Structural and functional roles of ether lipids

Abstract

Ether lipids, such as plasmalogens, are peroxisomederived glycerophospholipids in which the hydrocarbon chain at the sn-1 position of the glycerol backbone is attached by an ether bond, as opposed to an ester bond in the more common diacyl phospholipids. This seemingly simple biochemical change has profound structural and functional implications. Notably, the tendency of ether lipids to form non-lamellar inverted hexagonal structures in model membranes suggests that they have a role in facilitating membrane fusion processes. Ether lipids are also important for the organization and stability of lipid raft microdomains, cholesterol-rich membrane regions involved in cellular signaling. In addition to their structural roles, a subset of ether lipids are thought to function as endogenous antioxidants, and emerging studies suggest that they are involved in cell differentiation and signaling pathways. Here, we review the biology of ether lipids and their potential significance in human disorders, including neurological diseases, cancer, and metabolic disorders.

Key words： ether lipids; plasmalogen; phospholipid; peroxisomes; cancer; metabolic disorders

References

1 Albert DH, Anderson CE (1977) Ether-linked glycerolipids in human brain tumors . <?Pub Caret?>Lipids 12:188–192

2 Albert CJ, Thukkan AK, Heuertz RM (2003) Eosinophil peroxidase-derived reactive brominating species target the vinyl ether bond of plasmalogens generating a novel chemoattractant, alpha-bromo fatty aldehyde . J Biol Chem 278:8942–8950.

3 Alshehry ZH, Mundra PA, Barlow CK (2016) Plasma lipidomic profiles improve on traditional risk factors for the prediction of cardiovascular events in type 2 diabetes mellitus clinical perspective . Circulation 134:1637–1650.

4 Barøy T, Koster J, Strømme P (2015) A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform . Hum Mol Genet 24:5845–5854.

5 Barr J, Caballería J, Martínez-Arranz I (2012) Obesitydependent metabolic signatures associated with nonalcoholic fatty liver disease progression . J Proteome Res 11:2521–2532.

6 Benjamin DI, Cozzo A, Ji X (2013) Ether lipid generating enzyme AGPS alters the balance of structural and signaling lipids to fuel cancer pathogenicity . Proc Natl Acad Sci 110:14912–14917.

7 Bräutigam C, Engelmann B, Reiss D (1996) Plasmalogen phospholipids in plasma lipoproteins of normolipidemic donors and patients with hypercholesterolemia treated by LDL apheresis . Atherosclerosis 119:77–88

8 Braverman NE, Moser AB (2012) Functions of plasmalogen lipids in health and disease . Biochim Biophys Acta BBA Mol Basis Dis 1822:1442–1452.

9 Braverman N, Steel G, Obie C (1997) Human PEX7 encodes the peroxisomal PTS2 receptor and is responsible for rhizomelic chondrodysplasia punctata . Nat Genet 15:369–376

10 Braverman NE, Raymond GV, Rizzo WB (2016) Peroxisome biogenesis disorders in the Zellweger spectrum: an overview of current diagnosis, clinical manifestations, and treatment guidelines . Mol Genet Metab 117:313–321.

11 Brites P (2003) Impaired neuronal migration and endochondral ossification in Pex7 knockout mice: a model for rhizomelic chondrodysplasia punctata . Hum Mol Genet 12:2255–2267.

12 Brites P, Ferreira AS, Ferreira da Silva T (2011) Alkyl-glycerol rescues plasmalogen levels and pathology of ether-phospholipid deficient mice . PLoS ONE 6:e28539.

13 Brodde A, Teigler A, Brugger B (2012) Impaired neurotransmission in ether lipid-deficient nerve terminals . Hum Mol Genet 21:2713–2724.

14 Broniec A, Klosinski R, Pawlak A (2011) Interactions of plasmalogens and their diacyl analogs with singlet oxygen in selected model systems . Free Radic Biol Med 50:892–898.

15 Broniec A, Żądło A, Pawlak A (2017) Interaction of plasmenylcholine with free radicals in selected model systems . Free Radic Biol Med 106:368–378

16 Buchert R, Tawamie H, Smith C (2014) A peroxisomal disorder of severe intellectual disability, epilepsy, and cataracts due to fatty acyl-CoA reductase 1 deficiency . Am J Hum Genet 95:602–610.

