Journal of Molecular Neuroscience

, Volume 33, Issue 1, pp 56–66 | Cite as

Role of Liver and Plasma Lipoproteins in Selective Transport of n-3 Fatty Acids to Tissues: A Comparative Study of 14C-DHA and 3H-Oleic Acid Tracers

  • Alla Polozova
  • Norman SalemJrEmail author


We conducted a study aimed at a direct comparison of the plasma dynamics and uptake of docosahexaenoic (DHA) and oleic (OA) fatty acids by various organs. 14C-DHA and 3H-OA were intravenously co-injected into mice. At 5 min after injection, more than 40% of the 14C-DHA, but less than 20% of the 3H-OA, labels was associated with the liver. Heart uptake of 14C-DHA was three to four times greater compared to the 3H-OA label. Brain incorporation of 14C-DHA slowly rose to 0.7% at 24 h, but it remained at the 1–1.5% level for 3H-OA. Total 14C activity in plasma reached 2% of the injected dose at 20 min and leveled off at 0.5% after 1.5 h. Fifteen percent of 14C-DHA plasma activity at 30 min was associated with non-esterified fatty acids, whereas about 85% was recovered in triglycerides in very low-density lipoprotein (VLDL) and LDL fractions. Only 30% of 3H-OA derived activity was found in the VLDL fraction at 30 min. All 3H activity in plasma at later time points was in catabolite fractions. These findings demonstrate that liver plays an important role in the initial selectivity for DHA. It is likely that DHA is specifically taken up by liver, esterified, loaded into lipoproteins, and then delivered to brain, heart, and other target tissues.


