Abstract
The transport of fatty acids (FA) across membranes can be described by three fundamental steps: adsorption, transmembrane movement, and desorption. In model membranes, these steps are all rapid and spontaneous for most fatty acids, suggesting that FA can enter cells by free diffusion rather than by protein-mediated mechanisms. Here we present new fluorescence approaches that measure adsorption and transmembrane movement of FA independently. We show that FA adsorb to the plasma membrane of adipocytes and diffuse through the membrane by the flip-flop mechanism within the time resolution of our measurements (∼5 s). Thus we show that passive diffusion is a viable mechanism, although we did not evaluate its exclusivity. Important implications of the diffusion mechanism for neural cells are that all types of FA could be available and that selectivity is controlled by metabolism. Studies of FA uptake into brain endothelial cells and other brain cell types need to be performed to determine mechanisms of uptake, and metabolism of FA must be separated in order to understand the role of membrane transport in the overall up take process.
Similar content being viewed by others
References
Abumrad N., Harmon C., and Ibrahimi A. (1998) Membrane transport of long-chain fatty acids: evidence for a facilitated process. J. Lipid Res. 39(12), 2309–2318.
Cabral D. J., Small D. M., Lilly H. S., and Hamilton J. A. (1987) Transbilayer movement of bile acids in model membranes. Biochemistry 26(7), 1801–1804.
Civelek V. N., Hamilton J. A., Tornheim K., Kelly K. L., and Corkey B. E. (1996) Intracellular pH in adipocytes: effects of free fatty acid diffusion across the plasma membrane, lipolytic agonists, and insulin. Proc. Natl. Acad. Sci. USA 93(19), 10,139–10,144.
Daniels C., Noy N., and Zakim, D. (1985) Rates of hydration of fatty acids bound to unilamellar vesicles of phosphatidylcholine or to albumin. Biochemistry 24(13), 3286–3292.
Darnell J., Lodish H., and Baltimore D. (1990) Molecular Cell Biology. Scientific American Books, Inc., New York.
Dietschy J. M. (1978) General principles governing movement of lipids across biological membranes, in Disturbances in Lipid and Lipoprotein Metabolism (Dietschy J. M., Gotto J., Ontko A. M., and Ontko J. A., eds.), American Physiological Society, Bethesda, MD, pp. 1–29.
Fischer H., Gottschilch R., and Seelig A. (1998) Blood-brain barrier permeation: Molecular parameters governing passive diffusion. J. Membrane Biol. 165, 201–211.
Hamilton J. A., Civelek V. N., Kamp F., Tornheim K., and Corkey B. E. (1994) Changes in internal pH caused by movement of fatty acids into and out of clonal pancreatic beta-cells (HIT). J. Biol. Chem. 269(33), 20,852–20,856.
Hamilton J. A. (1995) 13-C NMR studies of the interactions of fatty acids with phospholipid bilayers, plasma lipoprotein, and proteins, in Carbon-13 NMR Spectroscopy. (Beckman N., ed.), Academic Press, USA, pp. 117–157.
Hamilton J. A. (1998) Fatty acid transport: difficult or easy? J. Lipid. Res. 39(3), 467–481.
Hamilton J. A. (1999) Transport of fatty acids across membranes by the diffusion mechanism. Prostaglandins Leukot. Essent. Fatty Acids 60(5–6), 291–297.
Hamilton J. A. and Kamp, F. (1999) How are free fatty acids transported in membranes? Is it by proteins or by free diffusion through the lipids? Diabetes 48(12), 2255–2269.
Herman R., Leaf A., and Schwartz W. (1964) Diffusion of weak acids across the toad bladder. J. Gen. Physiol. 48, 379–389.
Ho J. K., Moser H., Kishimoto Y., and Hamilton J. A. (1995) Interactions of a very long chain fatty acid with model membranes and serum albumin. Implications for the pathogenesis of adrenoleukodystrophy. J. Clin. Invest. 96(3), 1455–1463.
Kamp F. and Hamilton J. A. (1992) pH gradients across phospholipid membranes caused by fast flip-flop of un-ionized fatty acids. Proc. Natl. Acad. Sci. USA 89(23), 11,367–11,370.
