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Genetic and Metabolic Determinants of Fatty Acid Chain Length and Desaturation, Their Incorporation into Lipid Classes and Their Effects on Risk of Vascular and Metabolic Disease

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Abstract

Chronic fatty acid overload is a major determinant of vascular and metabolic diseases associated with excess western diet and sedentary lifestyle. Beyond the complex traits behind diabetes and obesity (diabesity), a number of rare genetic disorders related to mitochondrial and peroxisomal function and metabolic myopathies directly affect fatty acid metabolism. The detailed molecular analysis of these disorders will provide deeper insight into the genetic and metabolic determinants of lipid metabolism. Fatty acids are either synthesized de novo or taken up as nutrients. The elongation and desaturation of fatty acids follows several distinct pathways regulated by desaturases and elongases. Unsaturated fatty acids are precursors for prostanoid synthesis, which have pro- and anti-inflammatory or -aggregatory and -proliferative effects. Fatty acids are differentially incorporated into acylglycerols, cholesterylesters, glycerophospholipids and sphingolipids, with the latter being major membrane constituents but are also involved in signalling and metabolic regulation. Fatty acid b-oxidation in mitochondria provides energy. Thus, fatty acid metabolism is the result of the complex interaction of synthesis, remodelling and b-oxidation with some minor lipid species being involved in signalling and other regulatory mechanisms.

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References

  1. Giacco F, Brownlee M (2010) Oxidative stress and diabetic complications. Circ Res 107(9):1058–1070

    PubMed  CAS  Google Scholar 

  2. Jump DB (2011) Fatty acid regulation of hepatic lipid metabolism. Curr Opin Clin Nutr Metab Care 14(2):115–120

    PubMed  CAS  Google Scholar 

  3. Smith S, Witkowski A, Joshi AK (2003) Structural and functional organization of the animal fatty acid synthase. Prog Lipid Res 42(4):289–317

    PubMed  CAS  Google Scholar 

  4. Chirala SS, Wakil SJ (2004) Structure and function of animal fatty acid synthase. Lipids 39(11):1045–1053

    PubMed  CAS  Google Scholar 

  5. Swinnen J, Brusselmans K, Verhoeven G (2006) Increased lipigenesis in cancer: new players, novel targets. Curr Opin Clin Nutr Metab Care 9:358–365

    PubMed  CAS  Google Scholar 

  6. Turyn J et al (2003) Increased activity of glycerol 3-phosphate dehydrogenase and other lipigenic enzymes in human bladder cancer. Horm Metab Res 35:565–569

    PubMed  CAS  Google Scholar 

  7. Kuhajda FP (2000) Fatty acid synthase and human cancer: new perspectives on its role in tumor biology. Nutrition 16:202–208

    PubMed  CAS  Google Scholar 

  8. Dowell P, Hu Z, Lane MD (2005) Monitoring energy balance: metabolites of fatty acid synthesis as hypothalamic sensors. Annu Rev Biochem 74:515–534

    PubMed  CAS  Google Scholar 

  9. Munday MR (2002) Regulation of mammalian acetyl-CoA carboxylase. Biochem Soc Trans 30(Pt 6):1059–1064

    PubMed  CAS  Google Scholar 

  10. Brownsey RW, Boone AN, Elliott JE, Kulpa JE, Lee WM (2006) Regulation of acetyl-CoA carboxylase. Biochem Soc Trans 34(Pt 2):223–227

    PubMed  CAS  Google Scholar 

  11. Adida A, Spener F (2002) Intracellular lipid binding proteins and nuclear receptors involved in branched-chain fatty acid signaling. Prostaglandins Leukot Essent Fatty Acids 67(2–3):91–98

    PubMed  CAS  Google Scholar 

  12. Kurzchalia TV, Entchev EV, Schwudke D, Zagoriy V, Matyash V, Bogdanova A, Habermann B et al (2008) LET-767 is required for the production of branched chain and long chain fatty acids in Caenorhabditis elegans. J Biol Chem 283(25):17550–17560

    PubMed  Google Scholar 

  13. Mitchell GA, Kassovska-Bratinova S, Boukaftane Y, Robert MF, Wang SP, Ashmarina L et al (1995) Medical aspects of ketone body metabolism. Clin Invest Med 18(3):193–216

    PubMed  CAS  Google Scholar 

  14. Neely JR, Rovetto MJ, Oram JF (1972) Myocardial utilization of carbohydrate and lipids. Prog Cardiovasc Dis 15:289–329

    PubMed  CAS  Google Scholar 

  15. McGarry JD, Brown NF (1997) The mitochondrial carnitine palmitoyltransferase system. From concept to molecular analysis. Eur J Biochem 244:1–14

    PubMed  CAS  Google Scholar 

  16. Kerner J, Hoppel C (2000) Fatty acid import into mitochondria. Biochim Biophys Acta 1486:1–17

    PubMed  CAS  Google Scholar 

  17. Lea W, Abbas AS, Sprecher H, Vockley J, Schulz H (2000) Longchain acyl-CoA dehydrogenase is a key enzyme in the mitochondrial beta-oxidation of unsaturated fatty acids. Biochim Biophys Acta 1485:121–128

