Ceramides: focus on obesity
https://doi.org/10.14341/omet12565
Abstract
It is generally known that obesity increases the risk of developing cardiovascular disease. A pathological increase in the mass of adipose tissue leads to a violation of the control of lipid accumulation at the molecular level, abnormal lipid metabolism with the formation of metabolites, which are critical for the development of these pathologies against the background of obesity. Ceramides are one of these metabolites. Ceramides perform many physiological functions, but under pathological conditions they induce insulin resistance, uncouple cellular respiration and phosphorylation, activate cell apoptosis, and play an important role in the induction of adipose tissue dysfunction. Altering ceramide biosynthesis through dysregulation of key enzymes leads to the formation and accumulation of ceramides, which block insulin signaling and induce adipose tissue inflammation.
This review highlights the metabolism of ceramides, the reasons for their ectopic deposition in tissues in obesity, as well as potential intracellular signaling pathways that modulate ceramide activity.
About the Authors
Yulia A. Dyleva
https://www.mendeley.com/profiles/yulia-dyleva/
Federal State Budgetary Scientific Institution Research Institute for Complex Issues of Cardiovascular Diseases
Russian Federation
Competing Interests: not
Federal State Budgetary Scientific Institution Research Institute for Complex Issues of Cardiovascular Diseases
Russian Federation
Yulia A. Dyleva, MD, PhD, ORCID: https://orcid.org/0000-0002-6890-3287, ResearcherID: O-3883-2015, Scopus Author ID: 49360983500, eLibrary SPIN: 2064-6262, e-mail: dyleva87@yandex.ru
6, Sosnoviy blvd, 650002, Kemerovo
Competing Interests: not
Olga V. Gruzdeva
Federal State Budgetary Scientific Institution Research Institute for Complex Issues of Cardiovascular Diseases
Russian Federation
Competing Interests: not
Russian Federation
Olga V. Gruzdeva, MD, PhD, ORCID: https://orcid.org/0000-0002-7780-829X, ResearcherID: P-9723-2015, Scopus Author ID: 6507406046, eLibrary SPIN: 4322-0963, e-mail: o_gruzdeva@mail.ru
Kemerovo
Competing Interests: not
Ekaterina V. Belik
Federal State Budgetary Scientific Institution Research Institute for Complex Issues of Cardiovascular Diseases
Russian Federation
Competing Interests: not
Russian Federation
Ekaterina V. Belik, ORCID://orcid.org/0000-0003-3996-3325, ResearcherID: I-7850-2017, Scopus Author ID: 57188768885, eLibrary SPIN: 5705-9143, e-mail: sionina.ev@mail.ru
Kemerovo
Competing Interests: not
References
1. Gorski J. Ceramide and Insulin Resistance: How Should the Issue Be Approached? Diabetes. 2012;61(12):3081-3083. doi: https://doi.org/10.2337/db12-1157
2. Rutkowski JM, Stern JH, Scherer PE. The cell biology of fat expansion. J Cell Biol. 2015;208(5):501-512. doi: https://doi.org/10.1083/jcb.201409063
3. Muoio DM, Neufer PD. Lipid-Induced Mitochondrial Stress and Insulin Action in Muscle. Cell Metab. 2012;15(5):595-605. doi: https://doi.org/10.1016/j.cmet.2012.04.010
4. Alessenko AV., Zateyshchikov DA, Lebedev AT, Kurochkin IN. Participation of Sphingolipids in the Pathogenesis of Atherosclerosis. Kardiologiia. 2019;59(8):77-87. (In Russ.). doi: https://doi.org/10.18087/cardio.2019.8.10270
5. Kuzmenko DI, Klimenteva TK. Ceramide: a role in apoptosis and pathogenesis of insulin resistance. Biochemistry (Moscow). 2016;81(9):1155-1171. (In Russ.).
