Prostaglandins, Leukotrienes and Essential Fatty Acids
Volume 80, Issue 2 , Pages 85-91 , February 2009

α-Linolenic acid supplementation and conversion to n-3 long-chain polyunsaturated fatty acids in humans

  • J. Thomas Brenna

      Affiliations

    • Division of Nutritional Sciences, Cornell University, Savage Hall, Ithaca, NY 14853, USA
    • Corresponding Author InformationCorresponding author.
    • ,
  • Norman Salem Jr.

      Affiliations

    • Martek Biosciences Inc., 6480 Dobbin Road, Columbia, MD 21045, USA
    • ,
  • Andrew J. Sinclair

      Affiliations

    • Deakin University, School of Exercise & Nutrition Sciences & Metabolic Research Unit, 221 Burwood Highway, Burwood, Victoria 3125, Australia
    • ,
  • Stephen C. Cunnane

      Affiliations

    • Research Center on Aging, Université de Sherbrooke, Sherbrooke, Quebec, Canada
    • ,
  • for the International Society for the Study of Fatty Acids and Lipids, ISSFAL

Received 15 January 2009 ,Accepted 15 January 2009.

References 

  1. Bloedon LT, Balikai S, Chittams J, et al. Flaxseed and cardiovascular risk factors: results from a double blind, randomized, controlled clinical trial. J. Am. Coll. Nutr. 2008;27:65–74
  2. Terano T, Hirai A, Hamazaki T, et al. Effect of oral administration of highly purified eicosapentaenoic acid on platelet function, blood viscosity and red cell deformability in healthy human subjects. Atherosclerosis. 1983;46:321–331
  3. Hirai A, Terano T, Saito H, et al. Omega-3 fatty acids: epidemiological and clinical aspects. In:  Spiller GA,  Scala J editor. New Protective Roles for Selected Nutrients. New York: Alan R. Liss; 1989;p. 229–252
  4. Goyens PL, Spilker ME, Zock PL, et al. Conversion of alpha-linolenic acid in humans is influenced by the absolute amounts of alpha-linolenic acid and linoleic acid in the diet and not by their ratio. Am. J. Clin. Nutr. 2006;84:44–53
  5. Harper CR, Edwards MJ, DeFilipis AP, et al. Flaxseed oil increases the plasma concentrations of cardioprotective (n-3) fatty acids in humans. J. Nutr. 2006;136:83–87
  6. Grimsgaard S, Bonaa KH, Hansen JB, et al. Highly purified eicosapentaenoic acid and docosahexaenoic acid in humans have similar triacylglycerol-lowering effects but divergent effects on serum fatty acids. Am. J. Clin. Nutr. 1997;66:649–659
  7. de Groot RH, Hornstra G, van Houwelingen AC, et al. Effect of alpha-linolenic acid supplementation during pregnancy on maternal and neonatal polyunsaturated fatty acid status and pregnancy outcome. Am. J. Clin. Nutr. 2004;79:251–260
  8. Mori TA, Burke V, Puddey IB, et al. Purified eicosapentaenoic and docosahexaenoic acids have differential effects on serum lipids and lipoproteins, ldl particle size, glucose, and insulin in mildly hyperlipidemic men. Am. J. Clin. Nutr. 2000;71:1085–1094
  9. James MJ, Ursin VM, Cleland LG. Metabolism of stearidonic acid in human subjects: comparison with the metabolism of other n-3 fatty acids. Am. J. Clin. Nutr. 2003;77:1140–1145
  10. Park Y, Harris W. EPA, but not DHA, decreases mean platelet volume in normal subjects. Lipids. 2002;37:941–946
  11. Woodman RJ, Mori TA, Burke V, et al. Effects of purified eicosapentaenoic and docosahexaenoic acids on glycemic control, blood pressure, and serum lipids in type 2 diabetic patients with treated hypertension. Am. J. Clin. Nutr. 2002;76:1007–1015