    PubMed  CAS  Google Scholar 

  18. Kamijo T, Aoyama T, Komiyama A, Hashimoto T (1994) Structural analysis of cDNAs for subunits of human mitochondrial fatty acid beta-oxidation trifunctional protein. Biochem Biophys Res Commun 199:818–825

    PubMed  CAS  Google Scholar 

  19. Eaton S, Bartlett K, Pourfarzam M (1996) Mammalian mitochondrial beta-oxidation. Biochem J 320(Pt 2):345–357

    PubMed  CAS  Google Scholar 

  20. Wanders RJ, Vreken P, den Boer ME, Wijburg FA, van Gennip AH, Ijlst L (1999) Disorders of mitochondrial fatty acyl-CoA beta-oxidation. J Inherit Metab Dis 22:442–487

    PubMed  CAS  Google Scholar 

  21. Wenz T, Hielscher R, Hellwig P, Schagger H, Richers S, Hunte C (2009) Role of phospholipids in respiratory cytochrome bc(1) complex catalysis and supercomplex formation. Biochim Biophys Acta 1787(6):609–616

    PubMed  CAS  Google Scholar 

  22. McKenzie M, Lazarou M, Thorburn DR, Ryan MT (2006) Mitochondrial respiratory chain supercomplexes are destabilized in Barth Syndrome patients. J Mol Biol 361(3):462–469

    PubMed  CAS  Google Scholar 

  23. Knights KM (1998) Role of hepatic fatty acid: coenzyme A ligases in the metabolism of xenobiotic carboxylic acids. Clin Exp Pharmacol Physiol 25(10):776–782

    PubMed  CAS  Google Scholar 

  24. Mukherji M, Schofield CJ, Wierzbicki AS, Jansen GA, Wanders RJ, Lloyd MD (2003) The chemical biology of branched-chain lipid metabolism. Prog Lipid Res 42(5):359–376

    PubMed  CAS  Google Scholar 

  25. Glaser C, Lattka E, Rzehak P, Steer C, Koletzko B (2011) Genetic variation in polyunsaturated fatty acid metabolism and its potential relevance for human development and health. Matern Child Nutr 7(Suppl 2):27–40

    PubMed  Google Scholar 

  26. Jeffrey BG, Weisingerb HS, Neuringer M, Mitcheli DC (2001) The role of docosahexaenoic acid in retinal function. Lipids 36:859–871

    PubMed  CAS  Google Scholar 

  27. Salem N Jr, Litman B, Kim HY, Gawrisch K (2001) Mechanisms of action of docosahexaenoic acid in the nervous system. Lipids 36:945–959

    PubMed  CAS  Google Scholar 

  28. Uauy R et al (2001) Essential fatty acids in visual and brain development. Lipids 36:885–895

    PubMed  CAS  Google Scholar 

  29. Brash AR (2001) Arachidonic acid as a bioactive molecule. J Clin Invest 107:1339–1345

    PubMed  CAS  Google Scholar 

  30. Osumi N (2010) Fatty acid signal, neurogenesis, and psychiatric disorders. Nihon Shinkei Seishin Yakurigaku Zasshi 30(3):141–148

    PubMed  CAS  Google Scholar 

  31. Fitzpatrick FA, Soberman R (2001) Regulated formation of eicosanoids. J Clin Invest 107:1347–1351

    PubMed  CAS  Google Scholar 

  32. Zhou L, Nilsson A (2001) Sources of eicosanoid precursor fatty acid pools in tissues. J Lipid Res 42:1521–1542

    PubMed  CAS  Google Scholar 

  33. Szefel J, Piotrowska M, Kruszewski WJ, Jankun J, Lysiak-Szydlowska W, Skrzypczak-Jankun E (2011) Eicosanoids in prevention and management of diseases. Curr Mol Med 11(1):13–25

    PubMed  CAS  Google Scholar 

  34. Toborek M, Lee YW, Kaiser S, Hennig B (2002) Measurement of inflammatory properties of fatty acids in human endothelial cells. Methods Enzymol 352:198–219

    PubMed  CAS  Google Scholar 

  35. Lauritzen I et al (2000) Polyunsaturated fatty acids are potent neuroprotectors. EMBO J 19:1784–1793

    PubMed  CAS  Google Scholar 

  36. Bousquet M, Gibrat C, Saint-Pierre M, Julien C, Calon F, Cicchetti F (2009) Modulation of brain-derived neurotrophic factor as a potential neuroprotective mechanism of action of omega-3 fatty acids in a parkinsonian animal model. Prog Neuropsychopharmacol Biol Psychiatry 33(8):1401–1408, 13

    PubMed  CAS  Google Scholar 

  37. Kelley DS (2001) Modulation of human immune and inflammatory responses by dietary fatty acids. Nutrition 17:669–673

    PubMed  CAS  Google Scholar 

  38. Stables MJ, Gilroy DW (2011) Old and new generation lipid mediators in acute inflammation and resolution. Prog Lipid Res 50(1):35–51

    PubMed  CAS  Google Scholar 

  39. Dewailly E et al (2001) n-3 fatty acids and cardiovascular disease risk factors among the Inuit of Nunavik. Am J Clin Nutr 74:464–473

