins Orm1 and Orm2 to control sphingolipid homeostasis in Saccharomyces cerevisiae. Proceedings of the National Academy of Sciences of the United States of America, 108, 19222–19227.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Sun, Y., Miao, Y., Yamane, Y., Zhang, C., Shokat, K. M., Takematsu, H., et al. (2012). Orm protein phosphoregulation mediates transient sphingolipid biosynthesis response to heat stress via the Pkh-Ypk and Cdc55-PP2A pathways. Molecular Biology of the Cell, 23, 2388–2398.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Shimobayashi, M., Oppliger, W., Moes, S., Jeno, P., & Hall, M. N. (2013). TORC1-regulated protein kinase Npr1 phosphorylates Orm to stimulate complex sphingolipid synthesis. Molecular Biology of the Cell, 24, 870–881.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. GrandPre, T., Nakamura, F., Vartanian, T., & Strittmatter, S. M. (2000). Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein. Nature, 403, 439–444.

    Article  CAS  PubMed  Google Scholar 

  42. Cantalupo, A., Zhang, Y., Kothiya, M., Galvani, S., Obinata, H., Bucci, M., et al. (2015). Nogo-B regulates endothelial sphingolipid homeostasis to control vascular function and blood pressure. Nature Medicine, 21, 1028–1037.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Voeltz, G. K., Prinz, W. A., Shibata, Y., Rist, J. M., & Rapoport, T. A. (2006). A class of membrane proteins shaping the tubular endoplasmic reticulum. Cell, 124, 573–586.

    Article  CAS  PubMed  Google Scholar 

  44. Fournier, A. E., GrandPre, T., & Strittmatter, S. M. (2001). Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration. Nature, 409, 341–346.

    Article  CAS  PubMed  Google Scholar 

  45. Miao, R. Q., Gao, Y., Harrison, K. D., Prendergast, J., Acevedo, L. M., Yu, J., et al. (2006). Identification of a receptor necessary for Nogo-B stimulated chemotaxis and morphogenesis of endothelial cells. Proceedings of the National Academy of Sciences of the United States of America, 103, 10997–11002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Hammad, S. M., Pierce, J. S., Soodavar, F., Smith, K. J., Al Gadban, M. M., Rembiesa, B., et al. (2010). Blood sphingolipidomics in healthy humans: Impact of sample collection methodology. Journal of Lipid Research, 51, 3074–3087.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Iqbal, J., Walsh, M. T., Hammad, S. M., Cuchel, M., Tarugi, P., Hegele, R. A., et al. (2015). Microsomal triglyceride transfer protein transfers and determines plasma concentrations of ceramide and sphingomyelin but not glycosylceramide. The Journal of Biological Chemistry, 290, 25863–25875.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Bharath, L. P., Ruan, T., Li, Y., Ravindran, A., Wan, X., Nhan, J. K., et al. (2015). Ceramide-initiated protein phosphatase 2A activation contributes to arterial dysfunction in vivo. Diabetes, 64, 3914–3926.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Freed, J. K., Beyer, A. M., LoGiudice, J. A., Hockenberry, J. C., & Gutterman, D. D. (2014). Ceramide changes the mediator of flow-induced vasodilation from nitric oxide to hydrogen peroxide in the human microcirculation. Circulation Research, 115, 525–532.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Li, H., Junk, P., Huwiler, A., Burkhardt, C., Wallerath, T., Pfeilschifter, J., et al. (2002). Dual effect of ceramide on human endothelial cells: Induction of oxidative stress and transcriptional upregulation of endothelial nitric oxide synthase. Circulation, 106, 2250–2256.

    Article  CAS  PubMed  Google Scholar 

  51. Altura, B. M., Gebrewold, A., Zheng, T., & Altura, B. T. (2002). Sphingomyelinase and ceramide analogs induce vasoconstriction and leukocyte-endothelial interactions in cerebral venules in the intact rat brain: Insight into mechanisms and possible relation to brain injury and stroke. Brain Research Bulletin, 58, 271–278.

    Article  CAS  PubMed  Google Scholar 

  52. Zheng, T., Li, W., Wang, J., Altura, B. T., & Altura, B. M. (2000). Sphingomyelinase and ceramide analogs induce contraction and rises in [Ca(2+)](i) in canine cerebral vascular muscle. American Journal of Physiology. Heart and Circulatory Physiology, 278, 1421–1428.

