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. 1995 Sep;96(3):1455–1463. doi: 10.1172/JCI118182

Interactions of a very long chain fatty acid with model membranes and serum albumin. Implications for the pathogenesis of adrenoleukodystrophy.

J K Ho 1, H Moser 1, Y Kishimoto 1, J A Hamilton 1
PMCID: PMC185769  PMID: 7657817

Abstract

Adrenoleukodystrophy (ALD) is an inherited disorder of fatty acid metabolism marked by accumulation of very long chain saturated fatty acids (VLCFA), especially the 26-carbon acid, hexacosanoic acid (HA), in membranes and tissues. We have studied interactions of 13C-enriched HA with model membranes (phospholipid bilayer vesicles) and bovine serum albumin (BSA) by 13C NMR spectroscopy to compare properties of HA with those of typical dietary fatty acids. In phospholipid bilayers the carboxyl group of HA is localized in the aqueous interface, with an apparent pKa (7.4) similar to other fatty acids; the acyl chain must then penetrate very deeply into the membrane. Desorption of HA from vesicles (t1+2 = 3 h) is orders of magnitude slower than shorter chain fatty acids. In mixtures of vesicles and BSA, HA partitions much more favorably to phospholipid bilayers than typical fatty acids. BSA binds a maximum of only 1 mole of HA at one binding site. Calorimetric experiments show strong perturbations of acyl chains of phospholipids by HA. We predict that disruptive effects of VLCFA on cell membrane structure and function may explain the neurological manifestations of ALD patients. These effects will be further amplified by slow desorption of VLCFA from membranes and by the ineffective binding to serum albumin.