    PubMed  CAS  Google Scholar 

  40. Martinez M (2001) Restoring the DHA levels in the brains of Zellweger patients. J Mol Neurosci 16:309–316

    PubMed  CAS  Google Scholar 

  41. Ferdinandusse S, Jansen GA, Waterham HR, van Roermund CW et al (2001) Peroxisomal fatty acid alpha- and beta-oxidation in humans: enzymology, peroxisomal metabolite transporters and peroxisomal diseases. Biochem Soc Trans 29(Pt 2):250–267

    PubMed  Google Scholar 

  42. Sprecher H, Chen Q, Yin FQ (1999) Regulation of the biosynthesis of 22:5n-6 and 22:6n-3: a complex intracellular process. Lipids 34:S153–S156

    PubMed  CAS  Google Scholar 

  43. Broughton KS, Wade JW (2002) Total fat and (n-3:n-6) fat ratios influence eicosanoid production in mice. J Nutr 132:88–94

    PubMed  CAS  Google Scholar 

  44. Fischer SM, Cameron GS, Baldwin JK, Jasheway DW, Patrick KE, Belury MA (1989) The arachidonic acid cascade and multistage carcinogenesis in mouse skin. Prog Clin Biol Res 298:249–264

    PubMed  CAS  Google Scholar 

  45. Zechner R, Kienesberger PC, Haemmerle G, Zimmermann R, Lass A (2009) Adipose triglyceride lipase and the lipolytic catabolism of cellular fat stores. J Lipid Res 50(1):3–21

    PubMed  CAS  Google Scholar 

  46. Watt MJ, Steinberg GR (2008) Regulation and function of triacylglycerol lipases in cellular metabolism. Biochem J 414(3):313–325

    PubMed  CAS  Google Scholar 

  47. Kimmel AR, Brasaemle DL, McAndrews-Hill M, Sztalryd C, Londos C (2010) Adoption of PERILIPIN as a unifying nomenclature for the mammalian PAT-family of intracellular lipid storage droplet proteins. J Lipid Res 51(3):468–471

    PubMed  CAS  Google Scholar 

  48. Paul A, Chan L, Bickel PE (2008) The PAT family of lipid droplet proteins in heart and vascular cells. Curr Hypertens Rep 10(6):461–466

    PubMed  CAS  Google Scholar 

  49. Kudo I, Murakami M (2002) Phospholipase A2 enzymes. Prostaglandins Other Lipid Mediat 68–69:3–58

    PubMed  Google Scholar 

  50. Akiba S, Sato T (2004) Cellular function of calcium-independent phospholipase A2. Biol Pharm Bull 27(8):1174–1178

    PubMed  CAS  Google Scholar 

  51. Ravichandran KS, Lorenz U (2007) Engulfment of apoptotic cells: signals for a good meal. Nat Rev Immunol 7(12):964–974

    PubMed  CAS  Google Scholar 

  52. Gao S et al (2006) Phospholipid hydroxyalkenals, a subset of recently discovered endogenous CD36 ligands, spontaneously generate novel furan-containing phospholipids lacking CD36 binding activity in vivo. J Biol Chem 281(42):31298–31308

    PubMed  CAS  Google Scholar 

  53. Botchkarev VA et al (1997) A simple immunofluorescence technique for simultaneous visualization of mast cells and nerve fibers reveals selectivity and hair cycle-dependent changes in mast cell-nerve fiber contacts in murine skin. Arch Dermatol Res 289(5):292–302

    PubMed  CAS  Google Scholar 

  54. Ulmer JB, Donnelly JJ, Liu MA (1994) Presentation of an exogenous antigen by major histocompatibility complex class I molecules. Eur J Immunol 24(7):1590–1596

    PubMed  CAS  Google Scholar 

  55. Burger KN, Demel RA, Schmid SL, de Kruijff B (2000) Dynamin is membrane-active: lipid insertion is induced by phosphoinositides and phosphatidic acid. Biochemistry 39:12485–12493

    PubMed  CAS  Google Scholar 

  56. Arneson LS, Kunz J, Anderson RA, Traub LM (1999) Coupled inositide phosphorylation and phospholipase D activation initiates clathrin-coat assembly on lysosomes. J Biol Chem 274:17794–17805

    PubMed  CAS  Google Scholar 

  57. Schmidt A, Wolde M, Thiele C, Fest W, Kratzin H, Podtelejnikov AV, Witke W, Huttner WB, Huttner HD (1999) Endophilin I mediates synaptic vesicle formation by transfer of arachidonate to lysophosphatidic acid. Nature 401:133–141

    PubMed  CAS  Google Scholar 

  58. Bi K, Roth MG, Ktistakis NT (1997) Phosphatidic acid formation by phospholipase D is required for transport from the endoplasmic reticulum to the Golgi complex. Curr Biol 7:301–307

    PubMed  CAS  Google Scholar 

  59. Chen YG, Siddhanta A, Austin CD, Hammond SM, Sung TC, Frohman MA, Morris AJ, Shields D (1997) Phospholipase D stimulates release of nascent secretory vesicles from the trans-Golgi network. J Cell Biol 138:495–504