6. Gault CR, Obeid LM, Hannun YA. An overview of sphingolipid metabolism: from synthesis to breakdown. Adv Exp Med Biol. 2010;688:1-23. doi: https://doi.org/10.1007/978-1-4419-6741-1_1
7. Ussher JR, Koves TR, Cadete VJJ, et al. Inhibition of De Novo Ceramide Synthesis Reverses Diet-Induced Insulin Resistance and Enhances Whole-Body Oxygen Consumption. Diabetes. 2010;59(10):2453-2464. doi: https://doi.org/10.2337/db09-1293
8. Levy M, Futerman AH. Mammalian ceramide synthases. IUBMB Life. 2010;59(10):NA-NA. doi: https://doi.org/10.1002/iub.319
9. Ginkel C, Hartmann D, vom Dorp K, et al. Ablation of Neuronal Ceramide Synthase 1 in Mice Decreases Ganglioside Levels and Expression of Myelin-associated Glycoprotein in Oligodendrocytes. J Biol Chem. 2012;287(50):41888-41902. doi: https://doi.org/10.1074/jbc.M112.413500
10. Gosejacob D, Jager PS, vom Dorp K, et al. Ceramide Synthase 5 Is Essential to Maintain C 16:0 -Ceramide Pools and Contributes to the Development of Diet-induced Obesity. J Biol Chem. 2016;291(13):6989-7003. doi: https://doi.org/10.1074/jbc.M115.691212
11. Michel C, van Echten-Deckert G, Rother J, et al. Characterization of Ceramide Synthesis. J Biol Chem. 1997;272(36):22432-22437. doi: https://doi.org/10.1074/jbc.272.36.22432
12. Rodriguez-Cuenca S, Barbarroja N, Vidal-Puig A. Dihydroceramide desaturase 1, the gatekeeper of ceramide induced lipotoxicity. Biochim Biophys Acta - Mol Cell Biol Lipids. 2015;1851(1):40-50. doi: https://doi.org/10.1016/jbbalip.2014.09.021
13. Mamtani M, Meikle PJ, Kulkarni H, et al. Plasma dihydroceramide species associate with waist circumference in Mexican American families. Obesity. 2014;22(3):950-956. doi: https://doi.org/10.1002/oby.20598
14. Mcilroy GD, Delibegovic M, Owen C, et al. Fenretinide treatment prevents diet-induced obesity in association with major alterations in retinoid homeostatic gene expression in adipose, liver, and hypothalamus. Diabetes. 2013;62(3):825-836. doi: https://doi.org/10.2337/db12-0458
15. Oaks J, Ogretmen B. Regulation of PP2A by Sphingolipid Metabolism and Signaling. Front Oncol. 2015;4:388. doi: https://doi.org/10.3389/fonc.2014.00388
16. Powell DJ, Hajduch E, Kular G, Hundal HS. Ceramide Disables 3-Phosphoinositide Binding to the pleckstrin homology domain of protein kinase B (PKB)/Akt by a PKCZ-dependent mechanism. Mol Cell Biol. 2003;23(21):7794-7808. doi: https://doi.org/10.1128/MCB.23.21.7794-7808.2003
17. Holland WL, Miller RA, Wang Z V., et al. Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin. Nat Med. 2011;17(1):55-63. doi: https://doi.org/10.1038/nm.2277
18. Boslem E, MacIntosh G, Preston AM, et al. A lipidomic screen of palmitate-treated MIN6 в-cells links sphingolipid metabolites with endoplasmic reticulum (ER) stress and impaired protein trafficking. Biochem J. 2011;435(1):267-276. doi: https://doi.org/10.1042/BJ20101867
19. Ramirez S, Martins L, Jacas J, et al. Hypothalamic Ceramide Levels Regulated by CPT1C Mediate the Orexigenic Effect of Ghrelin. Diabetes. 2013;62(7):2329-2337. doi: https://doi.org/10.2337/db12-1451
20. Holland WL, Bikman BT, Wang L-P et al. Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid-induced ceramide biosynthesis in mice. J Clin Invest. 2011;121(5):1858-1870. doi: https://doi.org/10.1172/JCI43378
21. Velloso LA, Folli F, Saad MJ. TLR4 at the crossroads of nutrients, gut microbiota, and metabolic inflammation. Endocr Rev. 2015. doi: https://doi.org/10.1210/er.2014-1100
22. Holland WL, Knotts TA, Chavez JA, et al. Lipid Mediators of Insulin Resistance. Nutr Rev. 2008;65:S39-S46. doi: https://doi.org/10.1111/j.1753-4887.2007.tb00327.x
23. Ye R, Scherer PE. Adiponectin, driver or passenger on the road to insulin sensitivity? Mol Metab. 2013;2(3):133-141. doi: https://doi.org/10.1016/j.molmet.2013.04.001