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Selected References

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  1. Aubourg P., Adamsbaum C., Lavallard-Rousseau M. C., Rocchiccioli F., Cartier N., Jambaqué I., Jakobezak C., Lemaitre A., Boureau F., Wolf C. A two-year trial of oleic and erucic acids ("Lorenzo's oil") as treatment for adrenomyeloneuropathy. N Engl J Med. 1993 Sep 9;329(11):745–752. doi: 10.1056/NEJM199309093291101. [DOI] [PubMed] [Google Scholar]
  2. Aubourg P., Blanche S., Jambaqué I., Rocchiccioli F., Kalifa G., Naud-Saudreau C., Rolland M. O., Debré M., Chaussain J. L., Griscelli C. Reversal of early neurologic and neuroradiologic manifestations of X-linked adrenoleukodystrophy by bone marrow transplantation. N Engl J Med. 1990 Jun 28;322(26):1860–1866. doi: 10.1056/NEJM199006283222607. [DOI] [PubMed] [Google Scholar]
  3. Bizzozero O. A., Zuñiga G., Lees M. B. Fatty acid composition of human myelin proteolipid protein in peroxisomal disorders. J Neurochem. 1991 Mar;56(3):872–878. doi: 10.1111/j.1471-4159.1991.tb02003.x. [DOI] [PubMed] [Google Scholar]
  4. Brown F. R., 3rd, Chen W. W., Kirschner D. A., Frayer K. L., Powers J. M., Moser A. B., Moser H. W. Myelin membrane from adrenoleukodystrophy brain white matter--biochemical properties. J Neurochem. 1983 Aug;41(2):341–348. doi: 10.1111/j.1471-4159.1983.tb04748.x. [DOI] [PubMed] [Google Scholar]
  5. Cistola D. P., Small D. M., Hamilton J. A. Carbon 13 NMR studies of saturated fatty acids bound to bovine serum albumin. I. The filling of individual fatty acid binding sites. J Biol Chem. 1987 Aug 15;262(23):10971–10979. [PubMed] [Google Scholar]
  6. Cistola D. P., Small D. M., Hamilton J. A. Carbon 13 NMR studies of saturated fatty acids bound to bovine serum albumin. II. Electrostatic interactions in individual fatty acid binding sites. J Biol Chem. 1987 Aug 15;262(23):10980–10985. [PubMed] [Google Scholar]
  7. Daniels C., Noy N., Zakim D. Rates of hydration of fatty acids bound to unilamellar vesicles of phosphatidylcholine or to albumin. Biochemistry. 1985 Jun 18;24(13):3286–3292. doi: 10.1021/bi00334a032. [DOI] [PubMed] [Google Scholar]
  8. Eliasz A. W., Chapman D., Ewing D. F. Phospholipid phase transitions. Effects of n-alcohols, n-monocarboxylic acids, phenylalkyl alcohols and quaternary ammonium compounds. Biochim Biophys Acta. 1976 Oct 5;448(2):220–230. doi: 10.1016/0005-2736(76)90238-8. [DOI] [PubMed] [Google Scholar]
  9. Griffin D. E., Moser H. W., Mendoza Q., Moench T. R., O'Toole S., Moser A. B. Identification of the inflammatory cells in the central nervous system of patients with adrenoleukodystrophy. Ann Neurol. 1985 Dec;18(6):660–664. doi: 10.1002/ana.410180606. [DOI] [PubMed] [Google Scholar]
  10. Hamilton J. A., Cistola D. P. Transfer of oleic acid between albumin and phospholipid vesicles. Proc Natl Acad Sci U S A. 1986 Jan;83(1):82–86. doi: 10.1073/pnas.83.1.82. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hamilton J. A. Medium-chain fatty acid binding to albumin and transfer to phospholipid bilayers. Proc Natl Acad Sci U S A. 1989 Apr;86(8):2663–2667. doi: 10.1073/pnas.86.8.2663. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hamilton J. A., Small D. M. Solubilization and localization of cholesteryl oleate in egg phosphatidylcholine vesicles. A carbon 13 NMR study. J Biol Chem. 1982 Jul 10;257(13):7318–7321. [PubMed] [Google Scholar]
  13. Huang J. M., Xian H., Bacaner M. Long-chain fatty acids activate calcium channels in ventricular myocytes. Proc Natl Acad Sci U S A. 1992 Jul 15;89(14):6452–6456. doi: 10.1073/pnas.89.14.6452. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kamp F., Hamilton J. A. pH gradients across phospholipid membranes caused by fast flip-flop of un-ionized fatty acids. Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11367–11370. doi: 10.1073/pnas.89.23.11367. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kantor H. L., Prestegard J. H. Fusion of phosphatidylcholine bilayer vesicles: role of free fatty acid. Biochemistry. 1978 Aug 22;17(17):3592–3597. doi: 10.1021/bi00610a027. [DOI] [PubMed] [Google Scholar]
  16. Knazek R. A., Rizzo W. B., Schulman J. D., Dave J. R. Membrane microviscosity is increased in the erythrocytes of patients with adrenoleukodystrophy and adrenomyeloneuropathy. J Clin Invest. 1983 Jul;72(1):245–248. doi: 10.1172/JCI110963. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Lazo O., Contreras M., Hashmi M., Stanley W., Irazu C., Singh I. Peroxisomal lignoceroyl-CoA ligase deficiency in childhood adrenoleukodystrophy and adrenomyeloneuropathy. Proc Natl Acad Sci U S A. 1988 Oct;85(20):7647–7651. doi: 10.1073/pnas.85.20.7647. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Lund-Katz S., Laboda H. M., McLean L. R., Phillips M. C. Influence of molecular packing and phospholipid type on rates of cholesterol exchange. Biochemistry. 1988 May 3;27(9):3416–3423. doi: 10.1021/bi00409a044. [DOI] [PubMed] [Google Scholar]
  19. Moser H. W., Moser A. B., Smith K. D., Bergin A., Borel J., Shankroff J., Stine O. C., Merette C., Ott J., Krivit W. Adrenoleukodystrophy: phenotypic variability and implications for therapy. J Inherit Metab Dis. 1992;15(4):645–664. doi: 10.1007/BF01799621. [DOI] [PubMed] [Google Scholar]
