Skip to main content
Log in

In Vivo Fatty Acid Incorporation into Brain Phospholipids in Relation to Signal Transduction and Membrane Remodeling

  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

A method and model are described to quantify in vivo turnover rates and half-lives of fatty acids within brain phospholipids. These “kinetic” parameters can be calculated by operational equations from measured rates of incorporation of intravenously injected fatty acid radiotracers into brain phospholipids. To do this, it is necessary to determine a “dilution factor” λ, which estimates the contribution to the brain precursor acyl-CoA pool of fatty acids released from phospholipids through the action of PLA1, or PLA2. Some calculated fatty acid half-lives are minutes to hours, consistent with active participation of phospholipids in brain function and structure. The fatty acid method can be used to identify enzyme targets of drugs acting on phospholipid metabolism. For example, a reduced brain turnover of arachidonate by chronic lithium, demonstrated in rats by the fatty acid method, suggests that this agent, which is used to treat bipolar disorder, has for its target an arachidonate-specific PLA2. In another context, when combined with in vivo imaging by quantitative autoradiography in rodents or positron emission tomography in macaques or humans, the fatty acid method can localize and quantify normal and modified PLA2-mediated signal transduction in brain.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. Porcellati, G., Goracci, G., and Arienti, G. Lipid turnover.1983. pp.277–294, in A.Lajtha (Ed.), Handbook of Neurochemistry, Vol. 5, New York: Plenum.

    Google Scholar 

  2. Fisher, S.K., and Agranoff, B.W.1987.Receptor activation and inositol lipid hydrolysis in neural tissues. J. Neurochem.48:999–1017.

    Google Scholar 

  3. Axelrod, J., Burch, R.M., and Jelsema, C.L.1988.Receptor-mediated activation of phospholipase A2 via GTP-binding proteins:arachidonic acid and its metabolites as second messengers.Trends Neurosci.11:117–123.

    Google Scholar 

  4. Stephenson, D.T., Manetta, J.V., White, D.L., Chiou, X.G., Cox, L., Gitter, B., May, P.C., Sharp, J.D., Kramer, R.M., and Clemens, J.A.1994.Calcium-sensitive cytosolic phospholipase A2 (cPLA2)is expressed in human brain astrocytes. Brain Res. 637:97–105.

    Google Scholar 

  5. Bazan, N.G., and Rodriguez de Turco, E.1980.Membrane lipids in the pathogenesis of brain edema:phospholipids and arachidonic acid, the earliest membrane components changed at the onset of ischemia. Adv.Neurol.28:197–205.

    Google Scholar 

  6. Rabin, O., Deutsch, J., Grange, E.,Pettigrew, K.D., Chang, M.C.J., Rapoport, S.I., and Purdon, A.D. 1997.Changes in cerebral acyl-CoA concentrations following ischemia-reperfusion in awake gerbils. J. Neurochem. 68:2111–2118.

    Google Scholar 

  7. Nariai, T., DeGeorge, J.J., Greig, N.H., and Rapoport, S.I. 1991.In vivo incorporation of [9, 10-3 H ]palmitate into a rat metastatic brain-tumor model. J. Neurosurg.74:643–649.

    Google Scholar 

  8. Castelli, M.G., Butti, G., Chiabrando, C., Cozzi, E., Fanelli, R., Gaetani, P., Silvani, V., and Paoletti, P.1987.Arachidonic acid metabolic profiles in human meningiomas and gliomas. J. Neuro-oncol. 5:369–375.

    Google Scholar 

  9. Singh, A.K.1994.Age-dependent neurotoxicity in rats chronically exposed to low level lead ingestion:phospholipid metabolism in synaptosomes and microvessels. Toxicol. Ind. Health 10:89–101.

    Google Scholar 

  10. Tithof, P.K., Ruehle, K., and Ganey, P.E.1996.Dieldrin and lindane activate neutrophils by a mechanism that involves calcium-independent phospholipase A2.Toxicologist 30 (no.l, part 2):54.

