Review

Fatty acid transport: difficult or easy?

Transport of unesterified fatty acids (FA) into cells has been viewed either as a simple diffusion process regulated mainly by lipid physical chemistry or as a more complex process involving protein catalysis. In this review FA transport in cell membranes is broken down into three essential steps: adsorption, transmembrane movement, and desorption. The physical properties of FA in aqueous, membrane, and protein environments relevant to transport mechanisms are discussed, with emphasis on recent information derived from NMR and fluorescence studies. Because of their low solubility in water and high hydrophobicity, FA bind rapidly and avidly to model membranes (phospholipid bilayers); if albumin is a donor, FA desorb rapidly to reach their equilibrium distribution between the membrane and albumin. The ionization properties of FA in a phospholipid bilayer result in a high population of the un-ionized form (~50%) at pH 7.4, which diffuses across the lipid bilayer (flip-flops) rapidly (t_1/2 < 1 sec). Desorption of FA from a phospholipid surface is slower than transmembrane movement and dependent on the FA chain length and unsaturation, but is rapid for typical dietary FA. These physical properties of FA in model systems predict that proteins are not essential for transport of FA through membranes. The only putative FA transport protein to be purified and reconstituted into phospholipid bilayers, the mitochondrial uncoupling protein (UCP1), was shown to transport the FA anion in response to FA flip-flop. New experiments with cells have found that FA movement into cells acidifies the cytosol, as predicted by the flip-flop model.— Hamilton, J. A. Fatty acid transport: difficult or easy? J. Lipid Res. 1998. 39: 467–481.

Supplementary key words: albumin, diffusion, fluorescence, intracellular pH, phospholipid bilayer, membrane, NMR, transbilayer movement, uncoupling protein, vesicles

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				V. A. Drover, D. V. Nguyen, C. C. Bastie, Y. F. Darlington, N. A. Abumrad, J. E. Pessin, E. London, D. Sahoo, and M. C. Phillips CD36 Mediates Both Cellular Uptake of Very Long Chain Fatty Acids and Their Intestinal Absorption in Mice J. Biol. Chem., May 9, 2008; 283(19): 13108 - 13115. [Abstract] [Full Text] [PDF]

				W. Hsueh, E. D. Abel, J. L. Breslow, N. Maeda, R. C. Davis, E. A. Fisher, H. Dansky, D. A. McClain, R. McIndoe, M. K. Wassef, et al. Recipes for Creating Animal Models of Diabetic Cardiovascular Disease Circ. Res., May 25, 2007; 100(10): 1415 - 1427. [Abstract] [Full Text] [PDF]

				W. Guo, N. Huang, J. Cai, W. Xie, and J. A. Hamilton Fatty acid transport and metabolism in HepG2 cells Am J Physiol Gastrointest Liver Physiol, March 1, 2006; 290(3): G528 - G534. [Abstract] [Full Text] [PDF]

				A R Weale, A G Edwards, M Bailey, and P A Lear Intestinal adaptation after massive intestinal resection Postgrad. Med. J., March 1, 2005; 81(953): 178 - 184. [Abstract] [Full Text] [PDF]

				K. Brunaldi, M. A. Miranda, F. Abdulkader, R. Curi, and J. Procopio Fatty acid flip-flop and proton transport determined by short-circuit current in planar bilayers J. Lipid Res., February 1, 2005; 46(2): 245 - 251. [Abstract] [Full Text] [PDF]

				L. Belayev, V. L. Marcheselli, L. Khoutorova, E. B. Rodriguez de Turco, R. Busto, M. D. Ginsberg, and N. G. Bazan Docosahexaenoic Acid Complexed to Albumin Elicits High-Grade Ischemic Neuroprotection Stroke, January 1, 2005; 36(1): 118 - 123. [Abstract] [Full Text] [PDF]

				J. P. Kampf and A. M. Kleinfeld Fatty Acid Transport in Adipocytes Monitored by Imaging Intracellular Free Fatty Acid Levels J. Biol. Chem., August 20, 2004; 279(34): 35775 - 35780. [Abstract] [Full Text] [PDF]

				I. A. Chen and J. W. Szostak A Kinetic Study of the Growth of Fatty Acid Vesicles Biophys. J., August 1, 2004; 87(2): 988 - 998. [Abstract] [Full Text] [PDF]

				M. Faraj and K. Cianflone Differential regulation of fatty acid trapping in mouse adipose tissue and muscle by ASP Am J Physiol Endocrinol Metab, July 1, 2004; 287(1): E150 - E159. [Abstract] [Full Text] [PDF]

				I. A. Chen and J. W. Szostak Membrane growth can generate a transmembrane pH gradient in fatty acid vesicles PNAS, May 25, 2004; 101(21): 7965 - 7970. [Abstract] [Full Text] [PDF]