  20. Murad S., Chen R. H., Kishimoto Y. alpha-Hydroxylation of fatty acids in brain. Substrate specificity and deuterium isotope effect. J Biol Chem. 1977 Aug 10;252(15):5206–5210. [PubMed] [Google Scholar]
  21. Nishizuka Y. Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science. 1992 Oct 23;258(5082):607–614. doi: 10.1126/science.1411571. [DOI] [PubMed] [Google Scholar]
  22. Ogino T., Suzuki K. Specificities of human and rat brain enzymes of cholesterol ester metabolism toward very long chain fatty acids: implication for biochemical pathogenesis of adrenoleukodystrophy. J Neurochem. 1981 Feb;36(2):776–779. doi: 10.1111/j.1471-4159.1981.tb01657.x. [DOI] [PubMed] [Google Scholar]
  23. Ordway R. W., Walsh J. V., Jr, Singer J. J. Arachidonic acid and other fatty acids directly activate potassium channels in smooth muscle cells. Science. 1989 Jun 9;244(4909):1176–1179. doi: 10.1126/science.2471269. [DOI] [PubMed] [Google Scholar]
  24. Parks J. S., Cistola D. P., Small D. M., Hamilton J. A. Interactions of the carboxyl group of oleic acid with bovine serum albumin: a 13C NMR study. J Biol Chem. 1983 Aug 10;258(15):9262–9269. [PubMed] [Google Scholar]
  25. Peitzsch R. M., McLaughlin S. Binding of acylated peptides and fatty acids to phospholipid vesicles: pertinence to myristoylated proteins. Biochemistry. 1993 Oct 5;32(39):10436–10443. doi: 10.1021/bi00090a020. [DOI] [PubMed] [Google Scholar]
  26. Poulos A., Gibson R., Sharp P., Beckman K., Grattan-Smith P. Very long chain fatty acids in X-linked adrenoleukodystrophy brain after treatment with Lorenzo's oil. Ann Neurol. 1994 Nov;36(5):741–746. doi: 10.1002/ana.410360509. [DOI] [PubMed] [Google Scholar]
  27. Poulos A. Very long chain fatty acids in higher animals--a review. Lipids. 1995 Jan;30(1):1–14. doi: 10.1007/BF02537036. [DOI] [PubMed] [Google Scholar]
  28. Powers J. M. Adreno-leukodystrophy (adreno-testiculo-leukomyelo-neuropathic-complex). Clin Neuropathol. 1985 Sep-Oct;4(5):181–199. [PubMed] [Google Scholar]
  29. Powers J. M., Liu Y., Moser A. B., Moser H. W. The inflammatory myelinopathy of adreno-leukodystrophy: cells, effector molecules, and pathogenetic implications. J Neuropathol Exp Neurol. 1992 Nov;51(6):630–643. doi: 10.1097/00005072-199211000-00007. [DOI] [PubMed] [Google Scholar]
  30. Powers J. M., Schaumburg H. H., Johnson A. B., Raine C. S. A correlative study of the adrenal cortex in adreno-leukodystrophy--evidence for a fatal intoxication with very long chain saturated fatty acids. Invest Cell Pathol. 1980 Oct-Dec;3(4):353–376. [PubMed] [Google Scholar]
  31. Rasmussen M., Moser A. B., Borel J., Khangoora S., Moser H. W. Brain, liver, and adipose tissue erucic and very long chain fatty acid levels in adrenoleukodystrophy patients treated with glyceryl trierucate and trioleate oils (Lorenzo's oil). Neurochem Res. 1994 Aug;19(8):1073–1082. doi: 10.1007/BF00968719. [DOI] [PubMed] [Google Scholar]
  32. Schullery S. E., Seder T. A., Weinstein D. A., Bryant D. A. Differential thermal analysis of dipalmitoylphosphatidylcholine--fatty acid mixtures. Biochemistry. 1981 Nov 24;20(24):6818–6824. doi: 10.1021/bi00527a012. [DOI] [PubMed] [Google Scholar]
  33. Singh I., Moser A. E., Goldfischer S., Moser H. W. Lignoceric acid is oxidized in the peroxisome: implications for the Zellweger cerebro-hepato-renal syndrome and adrenoleukodystrophy. Proc Natl Acad Sci U S A. 1984 Jul;81(13):4203–4207. doi: 10.1073/pnas.81.13.4203. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Spector A. A. Fatty acid binding to plasma albumin. J Lipid Res. 1975 May;16(3):165–179. [PubMed] [Google Scholar]
  35. Spector A. A., Hoak J. C. An improved method for the addition of long-chain free fatty acid to protein solutions. Anal Biochem. 1969 Nov;32(2):297–302. doi: 10.1016/0003-2697(69)90089-x. [DOI] [PubMed] [Google Scholar]
  36. Theda C., Moser A. B., Powers J. M., Moser H. W. Phospholipids in X-linked adrenoleukodystrophy white matter: fatty acid abnormalities before the onset of demyelination. J Neurol Sci. 1992 Jul;110(1-2):195–204. doi: 10.1016/0022-510x(92)90028-j. [DOI] [PubMed] [Google Scholar]
  37. Wanders R. J., van Roermund C. W., van Wijland M. J., Schutgens R. B., van den Bosch H., Schram A. W., Tager J. M. Direct demonstration that the deficient oxidation of very long chain fatty acids in X-linked adrenoleukodystrophy is due to an impaired ability of peroxisomes to activate very long chain fatty acids. Biochem Biophys Res Commun. 1988 Jun 16;153(2):618–624. doi: 10.1016/s0006-291x(88)81140-9. [DOI] [PubMed] [Google Scholar]
  38. Watts R. W., Morgan S. H., Danpure C. J., Purkiss P., Calne R. Y., Rolles K., Baker L. R., Mansell M. A., Smith L. H., Merion R. M. Combined hepatic and renal transplantation in primary hyperoxaluria type I: clinical report of nine cases. Am J Med. 1991 Feb;90(2):179–188. [PubMed] [Google Scholar]
  39. Whitcomb R. W., Linehan W. M., Knazek R. A. Effects of long-chain, saturated fatty acids on membrane microviscosity and adrenocorticotropin responsiveness of human adrenocortical cells in vitro. J Clin Invest. 1988 Jan;81(1):185–188. doi: 10.1172/JCI113292. [DOI] [PMC free article] [PubMed] [Google Scholar]

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