    Google Scholar 

  11. Bourre, J.-M., Francois, M., Youyou, A., Dumont, O., Piciotti, M., Pascal, G., and Durand, G.1989.The effects of dietary cc-linolenic acid on the composition of nerve membranes, enzymatic activity, amplitude of electrophysiological parameters, resistance to poisons and performance of learning tasks in rats. J.Nutrit. 119:1880–1892.

    Google Scholar 

  12. Ginsberg, L., Rafique, S., Xuereb, J.H., Rapoport, S.I., and Gershfeld, N.L.1995.Disease and anatomic specificity of ethanolamine plasmalogen deficiency in Alzheimer's disease brain. Brain Res. 698:223–226.

    Google Scholar 

  13. Farooqui, A.A., Rapoport, S.I., and Horrocks, L.A.1997.Membrane phospholipid alterations in Alzheimer's disease: Deficiency of ethanolamine plasmalogens. Neurochem. Res. 22: 523–527.

    Google Scholar 

  14. Pettegrew, J.W., Moossy, J., Withers, G., McKeag, D., and Panchalingam, K.1988.31 P nuclear magnetic resonance study of the brain in Alzheimer's disease. J. Neuropathol. Exp. Neurol.47:235–248.

    Google Scholar 

  15. Hibbeln, J.R., Palmer, J.W., and Davis, J.M.1989.Are disturbances in lipid-protein interactions by phospholipase-A2 a predisposing factor in affective illness? Biol. Psychiatry25:945–961.

    Google Scholar 

  16. Stoll, A.L., Severus, W.E., Freeman, M.P., Rueter, S., Zboyan, H.A., Diamond, E., Cress, K.K., and Marangell, L.B. 1999.Omega 3 fatty acids in bipolar disorder:A preliminary double-blind, placebo-controlled trial. Arch. Gen. Psychiatry56:407–412.

    Google Scholar 

  17. Robinson, P.J., Noronha, J., De George, J.J., Freed, L.M., Nariai, T., and Rapoport, S.I.1992.A quantitative method for measuring regional in vivo fatty-acid incorporation into and turnover within brain phospholipids:review and critical analysis. Brain Res. Rev.17:187–214.

    Google Scholar 

  18. Rapoport, S.I.1996.In vivo labeling of brain phospholipids by long-chain fatty acids:relation to turnover and function. Lipids 31: S97–S101.

    Google Scholar 

  19. Rapoport, S.I., Purdon, D., Shetty, H.U., Grange, E., Smith, Q., Jones, C., and Chang, M.C.J.1997.In vivo imaging of fatty acid incorporation into brain to examine signal transduction and neuroplasticity involving phospholipids. Ann. N. Y. Acad. Sci. 820:56–74.

    Google Scholar 

  20. Arai, T., Wakabayashi, S., Channing, M.A., Dunn, B.B., Der, M.G., Bell, J.M., Herscovitch, P., Eckelman, W.C., Rapoport, S.I., and Chang, M.C. 1995.Incorporation of [1-carbon-ll ] palmitate in monkey brain using PET. J. Nucl. Med.36: 2261–2267.

    Google Scholar 

  21. Chang, M.C.J., Arai, T., Freed, L.M., Wakabayashi, S., Channing, M.A., Dunn, B.B., Der, M.G., Bell, J.M., Sasaki, T., Herscovitch, P., Eckelman, W.C., and Rapoport, S.I.1997.Brain incorporation of [l-11 C ]-arachidonate in normocapnic and hypercapnic monkeys, measured with positron emission tomography. Brain Res.755:74–83.

    Google Scholar 

  22. Rapoport, S.I., Chang, M.C., Connolly, K., Carson, R., and Eckelman, W.C.1999.In vivo brain imaging of signal transduction using [11 C ]arachidonic acid and positron emission tomography.Soc. Neurosci.Abstr.24

  23. Nariai, T., DeGeorge, J.J., Lamour, Y., and Rapoport, S.I. 1991.In vivo brain incorporation of [l-14 C ]arachidonate in awake rats, with or without cholinergic stimulation, following unilateral lesioning of nucleus basalis magnocellularis. Brain Res. 559: 1–9.