    PubMed  CAS  Google Scholar 

  60. Weigert R et al (1999) CtBP/BARS induces fission of Golgi membranes by acylating lysophosphatidic acid. Nature 402:429–433

    PubMed  CAS  Google Scholar 

  61. Siddhanta DS (1998) Secretory vesicle budding from the trans-Golgi network is mediated by phosphatidic acid levels. J Biol Chem 273:17995–17998

    PubMed  CAS  Google Scholar 

  62. Huttner WB, Schmidt A (2000) Lipids, lipid modification and lipid-protein interaction in membrane budding and fission–insights from the roles of endophilin A1 and synaptophysin in synaptic vesicle endocytosis. Curr Opin Neurobiol 10:543–551

    PubMed  CAS  Google Scholar 

  63. Fang Y, Vilella-Bach M, Bachmann R, Flanigan A, Chen J (2001) Phosphatidic acid-­mediated mitogenic activation of mTOR signaling. Science 294:1942–1945

    PubMed  CAS  Google Scholar 

  64. Ghosh S, Strum JC, Sciorra VA, Daniel L, Bell RM (1996) Raf-1 kinase possesses distinct binding domains for phosphatidylserine and phosphatidic acid. Phosphatidic acid regulates the translocation of Raf-1 in 12-O-tetradecanoylphorbol-13-acetate-stimulated Madin-Darby canine kidney cells. J Biol Chem 271:8472–8480

    PubMed  CAS  Google Scholar 

  65. Rizzo MA, Shome K, Watkins SC, Romero G (2000) The recruitment of Raf-1 to membranes is mediated by direct interaction with phosphatidic acid and is independent of association with Ras. J Biol Chem 275(31):23911–23918

    PubMed  CAS  Google Scholar 

  66. Erickson RW, Langel-Peveri P, Traynor-Kaplan AE, Heyworth PG, Curnutte JT (1999) Activation of human neutrophil NADPH oxidase by phosphatidic acid or diacylglycerol in a cell-free system. Activity of diacylglycerol is dependent on its conversion to phosphatidic acid. Biol Chem 274:22243–22250

    CAS  Google Scholar 

  67. Waite KA, Wallin R, Qualliotine-Mann D, McPhail LC (1997) Phosphatidic acid-mediated phosphorylation of the NADPH oxidase component p47-phox. Evidence that phosphatidic acid may activate a novel protein kinase. J Biol Chem 272(24):15569–15578

    PubMed  CAS  Google Scholar 

  68. Manifava M, Thuring JW, Lim ZY, Packman L, Holmes AB, Ktistakis NT (2001) Differential binding of traffic-related proteins to phosphatidic acid- or phosphatidylinositol (4,5)- bisphosphate-coupled affinity reagents. J Biol Chem 276(12):8987–8994

    PubMed  CAS  Google Scholar 

  69. Williger BT, Ho WT, Exton JH (1999) Phospholipase D mediates matrix metalloproteinase-9 secretion in phorbol ester-stimulated human fibrosarcoma cells. J Biol Chem 274:735–738

    PubMed  CAS  Google Scholar 

  70. Choi JW et al (2010) LPA Receptors: subtypes and biological actions. Annu Rev Pharmacol 50:157–186

    CAS  Google Scholar 

  71. Hama K, Aoki J (2010) LPA3, a unique G protein-coupled receptor for lysophosphatidic acid. Prog Lipid Res 49:335–342

    PubMed  CAS  Google Scholar 

  72. Bartke N, Hannun YA (2009) Bioactive sphingolipids: metabolism and function. J Lipid Res 50(Suppl):91–96

    Google Scholar 

  73. Merrill AH (2002) De novo sphingolipid biosynthesis: a necessary, but dangerous, pathway. J Biol Chem 277:25843–25846

    PubMed  CAS  Google Scholar 

  74. Rao RP, Acharya JK (2008) Sphingolipids and membrane biology as determined from genetic models. Prostaglandins Other Lipid Mediat 85:1–16

    PubMed  CAS  Google Scholar 

  75. Hannun YA, Luberto C, Argraves KM (2001) Enzymes of sphingolipid metabolism: from modular to integrative signaling. Biochem J 40:4893–4903

    CAS  Google Scholar 

  76. Maceyka M et al (2005) SphK1 and SphK2, sphingosine kinase isoenzymes with opposing functions in sphingolipid metabolism. J Biol Chem 280:37118–37129

    PubMed  CAS  Google Scholar 

  77. Hornemann T, Wei Y, von Eckardstein A (2007) Is the mammalian serine palmitoyltransferase a high-molecular-mass complex? Biochem J 405(1):157–164

    PubMed  CAS  Google Scholar 

  78. Hornemann T, Penno A, Rütti MF, Ernst D, Kivrak-Pfiffner F, Rohrer L, von Eckardstein A (2009) The SPTLC3 subunit of serine palmitoyltransferase generates short chain sphingoid bases. J Biol Chem 284:26322–26330

    PubMed  CAS  Google Scholar 

  79. Rotthier A et al (2011) Characterization of two mutations in the SPTLC1 subunit of serine palmitoyltransferase associated with hereditary sensory and autonomic neuropathy type I. Hum Mutat 32:E2211–E2225