  12. Finnegan YE, Minihane AM, Leigh-Firbank EC, et al. Plant- and marine-derived n-3 polyunsaturated fatty acids have differential effects on fasting and postprandial blood lipid concentrations and on the susceptibility of ldl to oxidative modification in moderately hyperlipidemic subjects. Am. J. Clin. Nutr. 2003;77:783–795
  13. Brenna JT. Efficiency of conversion of alpha-linolenic acid to long chain n-3 fatty acids in man. Curr. Opin. Clin. Nutr. Metab. Care. 2002;5:127–132
  14. Burdge GC, Calder PC. Conversion of alpha-linolenic acid to longer chain polyunsaturated fatty acids in human adults. Reprod. Nutr. Dev. 2005;45:581–597
  15. Burdge G. Alpha-linolenic acid metabolism in men and women: nutritional and biological implications. Curr. Opin. Clin. Nutr. Metab. Care. 2004;7:137–144
  16. Plourde M, Cunnane SC. Extremely limited synthesis of long chain polyunsaturates in adults: Implications for their dietary essentiality and use as supplements. Appl. Physiol. Nutr. Metab. 2007;32:619–634
  17. Sinclair AJ, Attar-Bashi NM, Li D. What is the role of alpha-linolenic acid for mammals?. Lipids. 2002;37:1113–1123
  18. Peet M, Brind J, Ramchand CN, et al. Two double-blind placebo-controlled pilot studies of eicosapentaenoic acid in the treatment of schizophrenia. Schizophr. Res. 2001;49:243–251
  19. Wallace FA, Miles EA, Calder PC. Comparison of the effects of linseed oil and different doses of fish oil on mononuclear cell function in healthy human subjects. Br. J. Nutr. 2003;89:679–689
  20. Woods J, Ward G, Salem N. Is docosahexaenoic acid necessary in infant formula? Evaluation of high linolenate diets in the neonatal rat. Pediatr. Res. 1996;40:687–694
  21. Francois CA, Connor SL, Bolewicz LC, et al. Supplementing lactating women with flaxseed oil does not increase docosahexaenoic acid in their milk. Am. J. Clin. Nutr. 2003;77:226–233
  22. Abedin L, Lien EL, Vingrys AJ, et al. The effects of dietary alpha-linolenic acid compared with docosahexaenoic acid on brain, retina, liver, and heart in the guinea pig. Lipids. 1999;34:475–482
  23. Li D, Sinclair A, Wilson A, et al. Effect of dietary alpha-linolenic acid on thrombotic risk factors in vegetarian men. Am. J. Clin. Nutr. 1999;69:872–882
  24. Bowen RA, Clandinin MT. Maternal dietary 22: 6n-3 is more effective than 18: 3n-3 in increasing the 22: 6n-3 content in phospholipids of glial cells from neonatal rat brain. Br. J. Nutr. 2005;93:601–611
  25. Ezaki O, Takahashi M, Shigematsu T, et al. Long-term effects of dietary alpha-linolenic acid from perilla oil on serum fatty acids composition and on the risk factors of coronary heart disease in japanese elderly subjects. J. Nutr. Sci. Vitaminol. (Tokyo). 1999;45:759–772
  26. Lefkowitz W, Lim SY, Lin Y, et al. Where does the developing brain obtain its docosahexaenoic acid? Relative contributions of dietary alpha-linolenic acid, docosahexaenoic acid, and body stores in the developing rat. Pediatr. Res. 2005;57:157–165
  27. Allman MA, Pena MM, Pang D. Supplementation with flaxseed oil versus sunflowerseed oil in healthy young men consuming a low fat diet: effects on platelet composition and function. Eur. J. Clin. Nutr. 1995;49:169–178
  28. Nordstrom DC, Honkanen VE, Nasu Y, et al. Alpha-linolenic acid in the treatment of rheumatoid arthritis. A double-blind, placebo-controlled and randomized study: flaxseed vs. Safflower seed. Rheumatol. Int. 1995;14:231–234
  29. Fu Z, Sinclair AJ. Increased alpha-linolenic acid intake increases tissue alpha-linolenic acid content and apparent oxidation with little effect on tissue docosahexaenoic acid in the guinea pig. Lipids. 2000;35:395–400