    Google Scholar 

  24. Hayakawa, T., Chang, M.C.J., Bell, J.M., Seemann, R., Rapoport, S.I., and Appel, N.M.1998.Fatty acid incorporation depicts brain activity in a rat model of Parkinson's disease. Brain Res. 807:177–181.

    Google Scholar 

  25. Grange, E., Deutsch, J., Smith, Q.R., Chang, M., Rapoport, S.I., and Purdon, A.D.1995.Specific activity of brain palmitoyl-CoA pool provides rates of incorporation of palmitate in brain phospholipids in awake rats. J. Neurochem. 65:2290–2298.

    Google Scholar 

  26. Washizaki, K., Smith, Q.R., Rapoport, S.L, and Purdon, A.D. 1994.Brain arachidonic acid incorporation and precursor pool specific activity during intravenous infusion of unesterified [3 H ]arachidonate in the anesthetized rat. J. Neurochem. 63: 727–736.

    Google Scholar 

  27. Deutsch, J., Grange, E., Rapoport, S.I., and Purdon, A.D.1994.Isolation and quantitation of long chain acyl-coenzyme A esters in brain tissue by a solid phase extraction. Anal. Biochem. 220:321–323.

    Google Scholar 

  28. Deutsch, J., Rapoport, S.I., and Purdon, A.D.1996.Isolation and HPLC separation of polyunsaturated species of rat brain. acyl-CoA produced during decapitation-ischemia.Phosphorous, Sulfur, and Silicon 109–110:389–392.

    Google Scholar 

  29. Chang, M.C.J., Bell, J.M., Purdon, A.D., Chikhale, E.G., and Grange, E.1999.Dynamics of docosahexaenoic acid metabolism in the central nervous system:Lack of effect of chronic lithium treatment. Neurochem. Res. 24:399–406.

    Google Scholar 

  30. Folch, J., Lees, M., and Sloane Stanley, G.H. 1957.A simple method for the isolation and purification of total lipids from animal tissues. J. Biol. Chem. 226:497–509.

    Google Scholar 

  31. Skipski, V.P., Good, J.J., Barclay, M., and Reggio, R.B.1968.Quantitative analysis of simple lipid classes by thin-layer chromatography. Biochim. Biophys. Acta 152:10–19.

    Google Scholar 

  32. Bazan, N.G. Supply of n-3 polyunsaturated fatty acids and their significance in the central nervous system.1990.pp.1–24.in: R.J.Wurtman and J.J.Wurtman (Eds.), Nutrition and the Brain., Vol. 8, New York: Raven Press.

    Google Scholar 

  33. Staufenbiel, M.1988.Fatty acids covalently bound to erythrocyte proteins undergo a differential turnover in vivo. J. Biol. Chem.263:13615–13622.

    Google Scholar 

  34. Wosilait, W.D., and Soler-Argilaga, C.1975.A theoretical analysis of multiple binding of palmitate by bovine serum albumin: the relationship to uptake of free fatty acids by tissues. Life Sci.17:159–166.

    Google Scholar 

  35. Shafrir, E., Gatt, S., and Khasis, S.1965.Partition of fatty acids of 20–24 carbon atoms between serum albumin and lipoproteins. Biochim. Biophy. Acta.98:365–371.

    Google Scholar 

  36. Meresse, S., Delbart, C., Fruchart, J.-C., and Cecchelli, R.1989.Low-density lipoprotein receptor on endothelium of brain capillaries. J. Neurochem.53:340–345.

    Google Scholar 

  37. Dehouck, B., Fenart, L., Dehouck, M.P., Pierce, A., Torpier, G., and Cecchelli, R.1997.A new function for the LDL receptor: Transcytosis of LDL across the blood-brain barrier. J. Cell Biol. 138:877–889.

    Google Scholar 

  38. Purdon, D., Arai, T., and Rapoport, S.I.1997.No evidence for direct incorporation of esterified palmitic acid from plasma into brain lipids of awake adult rat. J. Lipid Res.38:526–530.

    Google Scholar 

  39. Scott, B.L., and Bazan, N.G.1989.Membrane docosahexaenoate is supplied to the developing brain and retina by the liver. Proc. Natl. Acad. Sci. U.S.A.86:2903–2907.

