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Cited by 237Sphingolipid Metabolism and SignalingLipid metabolism and biosynthesisCancer, Lipids, and Metabolism

Ceramide is metabolized to acylceramide and stored in lipid droplets

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Senkal, Can E., Salama, Mohamed F., Snider, Ashley J., Allopenna, Janet J., Rana, Nadia A., Koller, Antonius, Hannun, Yusuf A., Obeid, Lina M.·2017·Cell Metabolism
DOI 10.1016/j.cmet.2017.02.010PMC PMC5472424
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Abstract

In an approach aimed at defining interacting partners of ceramide synthases (CerSs), we found that fatty acyl-CoA synthase ACSL5 interacts with all CerSs. We demonstrate that ACSL5-generated FA-CoA was utilized with de novo ceramide for the generation of acylceramides, poorly studied ceramide metabolites. Functionally, inhibition of ceramide channeling to acylceramide enhanced accumulation of de novo ceramide and resulted in augmentation of ceramide-mediated apoptosis. Mechanistically, we show that acylceramide generation is catalyzed by diacylglycerol acyltransferase 2 (DGAT2) on lipid droplets. In summary, this study identifies a metabolic pathway of acylceramide generation and its sequestration in LDs in cells and in livers of mice on a high-fat diet. The study also implicates this pathway in ceramide-mediated apoptosis, and has implications in co-regulation of triglyceride and sphingolipid metabolisms.

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  • Cers are predominantly localized to cellular membranes.

    “Although we observed a modest, non‐significant increase in lipid droplet formation in APOE3‐Ch astrocytes under physiological conditions, Cers are predominantly localized to cellular membranes. 39”

    From Protective mechanisms against Alzheimer's disease in APOE3‐Christchurch homozygous astrocytes (2025) · cites this paper as [39]

    The Results section (“DGAT2 Produces Acylceramide at Lipid Droplets”; page not provided) locates CerS6, a ceramide-synthesizing enzyme, on ER membranes in control cells and lipid-droplet membranes after oleate loading. The Discussion describes acylceramide storage in lipid droplets, but neither passage establishes where ceramides themselves are predominantly localized. Searches for ceramide membrane localization and membrane-versus-droplet distribution found no decisive passage. (LLM, conf=0.74)

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Research works printed but not linked: 52