24. Colell A, Morales A, Fernandez-Checa JC, Garcia-Ruiz C. Ceramide generated by acidic sphingomyelinase contributes to tumor necrosis factor-a-mediated apoptosis in human colon HT-29 cells through glycosphingolipids formation. FEBS Lett. 2002;526(1-3):135-141. doi: https://doi.org/10.1016/S0014-5793(02)03140-X
25. Cuschieri J, Bulger E, Billgrin J, et al. Acid Sphingomyelinase Is Required for Lipid Raft TLR4 Complex Formation. Surg Infect (Larchmt). 2007;8(1):91-106. doi: https://doi.org/10.1089/sur.2006.050
26. Lyn-Cook LE, Lawton M, Tong M, et al. Hepatic Ceramide May Mediate Brain Insulin Resistance and Neurodegeneration in Type 2 Diabetes and Non-alcoholic Steatohepatitis. Bierhaus A, ed. J Alzheimer's Dis. 2009;16(4):715-729. doi: https://doi.org/10.3233/JAD-2009-0984
27. Patel SA, Hoehn KL, Lawrence RT, et al. Overexpression of the Adiponectin Receptor AdipoR1 in Rat Skeletal Muscle Amplifies Local Insulin Sensitivity. Endocrinology. 2012;153(11):5231-5246. doi: https://doi.org/10.1210/en.2012-1368
28. Serlie MJ, Allick G, Groener JE, et al. Chronic Treatment with Pioglitazone Does Not Protect Obese Patients with Diabetes Mellitus Type II from Free Fatty Acid-Induced Insulin Resistance. J Clin Endocrinol Metab. 2007;92(1):166-171. doi: https://doi.org/10.1210/jc.2006-1518
29. Hotamisligil GS, Spiegelman BM. Tumor Necrosis Factor: A Key Component of the Obesity-Diabetes Link. Diabetes. 1994;43(11):1271-1278. doi: https://doi.org/10.2337/diab.43.11.1271
30. Long SD, Pekala PH. Lipid mediators of insulin resistance: ceramide signalling down-regulates GLUT4 gene transcription in 3T3-L1 adipocytes. Biochem J. 1996;319(1):179-184. doi: https://doi.org/10.1042/bj3190179
31. Tagami S, Inokuchi J, Kabayama K, et al. Ganglioside GM3 Participates in the Pathological Conditions of Insulin Resistance. J Biol Chem. 2002;277(5):3085-3092. doi: https://doi.org/10.1074/jbc.M103705200
32. 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(8):1960-1968. doi: https://doi.org/10.2337/db07-0111
33. Hajduch E, Balendran A, Batty IH, et al. Ceramide impairs the insulin-dependent membrane recruitment of Protein Kinase B leading to a loss in downstream signalling in L6 skeletal muscle cells. Diabetologia. 2001;44(2):173-183. doi: https://doi.org/10.1007/s001250051596
34. Chaurasia B, Summers SA. Ceramides - Lipotoxic Inducers of Metabolic Disorders. Trends Endocrinol Metab. 2015;26(10):538-550. doi: https://doi.org/10.1016/j.tem.2015.07.006
35. Powell DJ, Turban S, Gray A, et al. Intracellular ceramide synthesis and protein kinase CZ activation play an essential role in palmitate-induced insulin resistance in rat L6 skeletal muscle cells. Biochem J. 2004;382(2):619-629. doi: https://doi.org/10.1042/BJ20040139
36. Hajduch E, Turban S, Le Liepvre X, et al. Targeting of PKCZ and PKB to caveolin-enriched microdomains represents a crucial step underpinning the disruption in PKB-directed signalling by ceramide. Biochem J. 2008;410(2):369-379. doi: https://doi.org/10.1042/BJ20070936
37. Turpin SM, Nicholls HT, Willmes DM, et al. Obesity-Induced CerS6-Dependent C16:0 Ceramide Production Promotes Weight Gain and Glucose Intolerance. Cell Metab. 2014;20(4):678-686. doi: https://doi.org/10.1016/j.cmet.2014.08.002
38. Blachnio-Zabielska AU, Koutsari C, Tchkonia T, Jensen MD. Sphingolipid Content of Human Adipose Tissue: Relationship to Adiponectin and Insulin Resistance. Obesity. 2012;20(12):2341-2347. doi: https://doi.org/10.1038/oby.2012.126
39. Blachnio-Zabielska AU, Baranowski M, Hirnle T, et al. Increased Bioactive Lipids Content in Human Subcutaneous and Epicardial Fat Tissue Correlates with Insulin Resistance. Lipids. 2012;47(12):1131-1141. doi: https://doi.org/10.1007/s11745-012-3722-x