17 Cader MZ, Boroviak K, Zhang Q (2016) C13orf31 (FAMIN) is a central regulator of immunometabolic function . Nat Immunol 17:1046–1056.

18 Chen X, Chen H, Dai M (2016) Plasma lipidomics profiling identified lipid biomarkers in distinguishing early-stage breast cancer from benign lesions . Oncotarget 7:36622–36631

19 da Silva TF, Sousa VF, Malheiro AR, Brites P (2012) The importance of ether-phospholipids: a view from the perspective of mouse models. Biochim Biophys Acta BBA Mol Basis Dis 1822:1501–1508.

20 da Silva TF, Eira J, Lopes AT (2014) Peripheral nervous system plasmalogens regulate Schwann cell differentiation and myelination . J Clin Investig 124:2560–2570.

21 Davies SS, Pontsler AV, Marathe GK (2001) Oxidized alkyl phospholipids are specific, high affinity peroxisome proliferatoractivated receptor ligands and agonists . J Biol Chem 276:16015–16023.

22 Eisinger K, Krautbauer S, Hebel T (2014) Lipidomic analysis of the liver from high-fat diet induced obese mice identifies changes in multiple lipid classes . Exp Mol Pathol 97:37–43.

23 Fabelo N, Martín V, Santpere G (2011) Severe alterations in lipid composition of frontal cortex lipid rafts from Parkinson’s disease and incidental Parkinson’s disease . Mol Med 17:1107

24 Facciotti F, Ramanjaneyulu GS, Lepore M (2012) Peroxisomederived lipids are self antigens that stimulate invariant natural killer T cells in the thymus . Nat Immunol 13:474–480.

25 Farooqui AA, Horrocks LA (2001) Book review: plasmalogens: workhorse lipids of membranes in normal and injured neurons and glia . Neuroscientist 7:232–245

26 Felder TK, Ring-Dimitriou S, Auer S (2017) Specific circulating phospholipids, acylcarnitines, amino acids and biogenic amines are aerobic exercise markers . J Sci Med Sport.

27 Fu S, Yang L, Li P (2011) Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity . Nature 473:528–531.

28 Gibellini F, Smith TK (2010) The Kennedy pathway—de novo synthesis of phosphatidylethanolamine and phosphatidylcholine . IUBMB Life 62:414–428

29 Ginsberg L, Rafique S, Xuereb JH (1995) Disease and anatomic specificity of ethanolamine plasmalogen deficiency in Alzheimer’s disease brain . Brain Res 698:223–226

30 Ginsberg L, Xuereb JH, Gershfeld NL (1998) Membrane instability, plasmalogen content, and Alzheimer’s disease . J Neurochem 70:2533–2538

31 Glaser PE, Gross RW (1994) Plasmenylethanolamine facilitates rapid membrane fusion: a stopped-flow kinetic investigation correlating the propensity of a major plasma membrane constituent to adopt an HII phase with its ability to promote membrane fusion . Biochemistry (Mosc) 33:5805–5812

32 Goodenowe DB, Cook LL, Liu J (2007) Peripheral ethanolamine plasmalogen deficiency: a logical causative factor in Alzheimer’s disease and dementia . J Lipid Res 48:2485–2498.

33 Graessler J, Schwudke D, Schwarz PEH (2009) Top-down lipidomics reveals ether lipid deficiency in blood plasma of hypertensive patients . PLoS ONE 4:e6261.

34 Grimm MOW, Kuchenbecker J, Rothhaar TL (2011) Plasmalogen synthesis is regulated via alkyl-dihydroxyacetonephosphatesynthase by amyloid precursor protein processing and is affected in Alzheimer’s disease: dysregulation of plasmalogen synthesis in AD . J Neurochem 116:916–925.

35 Hajra AK, Das AK (1996) Lipid biosynthesis in peroxisomesa . Ann NY Acad Sci 804:129–141

36 Han X (2005) Lipid alterations in the earliest clinically recognizable stage of Alzheimer’s disease: implication of the role of lipids in the pathogenesis of Alzheimer’s disease . Curr Alzheimer Res 2:65–77

37 Han XL, Gross RW (1990) Plasmenylcholine and phosphatidylcholine membrane bilayers possess distinct conformational motifs . Biochemistry (Mosc) 29:4992–4996

38 Han X, Holtzman DM, McKeel DW (2001) Plasmalogen deficiency in early Alzheimer’s disease subjects and in animal models: molecular characterization using electrospray ionization mass spectrometry . J Neurochem 77:1168–1180

39 Hillebrand M, Gersting SW, Lotz-Havla AS (2012) Identification of a new fatty acid synthesis-transport machinery at the peroxisomal membrane . J Biol Chem 287:210–221.