    Google Scholar 

  40. Svenson, A., Holmer, E., and Andersson, L.O.1974.A new method for the measurement of dissociation rates for complexes between small ligands and proteins as applied to the palmitate and bilirubin complexes with serum albumin. Biochim. Biophys. Acta. 342:54–59.

    Google Scholar 

  41. Pardridge, W.M., and Mietus, L.J.1980.Palmitate and cholesterol transport through the blood-brain barrier. J. Neurochem.34:463–466.

    Google Scholar 

  42. Robinson, P.J., and Rapoport, S.I.1986.Kinetics of protein binding determine rates of uptake of drugs by brain. Am. J. Physiol. 251: R1212-R1220.

    Google Scholar 

  43. Yamazaki, S., DeGeorge, J.J., Bell, I.M., and Rapoport, S.I. 1994.Effect of pentobarbital on incorporation of plasma palmitate into rat brain. Anesthesiology80:151–158.

    Google Scholar 

  44. Watkins, P.A.1997.Fatty acid activation. Prog. Lipid Res. 36:55–83.

    Google Scholar 

  45. Semenkovich, C.F.1997.Regulation of fatty acid synthase (FAS). Prog. Lipid Res.36:43–53.

    Google Scholar 

  46. Yamashita, A., Sugiura, T., and Waku, K.1997.Acyltransferases and transacylases involved in fatty acid remodeling of phospholipids and metabolism of bioactive lipids in mammalian cells. J. Biochem. 122:1–16.

    Google Scholar 

  47. Dennis, E.A.1994.Diversity of group types, regulation, and function of phospholipase A2. J. Biol. Chem.269: 13057–13060.

    Google Scholar 

  48. Pete, M.J., Ross, A.H., and Exton, J.H.1994.Purification and properties of phospholipase Al from bovine brain.J. Biol. Chem.269:19494–19500.

    Google Scholar 

  49. Noronha, J.G., Larson, D.M., and Rapoport, S.I.1989.Regional cerebral incorporation of plasma [14-C ]palmitate, and cerebral glucose utilization in water-deprived Long-Evans and Brattleboro rats. Exp. Neurol.103:267–276.

    Google Scholar 

  50. Greville, G.D., and Tubbs, P.K.1968.The catabolism of long-chain fatty acids in mammalian tissues. Essays Biochem.4: 155–212.

    Google Scholar 

  51. Tutwiler, G.F., Ho, W., and Mohrbacher, R.J.1981.2-Tetrade-cylglycidic acid.Methods Enzymol.72:533–551.

    Google Scholar 

  52. Chang, M.C.J., Wakabayashi, S., and Bell, J.M.1994.The effect of methyl palmoxirate on incorporation of [U-14 C ]palmitate into rat brain. Neurochem. Res. 19:1217–1223.

    Google Scholar 

  53. Chang, M.C.J., Connolly, C., Hill, D., Purdon, A.D., Hayakawa, T., Grimes, G., and Shetty, H.U. 1998.Pharmacokinetics of methyl palmoxirate, an inhibitor of B-oxidation, in rats and humans. Life Sci.63:PL297–PL302.

    Google Scholar 

  54. Osmundsen, H., Cervenka, J., and Bremer, J.1982.A role for 2, 4-enoyl-CoA reductase in mitochondrial B-oxidation of polyun-saturated fatty acids.Effects of treatment with clofibrate on oxidation of polyunsaturated acylcarnitines by isolated rat liver. Biochem.J. 208:749–757.

    Google Scholar 

  55. Murphy, E.1998.Personal communication.

  56. DeGeorge, J.J., Noronha, J.G., Bell, J.M., Robinson, P., and Rapoport, S.I.1989.Intravenous injection of [l-14 C ]arachidonate to examine regional brain lipid metabolism in unanesthetized rats. J.Neurosci. Res.24:413–423.

    Google Scholar 

  57. Noronha, J.G., Bell, J.M., and Rapoport, S.I.1990.Quantitative brain autoradiography of [9, 10-3 H ]palmitic acid incorporation into brain lipids.J.Neurosci. Res.26:196–208.