    PubMed  CAS  Google Scholar 

  80. Penno A et al (2010) Hereditary sensory neuropathy type 1 is caused by the accumulation of two neurotoxic sphingolipids. J Biol Chem 285:11178–11187

    PubMed  CAS  Google Scholar 

  81. Zitomer NC, Mitchell T, Voss KA, Bondy GS, Pruett ST, Garnier-Amblard EC et al (2009) Ceramide synthase inhibition by fumonisin B1 causes accumulation of 1-deoxysphinganine: a novel category of bioactive 1-deoxysphingoid bases and 1-deoxydihydroceramides biosynthesized by mammalian cell lines and animals. J Biol Chem 284(8):4786–4795

    PubMed  CAS  Google Scholar 

  82. Cowart LA, Hannun YA (2007) Selective substrate supply in the regulation of yeast de novo sphingolipid synthesis. J Biol Chem 282:12330–12340

    PubMed  CAS  Google Scholar 

  83. Holland WL, Summers SA (2008) Sphingolipids, insulin resistance, and metabolic disease: new insights from in vivo manipulation of sphingolipid metabolism. Endocr Rev 29:381–402

    PubMed  CAS  Google Scholar 

  84. Enomoto A, Omae F, Miyazaki M, Kozutsumi Y, Yubisui T, Suzuki A (2006) Dihydroceramide: sphinganine C-4-hydroxylation requires Des2 hydroxylase and the membrane form of cytochrome b5. Biochem J 397(2):289–295, 15

    PubMed  CAS  Google Scholar 

  85. Merrill AH, Sullards MC, Allegood JC, Kelly S, Wang E (2005) Sphingolipidomics: high-throughput, structure-specific, and quantitative analysis of sphingolipids by liquid chromatography tandem mass spectrometry. Methods 36:207–224

    PubMed  CAS  Google Scholar 

  86. Mizutani Y, Mitsutake S, Tsuji K, Kihara A, Igarashi Y (2009) Ceramide biosynthesis in keratinocyte and its role in skin function. Biochimie 91:784–790

    PubMed  CAS  Google Scholar 

  87. Van Meer G (2005) Cellular lipidomics. EMBO J 24:3159–3165

    PubMed  Google Scholar 

  88. Ohno Y, Suto S, Yamanaka M, Mizutani Y, Mitsutake S, Igarashi Y, Sassa T, Kihara A (2010) ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis. Proc Natl Acad Sci 107:18439–18444

    PubMed  CAS  Google Scholar 

  89. Sandhoff R (2010) Very long chain sphingolipids: tissue expression, function and synthesis. FEBS Lett 584:1907–1913

    PubMed  CAS  Google Scholar 

  90. Iwabuchi K et al (2008) Involvement of very long fatty acid-containing lactosylceramide in lactosylceramide-mediated superoxide generation and migration in neutrophils. Glycoconj J 25:357–374

    PubMed  CAS  Google Scholar 

  91. Oh CS, Toke DA, Mandala S, Martin CE (1997) ELO2 and ELO3, homologues of the saccharomyces cerevisiae ELO1 gene, function in fatty acid elongation and are required for sphingolipid formation. J Biol Chem 272:17376–17384

    PubMed  CAS  Google Scholar 

  92. McMahon A, Butovich IA, Kedzierski W (2011) Epidermal expression of an Elovl4 transgene rescues neonatal lethality of homozygous Stargardt disease-3 mice. J Lipid Res 52:1128–1138

    PubMed  CAS  Google Scholar 

  93. Hama H (2010) Fatty acid 2-Hydroxylation in mammalian sphingolipid biology. BBA Mol Cell Biol L 1801:405–414

    CAS  Google Scholar 

  94. Mizutani Y, Kihara A, Chiba H, Tojo H, Igarashi Y (2008) 2-Hydroxy-ceramide synthesis by ceramide synthase family: enzymatic basis for the preference of FA chain length. J Lipid Res 49:2356–2364

    PubMed  CAS  Google Scholar 

  95. Schaeren-Wiemers N, Van Der Bijl P, Schwab ME (1995) The UDP-galactose: ceramide galactosyltransferase: expression pattern in oligodendrocytes and schwann cells during myelination and substrate preference for hydroxyceramide. J Neurochem 65:2267–2278

    PubMed  CAS  Google Scholar 

  96. Jungersted JM, Hellgren LI, Jemec GBE, Agner T (2008) Lipids and skin barrier function − a clinical perspective. Contact Dermatitis 58:255–262

    PubMed  CAS  Google Scholar 

  97. Van Smeden J, Hoppel L, van der Heijden R, Hankemeier T, Vreeken RJ, Bouwstra JA (2011) LC/MS analysis of stratum corneum lipids: ceramide profiling and discovery. J Lipid Res 52:1211–1221

    PubMed  Google Scholar 

  98. Hu W, Ross JS, Geng T, Brice SE, Cowart LA (2011) Differential regulation of Dihydroceramide desaturase by palmitate vs. monounsaturated fatty acids: implications to insulin resistance. J Biol Chem 286:16596–16606