40 Hofer DC, Pessentheiner AR, Pelzmann HJ (2017) Critical role of the peroxisomal protein PEX16 in white adipocyte development and lipid homeostasis . Biochim Biophys Acta BBA Mol Cell Biol Lipids 1862:358–368.

41 Honsho M, Asaoku S, Fukumoto K, Fujiki Y (2013) Topogenesis and homeostasis of fatty acyl-CoA reductase 1 . J Biol Chem 288:34588–34598.

42 Hossain MS, Ifuku M, Take S (2013) Plasmalogens rescue neuronal cell death through an activation of AKT and ERK survival signaling . PLoS ONE 8:e83508.

43 Hossain MS, Mineno K, Katafuchi T (2016) Neuronal orphan G-Protein coupled receptor proteins mediate plasmalogensinduced activation of ERK and Akt signaling . PLOS ONE 11: e0150846.

44 Hua R, Cheng D, Coyaud É (2017) VAPs and ACBD5 tether peroxisomes to the ER for peroxisome maintenance and lipid homeostasis . J Cell Biol.

45 Huang JH, Park H, Iaconelli J (2016) Unbiased metabolite profiling of schizophrenia fibroblasts under stressful perturbations reveals dysregulation of plasmalogens and phosphatidylcholines . J Proteome Res.

46 James PF, Lake AC, Hajra AK (1997) An animal cell mutant with a deficiency in acyl/alkyl-dihydroxyacetone-phosphate reductase activity: effects on the biosynthesis of ether-linked and diacyl glycerolipids . J Biol Chem 272:23540–23546

47 Jang JE, Park H-S, Yoo HJ (2017) Protective role of endogenous plasmalogens against hepatic steatosis and steatohepatitis . Hepatology.

48 Khaselev N, Murphy RC (1999) Susceptibility of plasmenyl glycerophosphoethanolamine lipids containing arachidonate to oxidative degradation . Free Radic Biol Med 26:275–284

49 Komljenovic D, Sandhoff R, Teigler A (2009) Disruption of blood-testis barrier dynamics in ether-lipid-deficient mice . Cell Tissue Res 337:281–299.

50 LaBelle EF, Hajra AK (1974) Purification and kinetic properties of acyl and alkyl dihydroxyacetone phosphate oxidoreductase . J Biol Chem 249:6936–6944

51 Lankinen M, Schwab U, Kolehmainen M (2016) A healthy nordic diet alters the plasma lipidomic profile in adults with features of metabolic syndrome in a multicenter randomized dietary intervention . J Nutr 146:662–672.

52 Lenzen S, Drinkgern J, Tiedge M (1996) Low antioxidant enzyme gene expression in pancreatic islets compared with various other mouse tissues . Free Radic Biol Med 20:463–466

53 Li Z, Agellon LB, Allen TM (2006) The ratio of phosphatidylcholine to phosphatidylethanolamine influences membrane integrity and steatohepatitis . Cell Metab 3:321–331.

54 Lodhi IJ, Yin L, Jensen-Urstad APL (2012) Inhibiting adipose tissue lipogenesis reprograms thermogenesis and PPARγ activation to decrease diet-induced obesity . Cell Metab 16:189–201.

55 Lodhi IJ, Wei X, Yin L (2015) Peroxisomal lipid synthesis regulates inflammation by sustaining neutrophil membrane phospholipid composition and viability . Cell Metab 21:51–64.

56 Lohner K (1996) Is the high propensity of ethanolamine plasmalogens to form non-lamellar lipid structures manifested in the properties of biomembranes ? Chem Phys Lipids 81:167–184

57 Luoma AM, Kuo F, Cakici O (2015) Plasmalogen phospholipids protect internodal myelin from oxidative damage . Free Radic Biol Med 84:296–310.