    Article  Google Scholar 

  53. Zhang, Q. J., Holland, W. L., Wilson, L., Tanner, J. M., Kearns, D., Cahoon, J. M., et al. (2012). Ceramide mediates vascular dysfunction in diet-induced obesity by PP2A-mediated dephosphorylation of the eNOS-Akt complex. Diabetes, 61, 1848–1859.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Nilsson, A., & Duan, R. D. (2006). Absorption and lipoprotein transport of sphingomyelin. Journal of Lipid Research, 47, 154–171.

    Article  CAS  PubMed  Google Scholar 

  55. Tabas, I., Williams, K. J., & Boren, J. (2007). Subendothelial lipoprotein retention as the initiating process in atherosclerosis: Update and therapeutic implications. Circulation, 116, 1832–1844.

    Article  CAS  PubMed  Google Scholar 

  56. Schissel, S. L., Tweedie-Hardman, J., Rapp, J. H., Graham, G., Williams, K. J., & Tabas, I. (1996). Rabbit aorta and human atherosclerotic lesions hydrolyze the sphingomyelin of retained low-density lipoprotein. Proposed role for arterial-wall sphingomyelinase in subendothelial retention and aggregation of atherogenic lipoproteins. The Journal of Clinical Investigation, 98, 1455–1464.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Schissel, S. L., Jiang, X., Tweedie-Hardman, J., Jeong, T., Camejo, E. H., Najib, J., et al. (1998). Secretory sphingomyelinase, a product of the acid sphingomyelinase gene, can hydrolyze atherogenic lipoproteins at neutral pH. Implications for atherosclerotic lesion development. The Journal of Biological Chemistry, 273, 2738–2746.

    Article  CAS  PubMed  Google Scholar 

  58. Rodriguez, J., Catapano, A., Ghiselli, G. C., & Sirtori, C. R. (1976). Turnover and aortic uptake of very low density lipoproteins (VLDL) from hypercholesteremic rabbits as a model for testing antiatherosclerotic compounds. Advances in Experimental Medicine and Biology, 67, 169–189.

    Article  CAS  PubMed  Google Scholar 

  59. Jeong, T., Schissel, S. L., Tabas, I., Pownall, H. J., Tall, A. R., & Jiang, X. (1998). Increased sphingomyelin content of plasma lipoproteins in apolipoprotein E knockout mice reflects combined production and catabolic defects and enhances reactivity with mammalian sphingomyelinase. The Journal of Clinical Investigation, 101, 905–912.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Li, Z., Basterr, M. J., Hailemariam, T. K., Hojjati, M. R., Lu, S., Liu, J., et al. (2005). The effect of dietary sphingolipids on plasma sphingomyelin metabolism and atherosclerosis. Biochimica et Biophysica Acta, 1735, 130–134.

    Article  CAS  PubMed  Google Scholar 

  61. Nelson, J. C., Jiang, X. C., Tabas, I., Tall, A., & Shea, S. (2006). Plasma sphingomyelin and subclinical atherosclerosis: Findings from the multi-ethnic study of atherosclerosis. American Journal of Epidemiology, 163, 903–912.

    Article  PubMed  Google Scholar 

  62. de Mello, V. D., Lankinen, M., Schwab, U., Kolehmainen, M., Lehto, S., Seppanen-Laakso, T., et al. (2009). Link between plasma ceramides, inflammation and insulin resistance: Association with serum IL-6 concentration in patients with coronary heart disease. Diabetologia, 52, 2612–2615.

    Article  CAS  PubMed  Google Scholar 

  63. Yeboah, J., McNamara, C., Jiang, X. C., Tabas, I., Herrington, D. M., Burke, G. L., et al. (2010). Association of plasma sphingomyelin levels and incident coronary heart disease events in an adult population: Multi-ethnic study of atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology, 30, 628–633.

    Article  CAS  PubMed  Google Scholar 

  64. Fernandez, C., Sandin, M., Sampaio, J. L., Almgren, P., Narkiewicz, K., Hoffmann, M., et al. (2013). Plasma lipid composition and risk of developing cardiovascular disease. PLoS One, 8, e71846.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Pan, W., Yu, J., Shi, R., Yan, L., Yang, T., Li, Y., et al. (2014). Elevation of ceramide and activation of secretory acid sphingomyelinase in patients with acute coronary syndromes. Coronary Artery Disease, 25, 230–235.