  1. Atilla-Gokcumen GE Muro E Relat-Goberna J Sasse S Bedigian A Coughlin ML Garcia-Manyes S Eggert US 2014 Dividing cells regulate their lipid composition and localization Cell 156 428 439 24462247 PMC3909459
  2. Beverly LJ Howell LA Hernandez-Corbacho M Casson L Chipuk JE Siskind LJ 2013 BAK activation is necessary and sufficient to drive ceramide synthase-dependent ceramide accumulation following inhibition of BCL2-like proteins The Biochemical journal 452 111 119 23480852 PMC3642864
  3. Bielawski J Szulc ZM Hannun YA Bielawska A 2006 Simultaneous quantitative analysis of bioactive sphingolipids by high-performance liquid chromatography-tandem mass spectrometry Methods 39 82 91 16828308
  4. Brasaemle DL Dolios G Shapiro L Wang R 2004 Proteomic analysis of proteins associated with lipid droplets of basal and lipolytically stimulated 3T3-L1 adipocytes The Journal of biological chemistry 279 46835 46842 15337753
  5. Bu SY Mashek DG 2010 Hepatic long-chain acyl-CoA synthetase 5 mediates fatty acid channeling between anabolic and catabolic pathways Journal of lipid research 51 3270 3280 20798351 PMC2952567
  6. Buhman KK Smith SJ Stone SJ Repa JJ Wong JS Knapp FF Jr Burri BJ Hamilton RL Abumrad NA Farese RV Jr 2002 DGAT1 is not essential for intestinal triacylglycerol absorption or chylomicron synthesis The Journal of biological chemistry 277 25474 25479 11959864
  7. Farese RV Jr Walther TC 2009 Lipid droplets finally get a little R-E-S-P-E-C-T Cell 139 855 860 19945371 PMC3097139
  8. Fujimoto Y Itabe H Kinoshita T Homma KJ Onoduka J Mori M Yamaguchi S Makita M Higashi Y Yamashita A 2007 Involvement of ACSL in local synthesis of neutral lipids in cytoplasmic lipid droplets in human hepatocyte HuH7 Journal of lipid research 48 1280 1292 17379924
  9. Futatsugi K Kung DW Orr ST Cabral S Hepworth D Aspnes G Bader S Bian J Boehm M Carpino PA 2015 Discovery and Optimization of Imidazopyridine-Based Inhibitors of Diacylglycerol Acyltransferase 2 (DGAT2) Journal of medicinal chemistry 58 7173 7185 26349027
  10. Grevengoed TJ Klett EL Coleman RA 2014 Acyl-CoA metabolism and partitioning Annual review of nutrition 34 1 30 PMC5881898 24819326
  11. Hannun YA Obeid LM 2008 Principles of bioactive lipid signalling: lessons from sphingolipids. Nature reviews Molecular cell biology 9 139 150 18216770
  12. Hannun YA Obeid LM 2011 Many ceramides The Journal of biological chemistry 286 27855 27862 21693702 PMC3151029
  13. Harris CA Haas JT Streeper RS Stone SJ Kumari M Yang K Han X Brownell N Gross RW Zechner R 2011 DGAT enzymes are required for triacylglycerol synthesis and lipid droplets in adipocytes Journal of lipid research 52 657 667 21317108 PMC3284159
  14. Hsieh K Lee YK Londos C Raaka BM Dalen KT Kimmel AR 2012 Perilipin family members preferentially sequester to either triacylglycerol-specific or cholesteryl-ester-specific intracellular lipid storage droplets Journal of cell science 125 4067 4076 22685330 PMC3482316
  15. Jensen SA Calvert AE Volpert G Kouri FM Hurley LA Luciano JP Wu Y Chalastanis A Futerman AH Stegh AH 2014 Bcl2L13 is a ceramide synthase inhibitor in glioblastoma Proceedings of the National Academy of Sciences of the United States of America 111 5682 5687 24706805 PMC3992626
  16. Jin Y McFie PJ Banman SL Brandt C Stone SJ 2014 Diacylglycerol Acyltransferase-2 (DGAT2) and Monoacylglycerol Acyltransferase-2 (MGAT2) Interact to Promote Triacylglycerol Synthesis The Journal of biological chemistry 289 28237 28248 25164810 PMC4192479
  17. Krahmer N Hilger M Kory N Wilfling F Stoehr G Mann M Farese RV Jr Walther TC 2013 Protein correlation profiles identify lipid droplet proteins with high confidence Molecular & cellular proteomics: MCP 12 1115 1126 23319140 PMC3650325
  18. Laviad EL Kelly S Merrill AH Jr Futerman AH 2012 Modulation of ceramide synthase activity via dimerization The Journal of biological chemistry 287 21025 21033 22539345 PMC3375526
  19. Li LO Klett EL Coleman RA 2010 Acyl-CoA synthesis, lipid metabolism and lipotoxicity Biochimica et biophysica acta 1801 246 251 19818872 PMC2824076
  20. Liu L Trent CM Fang X Son NH Jiang H Blaner WS Hu Y Yin YX Farese RV Jr Homma S 2014 Cardiomyocyte-specific loss of diacylglycerol acyltransferase 1 (DGAT1) reproduces the abnormalities in lipids found in severe heart failure The Journal of biological chemistry 289 29881 29891 25157099 PMC4207999
  21. Mashima T Sato S Okabe S Miyata S Matsuura M Sugimoto Y Tsuruo T Seimiya H 2009 Acyl-CoA synthetase as a cancer survival factor: its inhibition enhances the efficacy of etoposide Cancer science 100 1556 1562 19459852 PMC11158289
  22. McFie PJ Jin Y Banman SL Beauchamp E Berthiaume LG Stone SJ 2014 Characterization of the interaction of diacylglycerol acyltransferase-2 with the endoplasmic reticulum and lipid droplets Biochimica et biophysica acta 1841 1318 1328 24953780
  23. McFie PJ Stone SJ 2011 A fluorescent assay to quantitatively measure in vitro acyl CoA:diacylglycerol acyltransferase activity Journal of lipid research 52 1760 1764 21653930 PMC3151697
  24. Min J Mesika A Sivaguru M Van Veldhoven PP Alexander H Futerman AH Alexander S 2007 (Dihydro)ceramide synthase 1 regulated sensitivity to cisplatin is associated with the activation of p38 mitogen-activated protein kinase and is abrogated by sphingosine kinase 1 Molecular cancer research: MCR 5 801 812 17699106
  25. Monetti M Levin MC Watt MJ Sajan MP Marmor S Hubbard BK Stevens RD Bain JR Newgard CB Farese RV Sr 2007 Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver Cell metabolism 6 69 78 17618857
  26. Mullen TD Hannun YA Obeid LM 2012 Ceramide synthases at the centre of sphingolipid metabolism and biology The Biochemical journal 441 789 802 22248339 PMC3689921
  27. Mullen TD Jenkins RW Clarke CJ Bielawski J Hannun YA Obeid LM 2011 Ceramide synthase-dependent ceramide generation and programmed cell death: involvement of salvage pathway in regulating postmitochondrial events The Journal of biological chemistry 286 15929 15942 21388949 PMC3091202