  30. Cunnane SC, Hamadeh MJ, Liede AC, et al. Nutritional attributes of traditional flaxseed in healthy young adults. Am. J. Clin. Nutr. 1995;61:62–68
  31. Mantzioris E, James MJ, Gibson RA, et al. Differences exist in the relationships between dietary linoleic and alpha-linolenic acids and their respective long-chain metabolites. Am. J. Clin. Nutr. 1995;61:320–324
  32. Bowen RA, Clandinin MT. High dietary 18:3n-3 increases the 18:3n-3 but not the 22:6n-3 content in the whole body, brain, skin, epididymal fat pads, and muscles of suckling rat pups. Lipids. 2000;35:389–394
  33. Freese R, Mutanen M, Valsta LM, et al. Comparison of the effects of two diets rich in monounsaturated fatty acids differing in their linoleic/alpha-linolenic acid ratio on platelet aggregation. Thromb. Haemostasis. 1994;71:73–77
  34. Cunnane SC, Anderson MJ. The majority of dietary linoleate in growing rats is beta-oxidized or stored in visceral fat. J. Nutr. 1997;127:146–152
  35. Kelley DS, Nelson GJ, Love JE, et al. Dietary alpha-linolenic acid alters tissue fatty acid composition, but not blood lipids, lipoproteins or coagulation status in humans. Lipids. 1993;28:533–537
  36. Cunnane SC, Ryan MA, Nadeau CR, et al. Why is carbon from some polyunsaturates extensively recycled into lipid synthesis?. Lipids. 2003;38:477–484
  37. Chan JK, McDonald BE, Gerrard JM, et al. Effect of dietary alpha-linolenic acid and its ratio to linoleic acid on platelet and plasma fatty acids and thrombogenesis. Lipids. 1993;28:811–817
  38. Lin YH, Salem N. Whole body distribution of deuterated linoleic and alpha-linolenic acids and their metabolites in the rat. J. Lipid Res. 2007;48:2709–2724
  39. Mutanen M, Freese R, Valsta LM, et al. Rapeseed oil and sunflower oil diets enhance platelet in vitro aggregation and thromboxane production in healthy men when compared with milk fat or habitual diets. Thromb. Haemostasis. 1992;67:352–356
  40. Pawlosky R, Barnes A, Salem N. Essential fatty acid metabolism in the feline: relationship between liver and brain production of long-chain polyunsaturated fatty acids. J. Lipid Res. 1994;35:2032–2040
  41. Kwon JS, Snook JT, Wardlaw GM, et al. Effects of diets high in saturated fatty acids, canola oil, or safflower oil on platelet function, thromboxane b2 formation, and fatty acid composition of platelet phospholipids. Am. J. Clin. Nutr. 1991;54:351–358
  42. Rivers JP, Sinclair AJ, Craqford MA. Inability of the cat to desaturate essential fatty acids. Nature. 1975;258:171–173
  43. Clark KJ, Makrides M, Neumann MA, et al. Determination of the optimal ratio of linoleic acid to alpha-linolenic acid in infant formulas. J. Pediatr. 1992;120:S151–S158
  44. Heinemann KM, Waldron MK, Bigley KE, et al. Long-chain (n-3) polyunsaturated fatty acids are more efficient than alpha-linolenic acid in improving electroretinogram responses of puppies exposed during gestation, lactation, and weaning. J. Nutr. 2005;135:1960–1966
  45. Jensen CL, Chen H, Fraley JK, et al. Biochemical effects of dietary linoleic/alpha-linolenic acid ratio in term infants. Lipids. 1996;31:107–113
  46. Bauer JE, Heinemann KM, Bigley KE, et al. Maternal diet alpha-linolenic acid during gestation and lactation does not increase docosahexaenoic acid in canine milk. J. Nutr. 2004;134:2035S–2038S
  47. Huang MC, Craig-Schmidt MC. Arachidonate and docosahexaenoate added to infant formula influence fatty acid composition and subsequent eicosanoid production in neonatal pigs. J. Nutr. 1996;126:2199–2208