    Article  PubMed  Google Scholar 

  66. Tarasov, K., Ekroos, K., Suoniemi, M., Kauhanen, D., Sylvanne, T., Hurme, R., et al. (2014). Molecular lipids identify cardiovascular risk and are efficiently lowered by simvastatin and PCSK9 deficiency. The Journal of Clinical Endocrinology and Metabolism, 99, 45–52.

    Article  Google Scholar 

  67. Cheng, J. M., Suoniemi, M., Kardys, I., Vihervaara, T., de Boer, S. P., Akkerhuis, K. M., et al. (2015). Plasma concentrations of molecular lipid species in relation to coronary plaque characteristics and cardiovascular outcome: Results of the ATHEROREMO-IVUS study. Atherosclerosis, 243, 560–566.

    Article  CAS  PubMed  Google Scholar 

  68. Yu, J., Pan, W., Shi, R., Yang, T., Li, Y., Yu, G., et al. (2015). Ceramide is upregulated and associated with mortality in patients with chronic heart failure. The Canadian Journal of Cardiology, 31, 357–363.

    Article  PubMed  Google Scholar 

  69. Laaksonen, R., Ekroos, K., Sysi-Aho, M., Hilvo, M., Vihervaara, T., Kauhanen, D., et al. (2016). Plasma ceramides predict cardiovascular death in patients with stable coronary artery disease and acute coronary syndromes beyond LDL-cholesterol. European Heart Journal, 37, 1967–1976.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Havulinna, A. S., Sysi-Aho, M., Hilvo, M., Kauhanen, D., Hurme, R., Ekroos, K., et al. (2016). Circulating ceramides predict cardiovascular outcomes in the population-based FINRISK 2002 cohort. Arteriosclerosis, Thrombosis, and Vascular Biology, 36, 2424–2430.

    Article  CAS  PubMed  Google Scholar 

  71. Dinoff, A., Saleem, M., Herrmann, N., Mielke, M. M., Oh, P. I., Venkata, S. L. V., et al. (2017). Plasma sphingolipids and depressive symptoms in coronary artery disease. Brain and Behavior: A Cognitive Neuroscience Perspective, 7, e00836.

    Article  Google Scholar 

  72. Wang, D. D., Toledo, E., Hruby, A., Rosner, B. A., Willett, W. C., Sun, Q., et al. (2017). Plasma ceramides, mediterranean diet, and incident cardiovascular disease in the PREDIMED Trial (prevencion con dieta mediterranea). Circulation, 135, 2028–2040.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Lemaitre, R. N., Yu, C., Hoofnagle, A., Hari, N., Jensen, P. N., Fretts, A. M., et al. (2018). Circulating sphingolipids, insulin, HOMA-IR, and HOMA-B: The Strong Heart Family Study. Diabetes, 67, 1663–1672.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Meeusen, J. W., Donato, L. J., Bryant, S. C., Baudhuin, L. M., Berger, P. B., & Jaffe, A. S. (2018). Plasma ceramides. Arteriosclerosis, Thrombosis, and Vascular Biology, 38, 1933–1939.

    Article  CAS  PubMed  Google Scholar 

  75. Peterson, L. R., Xanthakis, V., Duncan, M. S., Gross, S., Friedrich, N., Völzke, H., et al. (2018). Ceramide remodeling and risk of cardiovascular events and mortality. Journal of the American Heart Association, 7, e007931.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Lemaitre, R. N., Jensen, P. N., Hoofnagle, A., McKnight, B., Fretts, A. M., King, I. B., et al. (2019). Plasma ceramides and sphingomyelins in relation to heart failure risk. Circulation, 12, e005708.

    CAS  PubMed  Google Scholar 

  77. Rahman, M. L., Feng, Y. A., Fiehn, O., Albert, P. S., Tsai, M. Y., Zhu, Y., et al. (2021). Plasma lipidomics profile in pregnancy and gestational diabetes risk: A prospective study in a multiracial/ethnic cohort. BMJ Open Diabetes Research & Care, 9, e001551.