  28. Okabe H Kishimoto Y 1977 In vivo metabolism of ceramides in rat brain. Fatty acid replacement and esterification of ceramide The Journal of biological chemistry 252 7068 7073 903352
  29. Olzmann JA Richter CM Kopito RR 2013 Spatial regulation of UBXD8 and p97/VCP controls ATGL-mediated lipid droplet turnover Proceedings of the National Academy of Sciences of the United States of America 110 1345 1350 23297223 PMC3557085
  30. Park JW Park WJ Futerman AH 2014 Ceramide synthases as potential targets for therapeutic intervention in human diseases Biochimica et biophysica acta 1841 671 681 24021978
  31. Poppelreuther M Rudolph B Du C Grossmann R Becker M Thiele C Ehehalt R Fullekrug J 2012 The N-terminal region of acyl-CoA synthetase 3 is essential for both the localization on lipid droplets and the function in fatty acid uptake Journal of lipid research 53 888 900 22357706 PMC3329388
  32. Qi W Fitchev PS Cornwell ML Greenberg J Cabe M Weber CR Roy HK Crawford SE Savkovic SD 2013 FOXO3 growth inhibition of colonic cells is dependent on intraepithelial lipid droplet density The Journal of biological chemistry 288 16274 16281 23603907 PMC3675566
  33. Raichur S Wang ST Chan PW Li Y Ching J Chaurasia B Dogra S Ohman MK Takeda K Sugii S 2014 CerS2 Haploinsufficiency Inhibits beta-Oxidation and Confers Susceptibility to Diet-Induced Steatohepatitis and Insulin Resistance Cell metabolism 20 687 695 25295789
  34. Realini N Solorzano C Pagliuca C Pizzirani D Armirotti A Luciani R Costi MP Bandiera T Piomelli D 2013 Discovery of highly potent acid ceramidase inhibitors with in vitro tumor chemosensitizing activity Scientific reports 3 1035 23301156 PMC3539145
  35. Russo SB Baicu CF Van Laer A Geng T Kasiganesan H Zile MR Cowart LA 2012 Ceramide synthase 5 mediates lipid-induced autophagy and hypertrophy in cardiomyocytes The Journal of clinical investigation 122 3919 3930 23023704 PMC3484448
  36. Senkal CE Ponnusamy S Rossi MJ Bialewski J Sinha D Jiang JC Jazwinski SM Hannun YA Ogretmen B 2007 Role of human longevity assurance gene 1 and C18-ceramide in chemotherapy-induced cell death in human head and neck squamous cell carcinomas Molecular cancer therapeutics 6 712 722 17308067
  37. Siskind LJ Mullen TD Romero Rosales K Clarke CJ Hernandez-Corbacho MJ Edinger AL Obeid LM 2010 The BCL-2 protein BAK is required for long-chain ceramide generation during apoptosis The Journal of biological chemistry 285 11818 11826 20172858 PMC2852918
  38. Soupene E Kuypers FA 2008 Mammalian long-chain acyl-CoA synthetases Experimental biology and medicine 233 507 521 18375835 PMC3377585
  39. Stone SJ Levin MC Farese RV Jr 2006 Membrane topology and identification of key functional amino acid residues of murine acyl-CoA:diacylglycerol acyltransferase-2 The Journal of biological chemistry 281 40273 40282 17035227
  40. Stone SJ Myers HM Watkins SM Brown BE Feingold KR Elias PM Farese RV Jr 2004 Lipopenia and skin barrier abnormalities in DGAT2-deficient mice The Journal of biological chemistry 279 11767 11776 14668353
  41. Takagi Y Nakagawa H Matsuo N Nomura T Takizawa M Imokawa G 2004 Biosynthesis of acylceramide in murine epidermis: characterization by inhibition of glucosylation and deglucosylation, and by substrate specificity The Journal of investigative dermatology 122 722 729 15086559
  42. Turpin SM Nicholls HT Willmes DM Mourier A Brodesser S Wunderlich CM Mauer J Xu E Hammerschmidt P Bronneke HS 2014 Obesity-Induced CerS6-Dependent C16:0 Ceramide Production Promotes Weight Gain and Glucose Intolerance Cell metabolism 20 678 686 25295788
  43. Vallee B Riezman H 2005 Lip1p: a novel subunit of acyl-CoA ceramide synthase The EMBO journal 24 730 741 15692566 PMC549621
  44. Voynova NS Vionnet C Ejsing CS Conzelmann A 2012 A novel pathway of ceramide metabolism in Saccharomyces cerevisiae The Biochemical journal 447 103 114 22738231
  45. Watkins PA Maiguel D Jia Z Pevsner J 2007 Evidence for 26 distinct acyl-coenzyme A synthetase genes in the human genome Journal of lipid research 48 2736 2750 17762044
  46. White-Gilbertson S Mullen T Senkal C Lu P Ogretmen B Obeid L Voelkel-Johnson C 2009 Ceramide synthase 6 modulates TRAIL sensitivity and nuclear translocation of active caspase-3 in colon cancer cells Oncogene 28 1132 1141 19137010 PMC2648838
  47. Wilfling F Wang H Haas JT Krahmer N Gould TJ Uchida A Cheng JX Graham M Christiano R Frohlich F 2013 Triacylglycerol synthesis enzymes mediate lipid droplet growth by relocalizing from the ER to lipid droplets Developmental cell 24 384 399 23415954 PMC3727400
  48. Wu X Li Y Wang J Wen X Marcus MT Daniels G Zhang DY Ye F Wang LH Du X 2013 Long chain fatty Acyl-CoA synthetase 4 is a biomarker for and mediator of hormone resistance in human breast cancer PloS one 8 e77060 24155918 PMC3796543
  49. Xu N Zhang SO Cole RA McKinney SA Guo F Haas JT Bobba S Farese RV Jr Mak HY 2012 The FATP1-DGAT2 complex facilitates lipid droplet expansion at the ER-lipid droplet interface The Journal of cell biology 198 895 911 22927462 PMC3432760
  50. Yen CL Brown CHT Monetti M Farese RV Jr 2005a A human skin multifunctional O-acyltransferase that catalyzes the synthesis of acylglycerols, waxes, and retinyl esters Journal of lipid research 46 2388 2397 16106050 PMC1540095
  51. Yen CL Monetti M Burri BJ Farese RV Jr 2005b The triacylglycerol synthesis enzyme DGAT1 also catalyzes the synthesis of diacylglycerols, waxes, and retinyl esters Journal of lipid research 46 1502 1511 15834126
  52. Yue S Li J Lee SY Lee HJ Shao T Song B Cheng L Masterson TA Liu X Ratliff TL 2014 Cholesteryl ester accumulation induced by PTEN loss and PI3K/AKT activation underlies human prostate cancer aggressiveness Cell metabolism 19 393 406 24606897 PMC3969850