58 Maeba R, Sawada Y, Shimasaki H (2002) Ethanolamine plasmalogens protect cholesterol-rich liposomal membranes from oxidation caused by free radicals . Chem Phys Lipids 120:145–151

59 Marrink S-J, Mark AE (2004) Molecular view of hexagonal phase formation in phospholipid membranes . Biophys J 87:3894–3900.

60 McIntyre TM, Pontsler AV, Silva AR (2003) Identification of an intracellular receptor for lysophosphatidic acid (LPA): LPA is a transcellular PPARγ agonist . Proc Natl Acad Sci 100:131–136

61 Morand OH, Zoeller RA, Raetz CR (1988) Disappearance of plasmalogens from membranes of animal cells subjected to photosensitized oxidation . J Biol Chem 263:11597–11606

62 Motley AM, Hettema EH, Hogenhout EM (1997) Rhizomelic chondrodysplasia punctata is a peroxisomal protein targeting disease caused by a non-functional PTS2 receptor . Nat Genet 15:377–380

63 Mueller HW, O’Flaherty JT, Wykle RL (1982) Ether lipid content and fatty acid distribution in rabbit polymorphonuclear neutrophil phospholipids . Lipids 17:72–77

64 Mueller HW, O’Flaherty JT, Greene DG (1984) 1-O-alkyl-linked glycerophospholipids of human neutrophils: distribution of arachidonate and other acyl residues in the ether-linked and diacyl species . J Lipid Res 25:383–388

65 Munn NJ (2003) Deficiency in ethanolamine plasmalogen leads to altered cholesterol transport . J Lipid Res 44:182–192.

66 Nagan N, Zoeller RA (2001) Plasmalogens: biosynthesis and functions . Prog Lipid Res 40:199–299

67 Orešič M, Simell S, Sysi-Aho M (2008) Dysregulation of lipid and amino acid metabolism precedes islet autoimmunity in children who later progress to type 1 diabetes .J Exp Med 205:2975–2984.

68 Paltauf F (1994) Ether lipids in biomembranes . Chem Phys Lipids 74:101–139

69 Piano V, Benjamin DI, Valente S (2015) Discovery of inhibitors for the ether lipid-generating enzyme AGPS as anti-cancer agents . ACS ChemBiol 10:2589–2597.

70 Pietiläinen KH, Sysi-Aho M, Rissanen A (2007) Acquired obesity is associated with changes in the serum lipidomic profile independent of genetic effects—a monozygotic twin study . PLoS ONE 2:e218.

71 Pietiläinen KH, Róg T, Seppänen-Laakso T (2011) Association of lipidome remodeling in the adipocyte membrane with acquired obesity in humans . PLoS Biol 9:e1000623.

72 Pike LJ, Han X, Chung K-N, Gross RW (2002) Lipid rafts are enriched in arachidonic acid and plasmenylethanolamine and their composition is independent of Caveolin-1 expression: a quantitative electrospray ionization/mass spectrometric analysis† . Biochemistry (Mosc) 41:2075–2088.

73 Purdue PE (1997) Rhizomelic chondrodysplasia punctata is caused by deficiency of human PEX7, a homologue of the yeast PTSZ . Nat Genet 15:381

74 Puri P, Wiest MM, Cheung O (2009) The plasma lipidomic signature of nonalcoholic steatohepatitis . Hepatology 50:1827–1838

75 Rasmiena AA, Barlow CK, Stefanovic N (2015) Plasmalogen modulation attenuates atherosclerosis in ApoE- and ApoE/GPx1-deficient mice . Atherosclerosis 243:598–608.

76 Reiss D, Beyer K, Engelmann B (1997) Delayed oxidative degradation of polyunsaturated diacyl phospholipids in the presence of plasmalogen phospholipids in vitro . Biochem J 323:807–814

77 Rodemer C, Thai T-P, Brugger B (2003) Inactivation of ether lipid biosynthesis causes male infertility, defects in eye development and optic nerve hypoplasia in mice . Hum Mol Genet 12:1881–1895.

78 RooS DS, Choppin PW (1984) Tumorigenicity of cell lines with altered lipid composition . Proc Natl Acad Sci 81:7622–7626

79 Skaff O, Pattison DI, Davies MJ (2008) The vinyl ether linkages of plasmalogens are favored targets for myeloperoxidase-derived oxidants: a kinetic study† . Biochemistry (Mosc) 47:8237–8245.