Kamp F., Zakim D., Zhang F., Noy N., and Hamilton J. A. (1995) Fatty acid flip-flop in phospholipid bilayers is extremely fast. Biochemistry 34(37), 11,928–11,937.
Kantor H. L. and Prestegard J. H. (1978) Fusion of phosphatidylcholine bilayer vesicles: role of free fatty acid. Biochemistry 17(17), 3592–3597.
Marbois B. N., Ajie H. O., Korsak R. A., Sensharma D. K., and Edmond J. (1992) The origin of palmitic acid in brain of the developing rat. Lipids 27(8), 587–592.
Mastrangelo A. M., Jeitner, T. M. and Eaton J. W. (1998) Oleic acid increases cell surface expression and activity of CD11b on human neutrophils. J. Immunol. 161(8), 4268–4275.
Moser H. W. and Moser A. B. (1989) X-linked adrenoleukodystrophy, in The Metabolic Basis of Inherited Disease. (Scriver C. R., Beaudet A. L., and Sly W. S., eds.), McGraw Hill, New York, pp. 1511–1532.
Moser H. W. (1997) Adrenoleukodystrophy: phenotype, genetics, pathogenesis and therapy. Brain 120(Pt 8), 1485–1508.
Paulussen R. J. A. and Veerkamp J. H. (1990) Intracellular fatty acid binding proteins: characteristics and function, in Subcellular Biochemistry, vol. 16 (Hilderson H. J., ed.), Plenum Press, New York, pp. 175–226.
Richieri G. V., Ogata R. T., and Kleinfeld A. M. (1992) A fluorescently labeled intestinal fatty acid binding protein. Interactions with fatty acids and its use in monitoring free fatty acids. J. Biol. Chem. 267(33), 23,495–23,501.
Robinson P. J., Noronha J., DeGeorge 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. Brain Res. Rev. 17(3), 187–214.
Spector A. A. (1975) Fatty acid binding to plasma albumin. J. Lipid Res. 16(3), 165–179.
Spector A. A. (1986) Plasma albumin as a lipoprotein, in Biochemistry and Biology of Plasma Lipoptotein. (Scanu, A. M. and Spector, A. A., eds.), Marcel Dekker, Inc., New York, pp. 247–279.
Stremmel W., Strohmeyer G., and Berk P. D. (1986) Hepatocellular uptake of oleate is energy dependent, sodium linked, and inhibited by an antibody to a hepatocyte plasma membrane fatty acid binding protein. Proc. Natl. Acad. Sci. USA 83(11), 3584–3588.
Trigatti B. L. and Gerber G. E. (1996) The effect of intracellular pH on long-chain fatty acid uptake in 3T3-L1 adipocytes: evidence that uptake involves the passive diffusion of protonated long-chain fatty acids across the plasma membrane. Biochem. J. 313(Pt 2), 487–494.
van der Vusse G. J., van Bilsen M., and Glatz J. F. C. (2000) Cardiac fatty acid uptake and transport in health and disease. Cardiovasc. Res. (45), 279–293.
Van Nieuwenhoven F. A., Verstijnen C. P., Van Eys G. J., Van Breda E., De Jong Y. F., Van der Vusse G. J., and Glatz J. F. (1994) Fatty acid transfer across the myocardial capillary wall: no evidence of a substantial role for cytoplasmic fatty acid-binding protein. J. Mol. Cell. Cardiol. 26(12), 1635–1647.
Xu H. E., Lambert M. H., Montana V. G., Parks D. J., Blanchard S. G., Brown P. J., et al. (1999) Molecular recognition of fatty acids by peroxisome proliferator-activated receptors. Mol. Cell 3(3), 397–403.
Zhang F., Kamp F., and Hamilton J. A. (1996) Dissociation of long and very long chain fatty acids from phospholipid bilayers. Biochemistry 35(50), 16,055–16,060.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Hamilton, J.A., Johnson, R.A., Corkey, B. et al. Fatty acid transport. J Mol Neurosci 16, 99–108 (2001). https://doi.org/10.1385/JMN:16:2-3:99
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1385/JMN:16:2-3:99