    Google Scholar 

  58. DeGeorge, J.J., Nariai, T., Yamazaki, S., Williams, W.M., and Rapoport, S.I.1991.Arecoline-stimulated brain incorporation of intravenously administered fatty acids in unanesthetized rats. J.Neurochem.56:352–355.

    Google Scholar 

  59. Nariai, T., DeGeorge, J.J., Greig, N.H., Genka, S., Rapoport, S.I., and Purdon, A.D.1994.Differences in rates of incorporation of intravenously injected radiolabeled fatty acids into phospholipids of intracerebrally implanted tumor and brain in awake rats. Clin. Exp. Metastasis12:213–225.

    Google Scholar 

  60. Deutsch, J., Rapoport, S.I., and Purdon, A.D.1997.Relation between free fatty acid and acyl-CoA concentrations in rat brain following decapitation. Neurochem. Res. 22:759–765.

    Google Scholar 

  61. Shetty, H.U., Smith, Q.R., Washizaki, K., Rapoport, S.I., and Purdon, A.D.1996.Identification of two molecular species of rat brain phosphatidylcholine that rapidly incorporate and turn over arachidonic acid in vivo. J. Neurochem.67:1702–1710.

    Google Scholar 

  62. Contreras, M.A., Chang, M.C.J., Kirkby, D., Bell, J.M., and Rapoport, S.I.1999.Reduced palmitate turnover in brain phospholipids of pentobarbital-anesthetized rats. Neurochem. Res. 24:833–841.

    Google Scholar 

  63. Purdon, A.D., and Rapoport, S.I.1998.Energy requirements for two aspects of phospholipid metabolism in mammalian brain. Biochem. J. 335:313–318.

    Google Scholar 

  64. Sun, G.Y., and Su, K.L.1979.Metabolism of arachidonoyl phosphoglycerides in mouse brain subcellular fractions. J. Neurochem.32:1053–1059.

    Google Scholar 

  65. Connor, W.E., Neuringer, M., and Lin, D.S.1990.Dietary effects on brain fatty acid composition: the reversibility of n-3 fatty acid deficiency and turnover of docosahexaenoic acid in the brain, erythrocytes, and plasma of rhesus monkeys. J. Lipid Res.31:237–247.

    Google Scholar 

  66. Stinson, A.M., Wiegand, R.D., and Anderson, R.E.1991.Recycling of docosahexaenoic acid in rat retinas during n-3 fatty acid deficiency. J. Lipid Res.32:2009–2017.

    Google Scholar 

  67. Farooqui, A.A., Yang, H.-C., Rosenberger, T.H., and Horrocks, L.A.1997.Phospholipase A2 and its role in brain tissue. J. Neurochem.69:889–901.

    Google Scholar 

  68. Berridge, M.J., Downes, C.P., and Hanley, M.R.1982.Lithium amplifies agonist-dependent phosphatidylinositol responses in brain and salivary glands. Biochem. J.206: 587–595.

    Google Scholar 

  69. Atack, J.R., Broughton, H.B., and Pollack, S.J.1995.Inositol monophosphatase-a putative target for Li+in the treatment of bipolar disorder.Trends Neurosci.18:343–349.

    Google Scholar 

  70. Chang, M.C.J., and Jones, C.R.1998.Chronic lithium treatment decreases brain phospholipase A2 activity. Neurochem. Res.23:887–892.

    Google Scholar 

  71. Cooper, J.R., Bloom, F.E., and Roth, R.H.1991.The Biochemical Basis of Neuropharmacology, 6th ed, pp.454, Oxford University Press, New York.

    Google Scholar 

  72. DeGeorge, J.L, Ousley, A.H., McCarthy, K.D., Lapetina, E.G., and Morell, P.1987.Acetylcholine stimulates selective liberation and re-esterification of arachidonate and accumulation of inositol phosphates and glycerophosphoinositol in C62B glioma cells. J. Biol. Chem. 262:8077–8083.