  48. de la Presa-Owens S, Innis SM, Rioux FM. Addition of triglycerides with arachidonic acid or docosahexaenoic acid to infant formula has tissue- and lipid class-specific effects on fatty acids and hepatic desaturase activities in formula-fed piglets. J. Nutr. 1998;128:1376–1384
  49. Arbuckle LD, Rioux FM, Mackinnon MJ, et al. Response of (n-3) and (n-6) fatty acids in piglet brain, liver and plasma to increasing, but low, fish oil supplementation of formula. J. Nutr. 1991;121:1536–1547
  50. Huang MC, Brenna JT, Chao AC, et al. Differential tissue dose responses of (n-3) and (n-6) PUFA in neonatal piglets fed docosahexaenoate and arachidonoate. J. Nutr. 2007;137:2049–2055
  51. Su HM, Bernardo L, Mirmiran M, et al. Dietary 18:3n-3 and 22:6n-3 as sources of 22:6n-3 accretion in neonatal baboon brain and associated organs. Lipids. 1999;34:S347–S350
  52. Su HM, Bernardo L, Mirmiran M, et al. Bioequivalence of dietary alpha-linolenic and docosahexaenoic acids as sources of docosahexaenoate accretion in brain and associated organs of neonatal baboons. Pediatr. Res. 1999;45:87–93
  53. Greiner RC, Winter J, Nathanielsz PW, et al. Brain docosahexaenoate accretion in fetal baboons: bioequivalence of dietary alpha-linolenic and docosahexaenoic acids. Pediatr. Res. 1997;42:826–834
  54. Diau GY, Loew ER, Wijendran V, et al. Docosahexaenoic and arachidonic acid influence on preterm baboon retinal composition and function. Invest. Ophthalmol. Vis. Sci. 2003;44:4559–4566
  55. Hsieh AT, Anthony JC, Diersen-Schade DA, et al. The influence of moderate and high dietary long chain polyunsaturated fatty acids (LCPUFA) on baboon neonate tissue fatty acids. Pediatr. Res. 2007;61:537–545
  56. Kothapalli KS, Anthony JC, Pan BS, et al. Differential cerebral cortex transcriptomes of baboon neonates consuming moderate and high docosahexaenoic acid formulas. PLoS One. 2007;2:e370
  57. Arterburn LM, Hall EB, Oken H. Distribution, interconversion, and dose response of n-3 fatty acids in humans. Am. J. Clin. Nutr. 2006;83:1467S–1476S
  58. Ghafoorunissa , Vani A, Laxmi R, et al. Effects of dietary alpha-linolenic acid from blended oils on biochemical indices of coronary heart disease in indians. Lipids. 2002;37:1077–1086
  59. Peet M, Horrobin DF. A dose-ranging exploratory study of the effects of ethyl-eicosapentaenoate in patients with persistent schizophrenic symptoms. J. Psychiatr. Res. 2002;36:7–18
  60. Harris WS, Lemke SL, Hansen SN, et al. Stearidonic acid-enriched soybean oil increased the omega-3 index, an emerging cardiovascular risk marker. Lipids. 2008;
  61. Cunnane SC, Francescutti V, Brenna JT, et al. Breast-fed infants achieve a higher rate of brain and whole body docosahexaenoate accumulation than formula-fed infants not consuming dietary docosahexaenoate. Lipids. 2000;35:105–111
  62. Innis SM, Hansen JW. Plasma fatty acid responses, metabolic effects, and safety of microalgal and fungal oils rich in arachidonic and docosahexaenoic acids in healthy adults. Am. J. Clin. Nutr. 1996;64:159–167
  63. Farquharson J, Cockburn F, Patrick WA, et al. Infant cerebral cortex phospholipid fatty-acid composition and diet. Lancet. 1992;340:810–813
  64. Makrides M, Neumann MA, Byard RW, et al. Fatty acid composition of brain, retina, and erythrocytes in breast- and formula-fed infants. Am. J. Clin. Nutr. 1994;60:189–194
  65. Jamieson EC, Farquharson J, Logan RW, et al. Infant cerebellar gray and white matter fatty acids in relation to age and diet. Lipids. 1999;34:1065–1071