Omega-3 Docosahexaenoic acid DHA Lipoproteins Fatty acid transport 



oleic acid


docosahexaenoic acid


cholesterol ester


non-esterified fatty acid














polyunsaturated fatty acid


  1. Abumrad, N., Harmon, C., & Ibrahimi, A. (1998). Membrane transport of long-chain fatty acids: Evidence for a facilitated process. Journal of Lipid Research, 39, 2309–2318.PubMedGoogle Scholar
  2. Agren, J. J., Julkunen, A., & Penttila, I. (1992). Rapid separation of serum-lipids for fatty-acid analysis by a single aminopropyl column. Journal of Lipid Research, 33, 1871–1876.PubMedGoogle Scholar
  3. Anderson, G. J., & Connor, W. E. (1988). Uptake of fatty acids by the developing rat brain. Lipids, 23, 286–290.PubMedCrossRefGoogle Scholar
  4. Balendiran, G. K., Schnutgen, F., Scapin, G., Borchers, T., Xhong, N., Lim, K., et al. (2000). Crystal structure and thermodynamic analysis of human brain fatty acid-binding protein. Journal of Biological Chemistry, 275, 27045–27054.PubMedGoogle Scholar
  5. Bazan, N. G., & Scott, B. L. (1990). Dietary omega-3 fatty acids and accumulation of docosahexaenoic acid in rod photoreceptor cells of the retina and at synapses. Upsala Journal of Medical Sciences, 48, 97–107.PubMedGoogle Scholar
  6. Billman, G. E., Kang, J. X., & Leaf, A. (1999). Prevention of sudden cardiac death by dietary pure omega-3 polyunsaturated fatty acids in dogs. Circulation, 99, 2452–2457.PubMedGoogle Scholar
  7. Bligh, E. G., & Dyer, W. J. (1959). A rapid method of total lipid extraction and purification. Canadian Journal of Biochemistry and Physiology, 37, 911–917.PubMedGoogle Scholar
  8. bo-Hashema, K. A. H., Cake, M. H., Lukas, M. A., & Knudsen J. (1999). Evaluation of the affinity and turnover number of both hepatic mitochondrial and microsomal carnitine acyltransferases: Relevance to intracellular partitioning of acyl-CoAs. Biochemistry, 38, 15840–15847.CrossRefGoogle Scholar
  9. Campbell, F. M., Gordon, M. J., & Dutta-Roy, A. K. (1998). Placental membrane fatty acid-binding protein preferentially binds arachidonic and docosahexaenoic acids. Life Sciences, 63, 235–240.PubMedCrossRefGoogle Scholar
  10. Christie, W. W. (1985). Rapid separation and quantification of lipid classes by high-performance liquid-chromatography and mass (light-scattering) detection. Journal of Lipid Research, 26, 507–512.PubMedGoogle Scholar
  11. Christie, W. W. (1986). Separation of lipid classes by high-performance liquid-chromatography with the mass detector. Journal of Chromatography, 361, 396–399.PubMedCrossRefGoogle Scholar
  12. Crabtree, J. T., Gordon, M. J., Campbell, F. M., & Dutta-Roy, A. K. (1998). Differential distribution and metabolism of arachidonic acid and docosahexaenoic acid by human placental choriocarcinoma (BeWo) cells. Molecular and Cellular Biochemistry, 185, 191–198.PubMedCrossRefGoogle Scholar
  13. Cunnane, S. C., Menard, C. R., Likhodii, S. S., Brenna, J. T., & Crawford, M. A. (1999). Carbon recycling into de novo lipogenesis is a major pathway in neonatal metabolism of linoleate and alpha-linolenate. Prostaglandins Leukotrienes and Essential Fatty Acids, 60, 387–392.CrossRefGoogle Scholar
  14. de Lorgeril, M., Salen, P., Defaye, P., Mabo, P. & Paillard, F. (2002). Dietary prevention of sudden cardiac death. European Heart Journal, 23, 277–285.PubMedCrossRefGoogle Scholar
  15. Dehouck, B., Fenart, L., Dehouck, M. P., Pierce, A., Torpier, G., & Cecchelli, R. (1997). A new function for the LDL receptor: Transcytosis of LDL across the blood-brain barrier. Journal of Cell Biology, 138, 877–889.PubMedCrossRefGoogle Scholar
  16. Desautels, M., & Dulos, R. A. (1988). Unchanged brown adipose tissue thermogenic capacity of mice selected for high body weight. Faseb Journal, 2, A1611.Google Scholar
  17. Dutta-Roy, A. K. (2000a). Cellular uptake of long-chain fatty acids: Role of membrane-associated fatty-acid-binding/transport proteins. Cellular and Molecular Life Sciences, 57, 1360–1372.PubMedCrossRefGoogle Scholar
  18. Dutta-Roy, A. K. (2000b). Transport mechanisms for long-chain polyunsaturated fatty acids in the human placenta. American Journal of Clinical Nutrition, 71, 315S–322S.PubMedGoogle Scholar