Cited by

Sorted by citations

Authors
Senkal, C. E., Salama, M. F., Snider, A. J., Allopenna, J. J., Rana, N. A., Koller, A., Hannun, Y. A., & Obeid, L. M.
Affiliations
  • Stony Brook University (US)
  • Mansoura University (EG)
  • Northport VA Medical Center (US)
  • Stony Brook Medicine (US)
Corresponding author
Obeid, Lina M.
ORCID
Venue
Cell Metabolism
Publisher
Elsevier BV
Published
2017-03
Volume
25
Issue
3
Pages
686-697
ISSN
1550-4131 (ISSN-L)
DOI
10.1016/j.cmet.2017.02.010
PMC
PMC5472424
OpenAlex
W2591604204
Cited by
237
References
4
Citations by year
2026: 14 · 2025: 28 · 2024: 30 · 2023: 26 · 2022: 20 · 2021: 38 · 2020: 31 · 2019: 24 · 2018: 18 · 2017: 8
FWCI
8.82
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Metabolism (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • NIH (F32GM108384, GM062887, P01CA097132)
  • Veterans Affairs Merit Award (5I01BX000156)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Keywords
ceramide metabolism, acylceramides, lipid droplets, ceramide synthase, ACSL5, fatty acyl-CoA, DGAT2, sphingolipid metabolism, triglyceride metabolism, high-fat diet, liver
MeSH terms
Protein Domains, Acylation, Animals, Ceramides, Coenzyme A Ligases, Feeding Behavior, Humans, Liver, Mice, Inbred C57BL, Oxidoreductases, Substrate Specificity, Gene Silencing, HCT116 Cells, Diacylglycerol O-Acyltransferase, Diet, High-Fat, Lipid Droplets

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