				A. J. K. Koo, J. B. Ohlrogge, and M. Pollard On the Export of Fatty Acids from the Chloroplast J. Biol. Chem., April 16, 2004; 279(16): 16101 - 16110. [Abstract] [Full Text] [PDF]

				J. Ulander and A. D. J. Haymet Permeation Across Hydrated DPPC Lipid Bilayers: Simulation of the Titrable Amphiphilic Drug Valproic Acid Biophys. J., December 1, 2003; 85(6): 3475 - 3484. [Abstract] [Full Text] [PDF]

				P. N. Black and C. C. DiRusso Transmembrane Movement of Exogenous Long-Chain Fatty Acids: Proteins, Enzymes, and Vectorial Esterification Microbiol. Mol. Biol. Rev., September 1, 2003; 67(3): 454 - 472. [Abstract] [Full Text] [PDF]

				D. G. Mashek and R. R. Grummer Short Communication: Net Uptake of Nonesterified Long Chain Fatty Acids by the Perfused Caudate Lobe of the Caprine Liver J Dairy Sci, April 1, 2003; 86(4): 1218 - 1220. [Abstract] [Full Text] [PDF]

				F. Kamp, W. Guo, R. Souto, P. F. Pilch, B. E. Corkey, and J. A. Hamilton Rapid Flip-flop of Oleic Acid across the Plasma Membrane of Adipocytes J. Biol. Chem., February 28, 2003; 278(10): 7988 - 7995. [Abstract] [Full Text] [PDF]

				P. Suriyaphol, D. Fenske, U. Zahringer, S.-R. Han, S. Bhakdi, and M. Husmann Enzymatically Modified Nonoxidized Low-Density Lipoprotein Induces Interleukin-8 in Human Endothelial Cells: Role of Free Fatty Acids Circulation, November 12, 2002; 106(20): 2581 - 2587. [Abstract] [Full Text] [PDF]

				J. K. Ho, R. I. Duclos Jr., and J. A. Hamilton Interactions of acyl carnitines with model membranes: a 13C-NMR study J. Lipid Res., September 1, 2002; 43(9): 1429 - 1439. [Abstract] [Full Text] [PDF]

				Z. Zou, C. C. DiRusso, V. Ctrnacta, and P. N. Black Fatty Acid Transport in Saccharomyces cerevisiae. DIRECTED MUTAGENESIS OF FAT1 DISTINGUISHES THE BIOCHEMICAL ACTIVITIES ASSOCIATED WITH Fat1p J. Biol. Chem., August 16, 2002; 277(34): 31062 - 31071. [Abstract] [Full Text] [PDF]

				H. Huang, O. Starodub, A. McIntosh, A. B. Kier, and F. Schroeder Liver Fatty Acid-binding Protein Targets Fatty Acids to the Nucleus. REAL TIME CONFOCAL AND MULTIPHOTON FLUORESCENCE IMAGING IN LIVING CELLS J. Biol. Chem., August 2, 2002; 277(32): 29139 - 29151. [Abstract] [Full Text] [PDF]

				M. Chen, Y. Yang, E. Braunstein, K. E. Georgeson, and C. M. Harmon Gut expression and regulation of FAT/CD36: possible role in fatty acid transport in rat enterocytes Am J Physiol Endocrinol Metab, November 1, 2001; 281(5): E916 - E923. [Abstract] [Full Text] [PDF]

				D. D. Stump, X. Fan, and P. D. Berk Oleic acid uptake and binding by rat adipocytes define dual pathways for cellular fatty acid uptake J. Lipid Res., April 1, 2001; 42(4): 509 - 520. [Abstract] [Full Text]

				H. Ruan and H. J. Pownall Overexpression of 1-Acyl-Glycerol-3-Phosphate Acyltransferase-{alpha} Enhances Lipid Storage in Cellular Models of Adipose Tissue and Skeletal Muscle Diabetes, February 1, 2001; 50(2): 233 - 240. [Abstract] [Full Text]

				F. Caserta, T. Tchkonia, V. N. Civelek, M. Prentki, N. F. Brown, J. D. McGarry, R. A. Forse, B. E. Corkey, J. A. Hamilton, and J. L. Kirkland Fat depot origin affects fatty acid handling in cultured rat and human preadipocytes Am J Physiol Endocrinol Metab, February 1, 2001; 280(2): E238 - E247. [Abstract] [Full Text] [PDF]

				S. Muthian, K. Nithipatikom, W. B. Campbell, and C. J. Hillard Synthesis and Characterization of a Fluorescent Substrate for the N-Arachidonoylethanolamine (Anandamide) Transmembrane Carrier J. Pharmacol. Exp. Ther., April 1, 2000; 293(1): 289 - 295. [Abstract] [Full Text]