    Article  Google Scholar 

  78. Chen, G. C., Chai, J. C., Yu, B., Michelotti, G. A., Grove, M. L., Fretts, A. M., et al. (2020). Serum sphingolipids and incident diabetes in a US population with high diabetes burden: The Hispanic Community Health Study/Study of Latinos (HCHS/SOL). The American Journal of Clinical Nutrition, 112, 57–65.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Rico, J. E., Specker, B., Perry, C. A., & McFadden, J. W. (2020). Plasma ceramides and triglycerides are elevated during pregnancy in association with markers of insulin resistance in hutterite women. Lipids, 55, 375–386.

    Article  CAS  PubMed  Google Scholar 

  80. Devlin, C. M., Leventhal, A. R., Kuriakose, G., Schuchman, E. H., Williams, K. J., & Tabas, I. (2008). Acid sphingomyelinase promotes lipoprotein retention within early atheromata and accelerates lesion progression. Arteriosclerosis, Thrombosis, and Vascular Biology, 28, 1723–1730.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Li, Z., Kabir, I., Jiang, H., Zhou, H., Libien, J., Zeng, J., et al. (2016). Liver serine palmitoyltransferase activity deficiency in early life impairs adherens junctions and promotes tumorigenesis. Hepatology, 64, 2089–2102.

    Article  CAS  PubMed  Google Scholar 

  82. Yamaoka, S., Miyaji, M., Kitano, T., Umehara, H., & Okazaki, T. (2004). Expression cloning of a human cDNA restoring sphingomyelin synthesis and cell growth in sphingomyelin synthase-defective lymphoid cells. The Journal of Biological Chemistry, 279, 18688–18693.

    Article  CAS  PubMed  Google Scholar 

  83. Huitema, K., van den Dikkenberg, J., Brouwers, J. F., & Holthuis, J. C. (2004). Identification of a family of animal sphingomyelin synthases. The EMBO Journal, 23, 33–44.

    Article  CAS  PubMed  Google Scholar 

  84. Liu, J., Huan, C., Chakraborty, M., Zhang, H., Lu, D., Kuo, M. S., et al. (2009). Macrophage sphingomyelin synthase 2 deficiency decreases atherosclerosis in mice. Circulation Research, 105, 295–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Adachi, R., Ogawa, K., Matsumoto, S. I., Satou, T., Tanaka, Y., Sakamoto, J., et al. (2017). Discovery and characterization of selective human sphingomyelin synthase 2 inhibitors. European Journal of Medicinal Chemistry, 136, 283–293.

    Article  CAS  PubMed  Google Scholar 

  86. Li, Y., Dong, J., Ding, T., Kuo, M. S., Cao, G., Jiang, X. C., et al. (2013). Sphingomyelin synthase 2 activity and liver steatosis: An effect of ceramide-mediated peroxisome proliferator-activated receptor gamma2 suppression. Arteriosclerosis, Thrombosis, and Vascular Biology, 33, 1513–1520.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Dong, J., Liu, J., Lou, B., Li, Z., Ye, X., Wu, M., et al. (2006). Adenovirus-mediated overexpression of sphingomyelin synthases 1 and 2 increases the atherogenic potential in mice. Journal of Lipid Research, 47, 1307–1314.

    Article  CAS  PubMed  Google Scholar 

  88. Liu, J., Zhang, H., Li, Z., Hailemariam, T. K., Chakraborty, M., Jiang, K., et al. (2009). Sphingomyelin synthase 2 is one of the determinants for plasma and liver sphingomyelin levels in mice. Arteriosclerosis, Thrombosis, and Vascular Biology, 29, 850–856.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Libby, P., Loscalzo, J., Ridker, P. M., Farkouh, M. E., Hsue, P. Y., Fuster, V., et al. (2018). Inflammation, immunity, and infection in atherothrombosis: JACC review topic of the week. Journal of the American College of Cardiology, 72, 2071–2081.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Cerbon, J., & del Carmen, L.-S. R. (2003). Diacylglycerol generated during sphingomyelin synthesis is involved in protein kinase C activation and cell proliferation in Madin-Darby canine kidney cells. The Biochemical Journal, 373, 917–924.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Ding, T., Li, Z., Hailemariam, T., Mukherjee, S., Maxfield, F. R., Wu, M. P., et al. (2008). SMS overexpression and knockdown: Impact on cellular sphingomyelin and diacylglycerol metabolism, and cell apoptosis. Journal of Lipid Research, 49, 376–385.