    PubMed  CAS  Google Scholar 

  99. Geeraert L, Mannaerts GP, van Veldhoven PP (1997) Conversion of dihydroceramide into ceramide: involvement of a desaturase. Biochem J 327:125–132

    PubMed  CAS  Google Scholar 

  100. Kudo N, Kumagai K, Tomishige N, Yamaji T, Wakatsuki S, Nishijima M, Hanada K, Kato R (2008) Structural basis for specific lipid recognition by CERT responsible for nonvesicular trafficking of ceramide. Proc Natl Acad Sci 105:488–493

    PubMed  CAS  Google Scholar 

  101. Yasuda S et al (2001) A novel inhibitor of ceramide trafficking from the endoplasmic reticulum to the site of sphingomyelin synthesis. J Biol Chem 276(47):43994–44002

    PubMed  CAS  Google Scholar 

  102. Tafesse FG, Ternes P, Holthuis JCM (2006) The multigenic sphingomyelin synthase family. J Biol Chem 281:29421–29425

    PubMed  CAS  Google Scholar 

  103. Yamaji T, Kumagai K, Tomishige N, Hanada K (2008) Two sphingolipid transfer proteins, CERT and FAPP2: their roles in sphingolipid metabolism. IUBMB Life 60:511–518

    PubMed  CAS  Google Scholar 

  104. Rao CS, Lin X, Pike HM, Molotkovsky JG, Brown RE (2004) Glycolipid transfer protein mediated transfer of glycosphingolipids between membranes: a model for action based on kinetic and thermodynamic analyses. Biochemistry 43(43):13805–13815

    PubMed  CAS  Google Scholar 

  105. Contreras F-X, Sánchez-Magraner L, Alonso A, Goñi FM (2010) Transbilayer (flip-flop) lipid motion and lipid scrambling in membranes. FEBS Lett 584:1779–1786

    PubMed  CAS  Google Scholar 

  106. Hisano Y, Kobayashi N, Kawahara A, Yamaguchi A, Nishi T (2011) The sphingosine 1-phosphate transporter, SPNS2, functions as a transporter of the phosphorylated form of the immunomodulating agent FTY720. J Biol Chem 286:1758–1766

    PubMed  CAS  Google Scholar 

  107. Gupta G, Surolia A (2010) Glycosphingolipids in microdomain formation and their spatial organization. FEBS Lett 584:1634–1641

    PubMed  CAS  Google Scholar 

  108. Nagao K, Takahashi K, Hanada K, Kioka N, Matsuo M, Ueda K (2007) Enhanced ApoA-I-dependent cholesterol efflux by ABCA1 from sphingomyelin-deficient chinese hamster ovary cells. J Biol Chem 282:14868–14874

    PubMed  CAS  Google Scholar 

  109. Cerbon J (2003) Diacylglycerol generated during sphingomyelin synthesis is involved in protein kinase C activation and cell proliferation in Madin-Darby canine kidney cells. Biochem J 373:917–924

    PubMed  CAS  Google Scholar 

  110. Meng A, Luberto C, Meier P, Bai A, Yang X, Hannun YA, Zhou D (2004) Sphingomyelin synthase as a potential target for D609-induced apoptosis in U937 human monocytic leukemia cells. Exp Cell Res 292:385–392

    PubMed  CAS  Google Scholar 

  111. Ding T, Li Z, Hailemariam T, Mukherjee S, Maxfield FR, Wu MP, Jiang XC (2008) SMS overexpression and knockdown: impact on cellular sphingomyelin and diacylglycerol metabolism, and cell apoptosis. J Lipid Res 49:376–385

    PubMed  CAS  Google Scholar 

  112. Iwabuchi K, Nakayama H, Iwahara C, Takamori K (2010) Significance of glycosphingolipid fatty acid chain length on membrane microdomain-mediated signal transduction. FEBS Lett 584:1642–1652

    PubMed  CAS  Google Scholar 

  113. Mullen TD, Jenkins RW, Clarke CJ, Bielawski J, Hannun YA, Obeid LM (2011) Ceramide synthase-dependent ceramide generation and programmed cell death. J Biol Chem 286:15929–15942

    PubMed  CAS  Google Scholar 

  114. Van Echten-Deckert G, Herget T (2006) Sphingolipid metabolism in neural cells. Biochim Biophys Acta 1758:1978–1994

    PubMed  Google Scholar 

  115. Xu Y-H, Barnes S, Sun Y, Grabowski GA (2010) Multi-system disorders of glycosphingolipid and ganglioside metabolism. J Lipid Res 51:1643–1675

    PubMed  CAS  Google Scholar 

  116. Hakomori S (2008) Structure and function of glycosphingolipids and sphingolipids: recollections and future trends. Biochim Biophys Acta 1780:325–346

    PubMed  CAS  Google Scholar 

  117. Regina Todeschini A, Hakomori S (2008) Functional role of glycosphingolipids and gangliosides in control of cell adhesion, motility, and growth, through glycosynaptic microdomains. Biochim Biophys Acta 1780:421–433

    PubMed  CAS  Google Scholar 

  118. Saito T, Hakomori SI (1971) Quantitative isolation of total glycosphingolipids from animal cells. J Lipid Res 12:257–259