  19. Edelstein, C. (1986). General properties of plasma lipoproteins and apolipoproteins. In A. M. Scanu & A. A. Spector (Eds.), Biochemistry and biology of plasma lipoproteins (pp. 495–505). New York: Marcel Dekker.Google Scholar
  20. Edmond, J. (2001). Essential polyunsaturated fatty acids and the barrier to the brain—The components of a model for transport. Journal of Molecular Neuroscience, 16, 181–193.PubMedCrossRefGoogle Scholar
  21. Edmond, J., Higa, T. A., Korsak, R. A., Bergner, E. A., & Lee, W. N. P. (1998). Fatty acid transport and utilization for the developing brain. Journal of Neurochemistry, 70, 1227–1234.PubMedCrossRefGoogle Scholar
  22. Edmond, J., Korsak, R. A., Morrow, J. W., Torokboth, G., & Catlin, D. H. (1991). Dietary cholesterol and the origin of cholesterol in the brain of developing rats. Journal of Nutrition, 121, 1323–1330.PubMedGoogle Scholar
  23. Ekstrom, B., Nilsson, A., & Akesson, B. (1989). Lipolysis of polyenoic fatty acid esters of human chylomicrons by lipoprotein lipase. European Journal of Clinical Investigation, 19, 259–264.PubMedCrossRefGoogle Scholar
  24. Folch, J., Lees, M., & Stanley, G. H. S. (1957). A simple method for the isolation and purification of total lipids from animal tissues. Journal of BiologicaL Chemistry, 226, 497–509.PubMedGoogle Scholar
  25. Gartner, K., Reulecke, W., Hackbarth, H., & Wollnik, F. (1987). Regression between muscular mass and body size in the comparison of mice, rats, rabbits, dogs, man and horses. Deutsche Tierarztliche Wochenschrift, 94, 52–53.PubMedGoogle Scholar
  26. Gibney, M. J., & Daly, E. (1994). The incorporation of N-3 polyunsaturated fatty-acids into plasma-lipid and lipoprotein fractions in the postprandial phase in healthy-volunteers. European Journal of Clinical Nutrition, 48, 866–872.PubMedGoogle Scholar
  27. Goti, D., Hrzenjak, A., Levak-Frank, S., Frank, S., van der Westhuyzen, D. R., Malle, E., et al. (2001). Scavenger receptor class B, type I is expressed in porcine brain capillary endothelial cells and contributes to selective uptake of HDL-associated vitamin E. Journal of Neurochemistry, 76, 498–508.PubMedCrossRefGoogle Scholar
  28. Haggarty, P., Page, K., Abramovich, D. R., Ashton, J., & Brown, D. (1997). Long-chain polyunsaturated fatty acid transport across the perfused human placenta. Placenta, 18, 635–642.PubMedCrossRefGoogle Scholar
  29. Harris, W. S., Park, Y., & Isley, W. L. (2003). Cardiovascular disease and long-chain omega-3 fatty acids. Current Opinion in Lipidology, 14, 9–14.PubMedCrossRefGoogle Scholar
  30. Heath, R. B., Karpe, F., Milne, R. W., Burdge, G. C., Wootton, S. A., & Frayn, K. N. (2003). Selective partitioning of dietary fatty acids into the VLDL TG pool in the early postprandial period. Journal of Lipid Research, 44, 2065–2072.PubMedCrossRefGoogle Scholar
  31. Herz, J. (2001). The LDL receptor gene family: (Un)expected signal transducers in the brain. Neuron, 29, 571–581.PubMedCrossRefGoogle Scholar
  32. Herz, J., & Bock, H. H. (2002). Lipoprotein receptors in the nervous system. Annual Review of Biochemistry, 71, 405–434.PubMedCrossRefGoogle Scholar
  33. Hirafuji, M., Machida, T., Hamaue, N., & Minami, M. (2003). Cardiovascular protective effects of n-3 polyunsaturated fatty acids with special emphasis on docosahexaenoic acid. Journal of Pharmacological Sciences, 92, 308–316.PubMedCrossRefGoogle Scholar
  34. Kang, J. X., & Leaf, A. (1996). Evidence that free polyunsaturated fatty acids modify Na+ channels by directly binding to the channel proteins. Proceedings of the National Academy of Sciences of the United States of America, 93, 3542–3546.PubMedCrossRefGoogle Scholar
  35. Kang, J. X., & Leaf, A. (2000). Prevention of fatal cardiac arrhythmias by polyunsaturated fatty acids. American Journal of Clinical Nutrition, 71, 202S–207S.PubMedGoogle Scholar
  36. Lagarde, M., Bernoud, N., Brossard, N., Lemaitre-Delaunay, D., Thies, F., Croset, M., et al. (2001). Lysophosphatidylcholine as a preferred carrier form of docosahexaenoic acid to the brain. Journal of Molecular Neuroscience, 16, 201–204.PubMedCrossRefGoogle Scholar
  37. Lands, W. E. M. (2003). Diets could prevent many diseases. Lipids, 38, 317–321.PubMedCrossRefGoogle Scholar