    Article  CAS  PubMed  Google Scholar 

  92. Deng, Y., Hu, J. C., He, S. H., Lou, B., Ding, T. B., Yang, J. T., et al. (2021). Sphingomyelin synthase 2 facilitates M2-like macrophage polarization and tumor progression in a mouse model of triple-negative breast cancer. Acta Pharmacologica Sinica, 42, 149–159.

    Article  CAS  PubMed  Google Scholar 

  93. Prymas, K., Swiatkowska, A., Traczyk, G., Ziemlinska, E., Dziewulska, A., Ciesielska, A., et al. (2020). Sphingomyelin synthase activity affects TRIF-dependent signaling of Toll-like receptor 4 in cells stimulated with lipopolysaccharide. Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, 1865, 158549.

    Article  CAS  PubMed  Google Scholar 

  94. Minuz, P., Fava, C., Vattemi, G., Arcaro, G., Riccadonna, M., Tonin, P., et al. (2012). Endothelial dysfunction and increased oxidative stress in mitochondrial diseases. Clinical Science (London, England), 122, 289–297.

    Article  CAS  Google Scholar 

  95. Wu, D., Li, D., Liu, Z., Liu, X., Zhou, S., & Duan, H. (2018). Role and underlying mechanism of SPATA12 in oxidative damage. Oncology Letters, 15, 3676–3684.

    PubMed  PubMed Central  Google Scholar 

  96. Zweerink, M. M., Edison, A. M., Wells, G. B., Pinto, W., & Lester, R. L. (1992). Characterization of a novel, potent, and specific inhibitor of serine palmitoyltransferase. The Journal of Biological Chemistry, 267, 25032–25038.

    Article  CAS  PubMed  Google Scholar 

  97. Mandala, S. M., Frommer, B. R., Thornton, R. A., Kurtz, M. B., Young, N. M., Cabello, M. A., et al. (1994). Inhibition of serine palmitoyl-transferase activity by lipoxamycin. The Journal of Antibiotics, 47, 376–379.

    Article  CAS  PubMed  Google Scholar 

  98. Miyake, Y., Kozutsumi, Y., Nakamura, S., Fujita, T., & Kawasaki, T. (1995). Serine palmitoyltransferase is the primary target of a sphingosine-like immunosuppressant, ISP-1/myriocin. Biochemical and Biophysical Research Communications, 211, 396–403.

    Article  CAS  PubMed  Google Scholar 

  99. Park, T. S., Panek, R. L., Mueller, S. B., Hanselman, J. C., Rosebury, W. S., Robertson, A. W., et al. (2004). Inhibition of sphingomyelin synthesis reduces atherogenesis in apolipoprotein E-knockout mice. Circulation, 110, 3465–3471.

    Article  CAS  PubMed  Google Scholar 

  100. Hojjati, M. R., Li, Z., Zhou, H., Tang, S., Huan, C., Ooi, E., et al. (2005). Effect of myriocin on plasma sphingolipid metabolism and atherosclerosis in apoE-deficient mice. The Journal of Biological Chemistry, 280, 10284–10289.

    Article  CAS  PubMed  Google Scholar 

  101. Holland, W. L., Brozinick, J. T., Wang, L. P., Hawkins, E. D., Sargent, K. M., Liu, Y., et al. (2007). Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell Metabolism, 5, 167–179.

    Article  CAS  PubMed  Google Scholar 

  102. Yang, R. X., Pan, Q., Liu, X. L., Zhou, D., Xin, F. Z., Zhao, Z. H., et al. (2019). Therapeutic effect and autophagy regulation of myriocin in nonalcoholic steatohepatitis. Lipids in Health and Disease, 18, 179.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Li, Z., Park, T. S., Li, Y., Pan, X., Iqbal, J., Lu, D., et al. (2009). Serine palmitoyltransferase (SPT) deficient mice absorb less cholesterol. Biochimica et Biophysica Acta, 1791, 297–306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Sano, O., Kazetani, K. I., Adachi, R., Kurasawa, O., Kawamoto, T., & Iwata, H. (2017). Using a biologically annotated library to analyze the anticancer mechanism of serine palmitoyl transferase (SPT) inhibitors. FEBS Open Bio, 7, 495–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Kojima, T., Asano, Y., Kurasawa, O., Hirata, Y., Iwamura, N., Wong, T. T., et al. (2018). Discovery of novel serine palmitoyltransferase inhibitors as cancer therapeutic agents. Bioorganic & Medicinal Chemistry, 26, 2452–2465.