    PubMed  CAS  Google Scholar 

  119. Kitatani K, Idkowiak-Baldys J, Hannun YA (2008) The sphingolipid salvage pathway in ceramide metabolism and signaling. Cell Signal 20:1010–1018

    PubMed  CAS  Google Scholar 

  120. Nilsson Å (2007) Sphingolipids in the gut? Which are the important issues? Eur J Lipid Sci Tech 109:971–976

    CAS  Google Scholar 

  121. Katsel P, Li C, Haroutunian V (2007) Gene expression alterations in the sphingolipid metabolism pathways during progression of dementia and alzheimer’s disease: a shift toward ceramide accumulation at the earliest recognizable stages of alzheimer’s disease? Neurochem Res 32:845–856

    PubMed  CAS  Google Scholar 

  122. Futerman AH, van Meer G (2004) The cell biology of lysosomal storage disorders. Nat Rev Mol Cell Biol 5:554–565

    PubMed  CAS  Google Scholar 

  123. Kolter T, Sandhoff K (2006) Sphingolipid metabolism diseases. Biochim Biophys Acta 1758:2057–2079

    PubMed  CAS  Google Scholar 

  124. Itagaki K, Hauser CJ (2003) Sphingosine 1-phosphate, a diffusible calcium influx factor mediating store-operated calcium entry. J Biol Chem 278:27540–27547

    PubMed  CAS  Google Scholar 

  125. Sabbadini RA (2011) Sphingosine-1-phosphate antibodies as potential agents in the treatment of cancer and age-related macular degeneration. Brit J Pharmacol 162:1225–1238

    CAS  Google Scholar 

  126. Allende ML, Bektas M, Lee BG, Bonifacino E, Kang J, Tuymetova G, Chen W, Saba JD, Proia RL (2010) Sphingosine-1-phosphate lyase deficiency produces a pro-inflammatory response while impairing neutrophil trafficking. J Biol Chem 286:7348–7358

    PubMed  Google Scholar 

  127. Le Stunff H, Giussani P, Maceyka M, Lépine S, Milstien S, Spiegel S (2007) Recycling of sphingosine is regulated by the concerted actions of sphingosine-1-phosphate phosphohydrolase 1 and sphingosine kinase 2. J Biol Chem 282:34372–34380

    PubMed  Google Scholar 

  128. Wilcken B (2010) Fatty acid oxidation disorders: outcome and long-term prognosis. J Inherit Metab Dis 33(5):501–506

    PubMed  CAS  Google Scholar 

  129. Innis SM (1993) Essential fatty acid requirements in human nutrition. Can J Physiol Pharmacol 71(9):699–706

    PubMed  CAS  Google Scholar 

  130. Yamaguchi T, Osumi T (2009) Chanarin-Dorfman syndrome: deficiency in CGI-58, a lipid droplet-bound coactivator of lipase. Biochim Biophys Acta 1791(6):519–523

    PubMed  CAS  Google Scholar 

  131. Chatrath H, Keilin S, Attar BM (2009) Cholesterol ester storage disease (CESD) diagnosed in an asymptomatic adult. Dig Dis Sci 54(1):168–173

    PubMed  Google Scholar 

  132. Lindberg DA (2009) Acute pancreatitis and hypertriglyceridemia. Gastroenterol Nurs 32(2):75–82

    PubMed  Google Scholar 

  133. Wang H, Eckel RH (2009) Lipoprotein lipase: from gene to obesity. Am J Physiol Endocrinol Metab 297(2):E271–E288

    PubMed  CAS  Google Scholar 

  134. Karackattu SL, Trigatti B, Krieger M (2006) Hepatic lipase deficiency delays atherosclerosis, myocardial infarction, and cardiac dysfunction and extends lifespan in SR-BI/apolipoprotein E double knockout mice. Arterioscler Thromb Vasc Biol 26(3):548–554

    PubMed  CAS  Google Scholar 

  135. Taschler U et al (2011) Monoglyceride lipase deficiency in mice impairs lipolysis and attenuates diet-induced insulin resistance. J Biol Chem 286(20):17467–17477

    PubMed  CAS  Google Scholar 

  136. Streeper RS, Koliwad SK, Villanueva CJ, Farese RV Jr (2006) Effects of DGAT1 deficiency on energy and glucose metabolism are independent of adiponectin. Am J Physiol Endocrinol Metab 291(2):E388–E394

    PubMed  CAS  Google Scholar 

  137. Zimmermann R, Lass A, Haemmerle G, Zechner R (2009) Fate of fat: the role of adipose triglyceride lipase in lipolysis. Biochim Biophys Acta 1791(6):494–500

    PubMed  CAS  Google Scholar 

  138. Hegyi T, Ostfeld B, Gardner K (1992) Medium chain acyl-coenzyme A dehydrogenase deficiency and SIDS. N J Med 89(5):385–392

    PubMed  CAS  Google Scholar 

  139. Roe CR, Millington DS, Norwood DL, Kodo N, Sprecher H, Mohammed BS et al (1990) 2,4-Dienoyl-coenzyme A reductase deficiency: a possible new disorder of fatty acid oxidation. J Clin Invest 85(5):1703–1707