  38. Lang, C. A., & Davis, R. A. (1990). Fish oil fatty acids impair VLDL assembly and or secretion by cultured rat hepatocytes. Journal of Lipid Research, 31, 2079–2086.PubMedGoogle Scholar
  39. Larque, E., Demmelmair, H., Berger, B., Hasbargen, U., & Koletzko, B. (2003). In vivo investigation of the placental transfer of C-13-labeled fatty acids in humans. Journal of Lipid Research, 44, 49–55.PubMedCrossRefGoogle Scholar
  40. Leaf, A., Kang, J. X., Xiao, Y. F., Billman, G. E., & Voskuyl, R. A. (1999). Functional and electrophysiologic effects of polyunsaturated fatty acids on excitable tissues: heart and brain. Prostaglandins Leukotrienes and Essential Fatty Acids, 60, 307–312.CrossRefGoogle Scholar
  41. Leaf, A., Xiao, Y. F., Kang, J. X., & Billman, G. E. (2003). Prevention of sudden cardiac death by n-3 polyunsaturated fatty acids. Pharmacology & Therapeutics, 98, 355–377.CrossRefGoogle Scholar
  42. Lottenberg, A. M. P., Oliveira, H. C. F., Nakandakare, E. R., & Quintao, E. C. R. (1992). Effect of dietary fish oil on the rate of very low-density-lipoprotein triacylglycerol formation and on the metabolism of chylomicrons. Lipids, 27, 326–330.PubMedCrossRefGoogle Scholar
  43. Marbois, B. N., Ajie, H. O., Korsak, R. A., Sensharma, D. K., & Edmond, J. (1992). The origin of palmitic acid in brain of the developing rat. Lipids, 27, 587–592.PubMedCrossRefGoogle Scholar
  44. Martin, D. D., Robbins, M. E. C., Spector, A. A., Wen, B. C., & Hussey, D. H. (1996). The fatty acid composition of human gliomas differs from that found in nonmalignant brain tissue. Lipids, 31, 1283–1288.PubMedCrossRefGoogle Scholar
  45. McArthur, M. J., Atshaves, B. P., Frolov, A., Foxworth, W. D., Kier, A. B., & Schroeder, F. (1999). Cellular uptake and intracellular trafficking of long chain fatty acids. Journal of Lipid Research, 40, 1371–1383.PubMedGoogle Scholar
  46. Melin, T., Qi, C., Bengtssonolivecrona, G., Akesson, B., & Nilsson, A. (1991). Hydrolysis of chylomicron polyenoic fatty acid esters with lipoprotein lipase and hepatic lipase. Biochimica et Biophysica Acta, 1075, 259–266.PubMedGoogle Scholar
  47. Meresse, S., Delbart, C., Fruchart, J. C., & Cecchelli, R. (1989). Low-density lipoprotein receptor on endothelium of brain capillaries. Journal of Neurochemistry, 53, 340–345.PubMedCrossRefGoogle Scholar
  48. Mitchell, D. C., Gawrisch, K., Litman, B. J., & Salem, N. (1998). Why is docosahexaenoic acid essential for nervous system function? Biochemical Society Transactions, 26, 365–370.PubMedGoogle Scholar
  49. Moriguchi, T., Loewke, J., Garrison, M., Catalan, J. N., & Salem, N. (2001). Reversal of docosahexaenoic acid deficiency in the rat brain, retina, liver, and serum. Journal of Lipid Research, 42, 419–427.PubMedGoogle Scholar
  50. Morris, M. D., & Chaikoff, L. L. (1961). Concerning incorporation of labeled cholesterol, fed to the mothers, into brain cholesterol of 20-day-old suckling rats. Journal of Neurochemistry, 8, 226–229.PubMedCrossRefGoogle Scholar
  51. Nair, S. S. D., Leitch, J. W., Falconer, J., & Garg, M. L. (1997). Prevention of cardiac arrhythmia by dietary (n-3) polyunsaturated fatty acids and their mechanism of action. Journal of Nutrition, 127, 383–393.PubMedGoogle Scholar
  52. Nair, S. S. D., Leitch, J., Falconer, J., & Garg, M. L. (1999). Cardiac (n-3) non-esterified fatty acids are selectively increased in fish oil-fed pigs following myocardial ischemia. Journal of Nutrition, 129, 1518–1523.PubMedGoogle Scholar
  53. Norris, A. W., & Spector, A. A. (2002). Very long chain n-3 and n-6 polyunsaturated fatty acids bind strongly to liver fatty acid-binding protein. Journal of Lipid Research, 43, 646–653.PubMedGoogle Scholar
  54. Panzenboeck, U., Balazs, Z., Sovic, A., Hrzenjak, A., Levak-Frank, S., Wintersperger, A., et al. (2002). ABCA1 and scavenger receptor class B, type I, are modulators of reverse sterol transport at an in vitro blood-brain barrier constituted of porcine brain capillary endothelial cells. Journal of Biological Chemistry, 277, 42781–42789.PubMedCrossRefGoogle Scholar