    Article  CAS  Google Scholar 

  106. Genin, M. J., Gonzalez Valcarcel, I. C., Holloway, W. G., Lamar, J., Mosior, M., Hawkins, E., et al. (2016). Imidazopyridine and pyrazolopiperidine derivatives as novel inhibitors of serine palmitoyl transferase. Journal of Medicinal Chemistry, 59, 5904–5910.

    Article  CAS  PubMed  Google Scholar 

  107. Li, Z., Zhang, H., Liu, J., Liang, C. P., Li, Y., Teitelman, G., et al. (2011). Reducing plasma membrane sphingomyelin increases insulin sensitivity. Molecular and Cellular Biology, 31, 4205–4218.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Mitsutake, S., Zama, K., Yokota, H., Yoshida, T., Tanaka, M., Mitsui, M., et al. (2011). Dynamic modification of sphingomyelin in lipid microdomains controls development of obesity, fatty liver, and type 2 diabetes. The Journal of Biological Chemistry, 286, 28544–28555.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Mo, M., Yang, J., Jiang, X. C., Cao, Y., Fei, J., Chen, Y., et al. (2018). Discovery of 4-benzyloxybenzo[d]isoxazole-3-amine derivatives as highly selective and orally efficacious human sphingomyelin synthase 2 inhibitors that reduce chronic inflammation in db/db mice. Journal of Medicinal Chemistry, 61, 8241–8254.

    Article  CAS  PubMed  Google Scholar 

  110. Li, Y., Huang, T., Lou, B., Ye, D., Qi, X., Li, X., et al. (2019). Discovery, synthesis and anti-atherosclerotic activities of a novel selective sphingomyelin synthase 2 inhibitor. European Journal of Medicinal Chemistry, 163, 864–882.

    Article  CAS  PubMed  Google Scholar 

  111. Huang, Y., Huang, T., Zhen, X., Li, Y., Mo, M., Ye, D., et al. (2019). A selective sphingomyelin synthase 2 inhibitor ameliorates diet induced insulin resistance via the IRS-1/Akt/GSK-3beta signaling pathway. Pharmazie, 74, 553–558.

    CAS  PubMed  Google Scholar 

  112. Yukawa, T., Nakahata, T., Okamoto, R., Ishichi, Y., Miyamoto, Y., Nishimura, S., et al. (2020). Discovery of 1,8-naphthyridin-2-one derivative as a potent and selective sphingomyelin synthase 2 inhibitor. Bioorganic & Medicinal Chemistry, 28, 115376.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported in part by the Gachon University Research fund of 2019 (GCU-2019-0824) and the National Research Foundation of Korea (NRF) funded by the Korean government (MSIP) to T-. S. P. (2020R1A2C2012833, NRF-2021R1A4A3031661).

Author information

Authors and Affiliations

  1. Department of Life Science, Gachon University, Sungnam, Gyeonggido, South Korea

    Tae-Sik Park, Shivani Devi, Amitesh Sharma, Goon-Tae Kim & Kyung-Hee Cho

Authors
  1. Tae-Sik Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shivani Devi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Amitesh Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Goon-Tae Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kyung-Hee Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tae-Sik Park .

Editor information

Editors and Affiliations

  1. Department of Cell Biology, SUNY Downstate Health Sciences University, Brooklyn, NY, USA

    Xian-Cheng Jiang

Rights and permissions

Reprints and permissions

Copyright information

© 2022 The Author(s), under exclusive licence to Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Park, TS., Devi, S., Sharma, A., Kim, GT., Cho, KH. (2022). De Novo Sphingolipid Biosynthesis in Atherosclerosis. In: Jiang, XC. (eds) Sphingolipid Metabolism and Metabolic Disease. Advances in Experimental Medicine and Biology, vol 1372. Springer, Singapore. https://doi.org/10.1007/978-981-19-0394-6_3

Download citation

Publish with us

Policies and ethics

Search

Navigation