    PubMed  CAS  Google Scholar 

  140. Miinalainen IJ, Schmitz W, Huotari A, Autio KJ, Soininen R, van Ver Loren TE et al (2009) Mitochondrial 2,4-dienoyl-CoA reductase deficiency in mice results in severe hypoglycemia with stress intolerance and unimpaired ketogenesis. PLoS Genet 5(7):e1000543

    PubMed  Google Scholar 

  141. Houtkooper RH, Turkenburg M, Poll-The BT, Karall D, Perez-Cerda C, Morrone A et al (2003) The enigmatic role of tafazzin in cardiolipin metabolism. Biochim Biophys Acta 1788(10):2003–2014

    Google Scholar 

  142. Reue K, Brindley DN (2008) Thematic review series: glycerolipids. Multiple roles for lipins/phosphatidate phosphatase enzymes in lipid metabolism. J Lipid Res 49(12):2493–2503

    PubMed  CAS  Google Scholar 

  143. Oaxaca-Castillo D et al (2007) Biochemical characterization of two functional human liver acyl-CoA oxidase isoforms 1a and 1b encoded by a single gene. Biochem Biophys Res Commun 360(2):314–319

    PubMed  CAS  Google Scholar 

  144. Sundaram SS, Bove KE, Lovell MA, Sokol RJ (2008) Mechanisms of disease: inborn errors of bile acid synthesis. Nat Clin Pract Gastroenterol Hepatol 5(8):456–468

    PubMed  CAS  Google Scholar 

  145. Kemp S, Wanders R (2010) Biochemical aspects of X-linked adrenoleukodystrophy. Brain Pathol 20(4):831–837

    PubMed  CAS  Google Scholar 

  146. Ferrer I, Aubourg P, Pujol A (2010) General aspects and neuropathology of X-linked adrenoleukodystrophy. Brain Pathol 20(4):817–830

    PubMed  CAS  Google Scholar 

  147. Wierzbicki AS (2007) Peroxisomal disorders affecting phytanic acid alpha-oxidation: a review. Biochem Soc Trans 35(Pt 5):881–886

    PubMed  CAS  Google Scholar 

  148. Ruether K et al (2010) Adult Refsum disease: a form of tapetoretinal dystrophy accessible to therapy. Surv Ophthalmol 55(6):531–538

    PubMed  Google Scholar 

  149. Chuang DT, Chuang JL, Wynn RM (2006) Lessons from genetic disorders of branched-chain amino acid metabolism. J Nutr 136(1 Suppl):243S–249S

    PubMed  CAS  Google Scholar 

  150. Deodato F, Boenzi S, Santorelli FM, Dionisi-Vici C (2006) Methylmalonic and propionic aciduria. Am J Med Genet C Semin Med Genet 142C(2):104–112

    PubMed  CAS  Google Scholar 

  151. Johnson A, O’Donnell C (2009) An open access database of genome-wide association results. BMC Med Genet 10:6

    PubMed  Google Scholar 

  152. Johansen CT, Wang J, Lanktree MB, Cao H, McIntyre AD, Ban MR et al (2010) Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia. Nat Genet 42(8):684–687

    PubMed  CAS  Google Scholar 

  153. Teslovich TM, Musunuru K, Smith AV, Edmondson AC, Stylianou IM, Koseki M et al (2010) Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466(7307):707–713

    PubMed  CAS  Google Scholar 

  154. Hicks AA et al (2009) Genetic determinants of circulating sphingolipid concentrations in European populations. PLoS Genet 5(10):e1000672

    PubMed  Google Scholar 

  155. Gieger C et al (2008) Genetics meets metabolomics: a genome-wide association study of metabolite profiles in human serum. PLoS Genet 4(11):e1000282

    PubMed  Google Scholar 

  156. Illig T, Gieger C, Zhai G, Romisch-Margl W, Wang-Sattler R, Prehn C et al (2010) A genome-wide perspective of genetic variation in human metabolism. Nat Genet 42(2):137–141

    PubMed  CAS  Google Scholar 

  157. Schaeffer L et al (2006) Common genetic variants of the FADS1 FADS2 gene cluster and their reconstructed haplotypes are associated with the fatty acid composition in phospholipids. Hum Mol Genet 15:1745–1756

    PubMed  CAS  Google Scholar 

  158. Fenger M, Linneberg A, Jorgensen T, Madsbad S, Sobye K, Eugen-Olsen J, Jeppesen J (2011) Genetics of the ceramide/sphingosine-1-phosphate rheostat in blood pressure regulation and hypertension. BMC Genet 12:44

    PubMed  Google Scholar 

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Acknowledgment

This work was supported by the “LipidomicNet” (Proposal Number 202272) project, funded under seventh framework program of the EU commission as well as the BMBF network project “Systems Biology Consortium on Metabotypes (SysMBo)”.

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Correspondence to Gerd Schmitz .

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Kopf, T., Peer, M., Schmitz, G. (2012). Genetic and Metabolic Determinants of Fatty Acid Chain Length and Desaturation, Their Incorporation into Lipid Classes and Their Effects on Risk of Vascular and Metabolic Disease. In: Suhre, K. (eds) Genetics Meets Metabolomics. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-1689-0_13

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