40. Turpin SM, Nicholls HT, Willmes DM, et al. Obesity-Induced CerS6-Dependent C16:0 Ceramide Production Promotes Weight Gain and Glucose Intolerance. Cell Metab. 2014;20(4):678-686. doi: https://doi.org/10.1016/j.cmet.2014.08.002
41. Zigdon H, Kogot-Levin A, Park J-W, et al. Ablation of Ceramide Synthase 2 Causes Chronic Oxidative Stress Due to Disruption of the Mitochondrial Respiratory Chain. J Biol Chem. 2013;288(7):4947-4956. doi: https://doi.org/10.1074/jbc.M112.402719
42. Setoyama D, Fujimura Y, Miura D. Metabolomics reveals that carnitine palmitoyltransferase-1 is a novel target for oxidative inactivation in human cells. Genes to Cells. 2013;18(12):1107-1119. doi: https://doi.org/10.1111/gtc.12098
43. Kogot-Levin A, Saada A. Ceramide and the mitochondrial respiratory chain. Biochimie. 2014;100:88-94. doi: https://doi.org/10.1016/j.biochi.2013.07.027
44. Bruce CR, Hoy AJ, Turner N, et al. Overexpression of Carnitine Palmitoyltransferase-1 in Skeletal Muscle Is Sufficient to Enhance Fatty Acid Oxidation and Improve High-Fat Diet-Induced Insulin Resistance. Diabetes. 2009;58(3):550-558. doi: https://doi.org/10.2337/db08-1078
45. Henique C, Mansouri A, Fumey G, et al. Increased mitochondrial fatty acid oxidation is sufficient to protect skeletal muscle cells from palmitate-induced apoptosis. J Biol Chem. 2010. doi: https://doi.org/10.1074/jbc.M110.170431
46. Cinar R, Godlewski G, Liu J, et al. Hepatic cannabinoid-1 receptors mediate diet-induced insulin resistance by increasing de novo synthesis of long-chain ceramides. Hepatology. 2014;59(1):143-153. doi: https://doi.org/10.1002/hep.26606
47. Schiffmann S, Hartmann D, Fuchs S, et al. Inhibitors of specific ceramide synthases. Biochimie. 2012;94(2):558-565. doi: https://doi.org/10.10167j.biochi.2011.09.007
48. Obeid L, Linardic C, Karolak L, Hannun Y. Programmed cell death induced by ceramide. Science (80-). 1993;259(5102):1769-1771. doi: https://doi.org/10.1126/science.8456305
49. Ussher JR. The role of cardiac lipotoxicity in the pathogenesis of diabetic cardiomyopathy. Expert Rev Cardiovasc Ther. 2014;12(3):345-358. doi: https://doi.org/10.1586/14779072.2014.891939
50. Chen M, Quintans J, Fuks Z, et al. Suppression of Bcl-2 messenger RNA production may mediate apoptosis after ionizing radiation, tumor necrosis factor alpha, and ceramide. Cancer Res. 1995;55(5):991-994.
51. Wu C-C, Bratton SB. Regulation of the Intrinsic Apoptosis Pathway by Reactive Oxygen Species. Antioxid Redox Signal. 2013;19(6):546-558. doi: https://doi.org/10.1089/ars.2012.4905
52. Sussman MA, Volkers M, Fischer K, et al. Myocardial AKT: The Omnipresent Nexus. Physiol Rev. 2011;91(3):1023-1070. doi: https://doi.org/10.1152/physrev.00024.2010
53. Scherer PE. Adipose Tissue: From Lipid Storage Compartment to Endocrine Organ. Diabetes. 2006;55(6):1537-1545. doi: https://doi.org/10.2337/db06-0263
54. Bonzon-Kulichenko E, Schwudke D, Gallardo N, et al. Central Leptin Regulates Total Ceramide Content and Sterol Regulatory Element Binding Protein-1C Proteolytic Maturation in Rat White Adipose Tissue. Endocrinology. 2009;150(1):169-178. doi: https://doi.org/10.1210/en.2008-0505
55. Gruzdeva O V., Akbasheva OE, Dyleva YA, et al. Adipokine and cytokine profiles of epicardial and subcutaneous adipose tissue in patients with coronary heart disease. Bulleten' eksperimental'noj biologii i mediciny. 2017;163(5):560-563. (In Russ.)
56. Holland WL, Adams AC, Brozinick JT, et al. An FGF21-Adiponectin-Ceramide Axis Controls Energy Expenditure and Insulin Action in Mice. Cell Metab. 2013;17(5):790-797. doi: https://doi.org/10.1016/j.cmet.2013.03.019
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Dyleva Yu.A., Gruzdeva O.V., Belik E.V. Ceramides: focus on obesity. Obesity and metabolism. 2020;17(3):307-315. (In Russ.) https://doi.org/10.14341/omet12565
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