    Google Scholar 

  73. Jones, C.R., Aral, T., Bell, J.M., and Rapoport, S.I.1996.Preferential in vivo incorporation of [3H ]arachidonic acid from blood into rat brain synaptosomal fractions before and after cholinergic stimulation. J. Neurochem.67:822–829.

    Google Scholar 

  74. Jones, C.R., Arai, T., and Rapoport, S.I.1997.Evidence for the involvement of docosahexaenoic acid in cholinergic stimulated signal transduction at the synapse. Neurochem. Res. 22:663–670.

    Google Scholar 

  75. Grange, E., Rabin, O., Bell, J., Rapoport, S.I., and Chang, M.C.J.1998.Manoalind, a phospholipase A2 inhibitor, inhibits arachidonate incorporation and turnover in brain phospholipids of awake rat. Neurochem. Res. 23:1251–1257.

    Google Scholar 

  76. Bogdanovic, N., Islam, A., Nilsson, L., Bergstrom, L., Winblad, B., and Adem, A.1993.Effects of nucleus basalis lesion on muscarinic receptor subtypes. Exp Brain Res97:225–232.

    Google Scholar 

  77. Yamazaki, S., Noronha, J.G., Bell, J.M., and Rapoport, S.I. 1989.Incorporation of plasma [14]C ]palmitate into the hypoglossal nucleus following unilateral axotomy of the hypoglossal nerve in adult rat, with and without regeneration. Brain Res. 477:19–28.

    Google Scholar 

  78. De Micheli, E., Chang, M.C.L, and Rapoport, S.I.1996.In vivo imaging of cortical membrane remodeling in rats with chronic unilateral ablation of nucleus basalis magnocellularis: Use of radiolabeled palmitic acid. Brain Res.735:36–41.

    Google Scholar 

  79. Holmes, T.C., Nitsch, R.M., Erfurth, A., and Wurtman, R.J. 1993.Phospholipid and phospholipid metabolites in rat frontal cortex are decreased following nucleus basalis lesions. Ann. N. Y. Acad. Sci. 695:241–243.

    Google Scholar 

  80. Scherman, D., Desnos, C., Darchen, F., Pollak, P., Javoy-Agid, P., and Agid, Y.1989.Striatal dopamine deficiency in Parkinson's disease: Role of aging. Ann.Neurol.26:551–557.

    Google Scholar 

  81. Biggs, C.S., and Starr, M.S.1997.Dopamine and glutamate control each other's release in the basal ganglia:a microdialysis study of the entopeduncular nucleus and substantia nigra. Neurosci. Biobehav. Rev.21:497–504.

    Google Scholar 

  82. Graham, W.C., Grossman, A.R., and Woodruff, G.N.1990.Autoradiographic studies in animal models of hemi-parkisonism reveal dopamine D2 but not Dl receptor supersensitivity.I.6-OHDA lesions of ascending mesencephalic dopaminergic pathways in the rat. Brain Res.514:93–102.

    Google Scholar 

  83. Hayakawa, T., Chang, M., Bell, J., Seemann, R., and Rapoport, S.I.1997.Effect of D2 dopamine receptor activation on [3H ]arachidonic acid incorporation in rats with unilateral 6-hydroxydopamine lesions. Soc. Neurosci. Abstr. 23:2432.

    Google Scholar 

  84. Rapoport, S.I. Anatomic and functional brain imaging in Alzheimer's disease.1995.pp. 1401–1415 in F.E. Bloom and D.J. Kupfer (eds.), Psychopharmacology:the Fourth Generation of Progress, New York: Raven.

    Google Scholar 

  85. Rapoport, S.I.1999.Investigative New Drug Application # 46, 139:Methyl palmoxirate.

  86. Chang, M.C.J., Grange, E., Rabin, O., and Bell, J.M.1997.Incorporation of [U-l4]C ]palmitate into rat brain:effect of an inhibitor of f5-oxidation. J. Lipid Res.38:295–300.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rapoport, S.I. In Vivo Fatty Acid Incorporation into Brain Phospholipids in Relation to Signal Transduction and Membrane Remodeling. Neurochem Res 24, 1403–1415 (1999). https://doi.org/10.1023/A:1022584707352

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1022584707352

Navigation