  66. Lands WE, Morris A, Libelt B. Quantitative effects of dietary polyunsaturated fats on the composition of fatty acids in rat tissues. Lipids. 1990;25:505–516
  67. Hibbeln JR, Nieminen LR, Lands WE. Increasing homicide rates and linoleic acid consumption among five western countries, 1961–2000. Lipids. 2004;39:1207–1213
  68. Brenner RR, Peluffo RO. Effect of saturated and unsaturated fatty acids on the desaturation in vitro of palmitic, stearic, oleic, linoleic, and linolenic acids. J. Biol. Chem. 1966;241:5213–5219
  69. Bourre JM, Dumont O, Pascal G, et al. Dietary alpha-linolenic acid at 1.3g/kg maintains maximal docosahexaenoic acid concentration in brain, heart and liver of adult rats. J. Nutr. 1993;123:1313–1319
  70. Mohrhauer H, Holman RT. Effect of linolenic acid upon the metabolism of linoleic acid. J. Nutr. 1963;81:67–74
  71. Arbuckle LD, Rioux FM, MacKinnon MJ, et al. Formula alpha-linolenic (18:3(n-3)) and linoleic (18:2(n-6)) acid influence neonatal piglet liver and brain saturated fatty acids, as well as docosahexaenoic acid (22:6(n-3)). Biochim. Biophys. Acta. 1992;1125:262–267
  72. Blank C, Neumann MA, Makrides M, et al. Optimizing DHA levels in piglets by lowering the linoleic acid to alpha-linolenic acid ratio. J. Lipid Res. 2002;43:1537–1543
  73. Sanders TA, Mistry M, Naismith DJ. The influence of a maternal diet rich in linoleic acid on brain and retinal docosahexaenoic acid in the rat. Br. J. Nutr. 1984;51:57–66
  74. Su HM, Keswick LA, Brenna JT. Increasing dietary linoleic acid in young rats increases and then decreases docosahexaenoic acid in retina but not in brain. Lipids. 1996;31:1289–1298
  75. Lands WE, Libelt B, Morris A, et al. Maintenance of lower proportions of (n-6) eicosanoid precursors in phospholipids of human plasma in response to added dietary (n-3) fatty acids. Biochim. Biophys. Acta. 1992;1180:147–162
  76. Hibbeln JR, Nieminen LR, Blasbalg TL, et al. Healthy intakes of n-3 and n-6 fatty acids: estimations considering worldwide diversity. Am. J. Clin. Nutr. 2006;83:1483S–1493S
  77. Lands B. A critique of paradoxes in current advice on dietary lipids. Prog. Lipid Res. 2008;47:77–106
  78. Sinclair AJ. Incorporation of radioactive polyunsaturated fatty acids into liver and brain of developing rat. Lipids. 1975;10:175–184
  79. Emken EA, Adlof RO, Rakoff H, et al. Metabolism in vivo of deuterium-labelled linolenic and linoleic acids in humans. Biochem. Soc. Trans. 1990;18:766–769
  80. Carnielli VP, Wattimena DJ, Luijendijk IH, et al. The very low birth weight premature infant is capable of synthesizing arachidonic and docosahexaenoic acids from linoleic and linolenic acids. Pediatr. Res. 1996;40:169–174
  81. Salem N, Wegher B, Mena P, et al. Arachidonic and docosahexaenoic acids are biosynthesized from their 18-carbon precursors in human infants. Proc. Natl. Acad. Sci. USA. 1996;93:49–54
  82. Sauerwald TU, Hachey DL, Jensen CL, et al. Intermediates in endogenous synthesis of c22:6 omega 3 and c20:4 omega 6 by term and preterm infants. Pediatr. Res. 1997;41:183–187
  83. Uauy R, Mena P, Wegher B, et al. Long chain polyunsaturated fatty acid formation in neonates: effect of gestational age and intrauterine growth. Pediatr. Res. 2000;47:127–135
  84. Carnielli VP, Simonato M, Verlato G, et al. Synthesis of long-chain polyunsaturated fatty acids in preterm newborns fed formula with long-chain polyunsaturated fatty acids. Am. J. Clin. Nutr. 2007;86:1323–1330