  55. Pardridge, W. M., & Mietus, L. J. (1980). Palmitate and cholesterol transport through the blood–brain barrier. Journal of Neurochemistry, 34, 463–466.PubMedCrossRefGoogle Scholar
  56. Parks, J. S., Johnson, F. L., Wilson, M. D., & Rudel, L. L. (1990). Effect of fish oil diet on hepatic lipid-metabolism in nonhuman primates: Lowering of secretion of hepatic triglyceride but not apoB. Journal of Lipid Research, 31, 455–466.PubMedGoogle Scholar
  57. Pawlosky, R., Barnes, A., & Salem, N. (1994). Essential fatty acid metabolism in the feline: relationship between liver and brain production of long-chain polyunsaturated fatty acids. Journal of Lipid Research, 35, 2032–2040.PubMedGoogle Scholar
  58. Polozova, A., Gionfriddo, E., & Salem, N., Jr. (2006) Effect of DHA on tissue targeting and metabolism of plasma lipoproteins. Prostaglandins, Leukotrienes and Essential Fatty Acids, 75(3), 183–190.CrossRefGoogle Scholar
  59. Pound, E. M., Kang, J. X., & Leaf, A. (2001). Partitioning of polyunsaturated fatty acids, which prevent cardiac arrhythmias, into phospholipid cell membranes. Journal of Lipid Research, 42, 346–351.PubMedGoogle Scholar
  60. Rapoport, S. I., Chang, M. C. J., & Spector, A. A. (2001). Delivery and turnover of plasma-derived essential PUFAs in mammalian brain. Journal of Lipid Research, 42, 678–685.PubMedGoogle Scholar
  61. Sadou, H., Leger, C. L., Descomps, B., Barjon, J. N., Monnier, L., & Depaulet, A. C. (1995). Differential incorporation of fish-oil eicosapentaenoate and docosahexaenoate into lipids of lipoprotein fractions as related to their glyceryl esterification: A short-term (postprandial) and long-term study in healthy humans. American Journal of Clinical Nutrition, 62, 1193–1200.PubMedGoogle Scholar
  62. Salem, N. (1989). Omega-3 fatty acids: Molecular and biochemical aspects. In G. A. Spiller & J. Scala, (Eds), New protective roles for selected nutrients (pp. 109–228). New York: Alan R. Liss, Inc.Google Scholar
  63. Schneider, W. J., & Nimpf, J. (2003). LDL receptor relatives at the crossroad of endocytosis and signaling. Cellular and Molecular Life Sciences, 60, 892–903.PubMedCrossRefGoogle Scholar
  64. Scott, B. L., & Bazan, N. G. (1989). Membrane docosahexaenoate is supplied to the developing brain and retina by the liver. Proceedings of the National Academy of Sciences of the United States of America, 86, 2903–2907.PubMedCrossRefGoogle Scholar
  65. Sinclair, A. J., & Crawford, M. A. (1972). Incorporation of linolenic acid and docosahexaenoic acid into liver and brain lipids of developing rats. Febs Letters, 26, 127–129.PubMedCrossRefGoogle Scholar
  66. Sovic, A., Balazs, Z., Hrzenjak, A., Reicher, H., Panzenboeck, U., Malle, E., et al. (2004). Scavenger receptor class B, type I mediates uptake of lipoprotein-associated phosphatidylcholine by primary porcine cerebrovascular endothelial cells. Neuroscience Letters, 368, 11–14.PubMedCrossRefGoogle Scholar
  67. Speake, B. K., Deans, E. A., & Powell, K. A. (2003). Differential incorporation of docosahexaenoic and arachidonic acids by the yolk sac membrane of the avian embryo. Comparative Biochemistry and Physiology B. Biochemistry & Molecular Biology, 136, 357–367.CrossRefGoogle Scholar
  68. Spector, A. A. (2001). Plasma free fatty acid and lipoproteins as sources of polyunsaturated fatty acid for the brain. Journal of Molecular Neuroscience, 16, 159–165.PubMedCrossRefGoogle Scholar
  69. Srivastava, R. A. K. (2003). Scavenger receptor class B type I expression in murine brain and regulation by estrogen and dietary cholesterol. Journal of the Neurological Sciences, 210, 11–18.PubMedCrossRefGoogle Scholar
  70. Strickland, D. K., Gonias, S. L., & Argraves, W. S. (2002). Diverse roles for the LDL receptor family. Trends in Endocrinology and Metabolism, 13, 66–74.PubMedCrossRefGoogle Scholar
  71. Weylandt, K. H., Kang, J. X., & Leaf, A. (1996). Polyunsaturated fatty acids exert antiarrhythmic actions as free acids rather than in phospholipids. Lipids, 31, 977–982.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2007

Authors and Affiliations

  1. 1.Laboratory of Membrane Biochemistry and BiophysicsNational Institute on Alcohol Abuse and AlcoholismBethesdaUSA

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