80 Snyder F (1999) The ether lipid trail: a historical perspective . Biochim Biophys Acta BBA Mol Cell Biol Lipids 1436:265–278

81 Snyder F, Wood R (1969) Alkyl and alk-1-enyl ethers of glycerol in lipids from normal and neoplastic human tissues . Cancer Res 29:251–257

82 Snyder F, Cress EA, Stephens N (1966) An unidentified lipid prevalent in tumors . Lipids 1:381–386

83 Snyder F, Blank ML, Morris HP (1969) Occurrence and nature of O-alkyl and O-alk-1-enyl moieties of glycerol in lipids of Morris transplanted hepatomas and normal rat liver . Biochim Biophys Acta BBA Lipids Lipid Metab 176:502–510

84 Steinberg SJ, Raymond GV, Braverman NE, Moser AB (2012) Peroxisome biogenesis disorders, Zellweger syndrome spectrum.

85 Teigler A, Komljenovic D, Draguhn A (2009) Defects in myelination, paranode organization and Purkinje cell innervation in the ether lipid-deficient mouse cerebellum . Hum Mol Genet 18:1897–1908.

86 Tessier C, Sweers K, Frajerman A (2016) Membrane lipidomics in schizophrenia patients: a correlational study with clinical and cognitive manifestations . Transl Psychiatry 6:e906.

87 Thukkani AK, Hsu F-F, Crowley JR (2002) Reactive chlorinating species produced during neutrophil activation target tissue plasmalogens: Production Of The Chemoattractant, 2-Chlorohexadecanal . J Biol Chem 277:3842–3849.

88 Tsukahara T, Tsukahara R, Yasuda S (2006) Different residues mediate recognition of 1-O-oleyllysophosphatidic acid and rosiglitazone in the ligand binding domain of peroxisome proliferatoractivated receptor . J Biol Chem 281:3398–3407.

89 Tulodziecka K, Diaz-Rohrer BB, Farley MM (2016) Remodeling of the postsynaptic plasma membrane during neural development . Mol Biol Cell 27:3480–3489

90 Volmer R, van der Ploeg K, Ron D (2013) Membrane lipid saturation activates endoplasmic reticulum unfolded protein response transducers through their transmembrane domains . Proc Natl Acad Sci 110:4628–4633.

91 Wang G, Wang T (2010) The role of plasmalogen in the oxidative stability of neutral lipids and phospholipids . J Agric Food Chem 58:2554–2561.

92 White AL, Modaff P, Holland-Morris F, Pauli RM (2003) Natural history of rhizomelic chondrodysplasia punctata . Am J Med Genet 118A:332–342.

93 Wood P, mankidy R, Ritchie S (2010) Circulating plasmalogen levels and Alzheimer disease assessment scale-cognitive scores in Alzheimer patients . J Psychiatry Neurosci 35:59–62.

94 Wood PL, Locke VA, Herling P (2016) Targeted lipidomics distinguishes patient subgroups in mild cognitive impairment (MCI) and late onset Alzheimer’s disease (LOAD) . BBA Clin 5:25–28.

95 Yamashita S, Kanno S, Nakagawa K (2015a) Extrinsic plasmalogens suppress neuronal apoptosis in mouse neuroblastoma Neuro-2A cells: importance of plasmalogen molecular species . RSC Adv 5:61012–61020.

96 Yamashita S, Kiko T, Fujiwara H (2015b) Alterations in the levels of amyloid-β, phospholipid hydroperoxide, and plasmalogen in the blood of patients with Alzheimer’s disease: possible interactions between amyloid-β and these lipids . J Alzheimers Dis 50:527–537.

97 Yen C-LE, Mar M, Zeisel SH (1999) Choline deficiency-induced apoptosis in PC12 cells is associated with diminished membrane phosphatidylcholine and sphingomyelin, accumulation of ceramide and diacylglycerol, and activation of a caspase . FASEB J 13:135–142

98 Zhang C, Baker DL, Yasuda S (2004) Lysophosphatidic acid induces neointima formation through PPARγ activation . J Exp Med 199:763–774.

99 Zoeller RA, Morand OH, Raetz CR (1988) A possible role for plasmalogens in protecting animal cells against photosensitized killing . J Biol Chem 263:11590–11596