  85. Burdge GC, Finnegan YE, Minihane AM, et al. Effect of altered dietary n-3 fatty acid intake upon plasma lipid fatty acid composition, conversion of [13c] alpha-linolenic acid to longer-chain fatty acids and partitioning towards beta-oxidation in older men. Br. J. Nutr. 2003;90:311–321
  86. Burdge GC, Wootton SA. Conversion of alpha-linolenic acid to eicosapentaenoic, docosapentaenoic and docosahexaenoic acids in young women. Br. J. Nutr. 2002;88:411–420
  87. Pawlosky RJ, Hibbeln JR, Novotny JA, et al. Physiological compartmental analysis of alpha-linolenic acid metabolism in adult humans. J. Lipid Res. 2001;42:1257–1265
  88. Vermunt SH, Mensink RP, Simonis MM, et al. Effects of dietary alpha-linolenic acid on the conversion and oxidation of 13c-alpha-linolenic acid. Lipids. 2000;35:137–142
  89. Pawlosky RJ, Hibbeln JR, Lin Y, et al. Effects of beef- and fish-based diets on the kinetics of n-3 fatty acid metabolism in human subjects. Am. J. Clin. Nutr. 2003;77:565–572
  90. McCloy U, Ryan MA, Pencharz PB, et al. A comparison of the metabolism of eighteen-carbon 13c-unsaturated fatty acids in healthy women. J. Lipid Res. 2004;45:474–485
  91. Hussein N, Ah-Sing E, Wilkinson P, et al. Long-chain conversion of [13c]linoleic acid and alpha-linolenic acid in response to marked changes in their dietary intake in men. J. Lipid Res. 2005;46:269–280
  92. Burdge GC, Jones AE, Wootton SA. Eicosapentaenoic and docosapentaenoic acids are the principal products of alpha-linolenic acid metabolism in young men*. Br. J. Nutr. 2002;88:355–363
  93. Pawlosky R, Hibbeln J, Lin Y, et al. n-3 fatty acid metabolism in women. Br. J. Nutr. 2003;90:993–994discussion 994–995
  94. Giltay EJ, Gooren LJ, Toorians AW, et al. Docosahexaenoic acid concentrations are higher in women than in men because of estrogenic effects. Am. J. Clin. Nutr. 2004;80:1167–1174
  95. Bakewell L, Burdge GC, Calder PC. Polyunsaturated fatty acid concentrations in young men and women consuming their habitual diets. Br. J. Nutr. 2006;96:93–99
  96. Mayes C, Burdge GC, Bingham A, et al. Variation in [u-13c] alpha linolenic acid absorption, beta-oxidation and conversion to docosahexaenoic acid in the pre-term infant fed a DHA-enriched formula. Pediatr. Res. 2006;59:271–275
  97. Pawlosky RJ, Hibbeln JR, Salem N. Compartmental analyses of plasma n-3 essential fatty acids among male and female smokers and nonsmokers. J. Lipid Res. 2007;48:935–943
  98. Hoffman DR, DeMar JC, Heird WC, et al. Impaired synthesis of DHA in patients with x-linked retinitis pigmentosa. J. Lipid Res. 2001;42:1395–1401
  99. Neuringer M, Connor WE, Lin DS, et al. Biochemical and functional effects of prenatal and postnatal omega 3 fatty acid deficiency on retina and brain in rhesus monkeys. Proc. Natl. Acad. Sci. USA. 1986;83:4021–4025
  100. Anderson GJ, Neuringer M, Lin DS, et al. Can prenatal n-3 fatty acid deficiency be completely reversed after birth? Effects on retinal and brain biochemistry and visual function in rhesus monkeys. Pediatr. Res. 2005;58:865–872
  101. Su HM, Huang MC, Saad NM, et al. Fetal baboons convert 18:3n-3 to 22:6n-3 in vivo. A stable isotope tracer study,. J. Lipid Res. 2001;42:581–586

☆ A statement on PUFA nutrition developed and edited based on input from ISSFAL members and accepted by vote of the ISSFAL Board of Directors.

PII: S0952-3278(09)00016-7

doi: 10.1016/j.plefa.2009.01.004

Prostaglandins, Leukotrienes and Essential Fatty Acids
Volume 80, Issue 2 , Pages 85-91 , February 2009

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