				F. Rakhshan, T. A. Day, R. D. Blakely, and E. L. Barker Carrier-Mediated Uptake of the Endogenous Cannabinoid Anandamide in RBL-2H3 Cells J. Pharmacol. Exp. Ther., March 1, 2000; 292(3): 960 - 967. [Abstract] [Full Text]

				M.-L. Wu, C.-C. Chan, and M.-J. Su Possible Mechanism(s) of Arachidonic Acid-Induced Intracellular Acidosis in Rat Cardiac Myocytes Circ. Res., February 18, 2000; 86 (3): e55 - e62. [Abstract] [Full Text] [PDF]

				G. J van der Vusse, M. van Bilsen, and J. F.C Glatz Cardiac fatty acid uptake and transport in health and disease Cardiovasc Res, January 14, 2000; 45(2): 279 - 293. [Abstract] [Full Text] [PDF]

				P. D. Berk, S.-L. Zhou, C.-L. Kiang, D. D. Stump, X. Fan, and M. W. Bradbury Selective Up-regulation of Fatty Acid Uptake by Adipocytes Characterizes Both Genetic and Diet-induced Obesity in Rodents J. Biol. Chem., October 1, 1999; 274(40): 28626 - 28631. [Abstract] [Full Text] [PDF]

				F. G. Schaap, B. Binas, H. Danneberg, G. J. van der Vusse, and J. F. C. Glatz Impaired Long-Chain Fatty Acid Utilization by Cardiac Myocytes Isolated From Mice Lacking the Heart-Type Fatty Acid Binding Protein Gene Circ. Res., August 20, 1999; 85(4): 329 - 337. [Abstract] [Full Text] [PDF]

				M. J. McArthur, B. P. Atshaves, A. Frolov, W. D. Foxworth, A. B. Kier, and F. Schroeder Cellular uptake and intracellular trafficking of long chain fatty acids J. Lipid Res., August 1, 1999; 40(8): 1371 - 1383. [Abstract] [Full Text]

				J. Luchoomun and M. M. Hussain Assembly and Secretion of Chylomicrons by Differentiated Caco-2 Cells. NASCENT TRIGLYCERIDES AND PREFORMED PHOSPHOLIPIDS ARE PREFERENTIALLY USED FOR LIPOPROTEIN ASSEMBLY J. Biol. Chem., July 9, 1999; 274(28): 19565 - 19572. [Abstract] [Full Text] [PDF]

				L. P. Turcotte, J. R. Swenberger, M. Z. Tucker, and A. J. Yee Training-induced elevation in FABPPM is associated with increased palmitate use in contracting muscle J Appl Physiol, July 1, 1999; 87(1): 285 - 293. [Abstract] [Full Text] [PDF]

				N. Abumrad, C. Harmon, and A. Ibrahimi Membrane transport of long-chain fatty acids: evidence for a facilitated process J. Lipid Res., December 1, 1998; 39(12): 2309 - 2318. [Abstract] [Full Text]

				C. T. Coburn, F. F. Knapp Jr., M. Febbraio, A. L. Beets, R. L. Silverstein, and N. A. Abumrad Defective Uptake and Utilization of Long Chain Fatty Acids in Muscle and Adipose Tissues of CD36 Knockout Mice J. Biol. Chem., October 13, 2000; 275(42): 32523 - 32529. [Abstract] [Full Text] [PDF]

				B. A. Ek-von Mentzer, F. Zhang, and J. A. Hamilton Binding of 13-HODE and 15-HETE to Phospholipid Bilayers, Albumin, and Intracellular Fatty Acid Binding Proteins. IMPLICATIONS FOR TRANSMEMBRANE AND INTRACELLULAR TRANSPORT AND FOR PROTECTION FROM LIPID PEROXIDATION J. Biol. Chem., May 4, 2001; 276(19): 15575 - 15580. [Abstract] [Full Text] [PDF]

				J. J. F. P. Luiken, Y. Arumugam, D. J. Dyck, R. C. Bell, M. M. L. Pelsers, L. P. Turcotte, N. N. Tandon, J. F. C. Glatz, and A. Bonen Increased Rates of Fatty Acid Uptake and Plasmalemmal Fatty Acid Transporters in Obese Zucker Rats J. Biol. Chem., October 26, 2001; 276(44): 40567 - 40573. [Abstract] [Full Text] [PDF]

				S. E. Lewis, L. L. Listenberger, D. S. Ory, and J. E. Schaffer Membrane Topology of the Murine Fatty Acid Transport Protein 1 J. Biol. Chem., September 28, 2001; 276(40): 37042 - 37050. [Abstract] [Full Text] [PDF]

				J. Ray, F. Noll, J. Daut, and P. J. Hanley Long-chain fatty acids increase basal metabolism and depolarize mitochondria in cardiac muscle cells Am J Physiol Heart Circ Physiol, April 1, 2002; 282(4): H1495 - H1501. [Abstract] [Full Text] [PDF]