The Biochemistry of n-3 Polyunsaturated Fatty Acids

polyunsaturated fatty acid central nervous system fatty acyl-CoA thioester non-esterified fatty acid phosphatidylserine phosphatidylcholine phosphatidylethanolamine rod outer segment retinoid X receptor liver X receptor peroxisome proliferator receptor sterol regulatory element-binding protein nuclear factor κB cyclooxygenase lipoxygenase cytochrome P450 monooxygenase activation function-2 insulin receptor T-cell receptor extracellular signal-regulated kinase Dietary n-3 polyunsaturated fatty acids (n-3 PUFA)1have effects on diverse physiological processes impacting normal health and chronic disease, such as the regulation of plasma lipid levels (1Rambjor G.S. Walen A.I. Windsor S.L. Harris W.S. Lipid. 1996; 31: S45-S49Crossref PubMed Google Scholar, 2Harris W.S. Am. J. Clin. Nutr. 1997; 65: 1645S-1654SCrossref PubMed Scopus (974) Google Scholar, 3Harris W.S. Hustvedt B-E. Hagen E. Green M.H. Lu G. Drevon C.A. J. Lipid Res. 1997; 38: 503-515Abstract Full Text PDF PubMed Google Scholar, 4Mori T.A. Burke V. Puddey I.B. Watts G.F. O'Neal D.N. Best J.D. Beilen L.J. Am. J. Clin. Nutr. 2000; 71: 1085-1094Crossref PubMed Scopus (523) Google Scholar), cardiovascular (5Nordoy A. Lipids. 1999; 34: S19-S22Crossref PubMed Google Scholar, 6Sellmayer A. Hrboticky N. Weber P.C. Lipids. 1999; 34: S13-S18Crossref PubMed Google Scholar, 7Leaf A. J. Nutr. Health Aging. 2001; 5: 173-178PubMed Google Scholar) and immune function (8Hwang D. Annu. Rev. Nutr. 2000; 20: 431-456Crossref PubMed Scopus (177) Google Scholar), insulin action (9Storlien L. Hulbert A.J. Else P.L. Curr. Opin. Clin. Nutr. Metab. Care. 1998; 1: 559-563Crossref PubMed Scopus (102) Google Scholar, 10Storlien L.H. Kriketos A.D. Calvert G.D. Baur L.A. Jenkins A.B. Prostaglandins Leukotrienes Essent. Fatty Acids. 1997; 57: 379-385Abstract Full Text PDF PubMed Scopus (76) Google Scholar), and neuronal development and visual function (11Salem Jr., N. Litman B. Kim H-Y. Gawrisch K. Lipids. 2001; 36: 945-959Crossref PubMed Scopus (772) Google Scholar) (see Table I, supplemental material). Ingestion ofn-3 PUFA will lead to their distribution to virtually every cell in the body with effects on membrane composition and function, eicosanoid synthesis, and signaling as well as the regulation of gene expression (11Salem Jr., N. Litman B. Kim H-Y. Gawrisch K. Lipids. 2001; 36: 945-959Crossref PubMed Scopus (772) Google Scholar, 12Jump D.B. Clarke S.D. Annu. Rev. Nutr. 1999; 19: 63-90Crossref PubMed Scopus (549) Google Scholar, 13Duplus, E., Glorian, M., and Forest, C. (2000) 275,30749–30752Google Scholar, 14Dubois R.N. Abramson S.B. Crofford L. Gupta R.A. Simon L.S. Van De Putte L.B.A. Lipsky P.E. FASEB J. 1998; 12: 1063-1073Crossref PubMed Scopus (2231) Google Scholar). However, cell-specific lipid metabolism as well as the expression of fatty acid-regulated transcription factors likely plays an important role in determining how cells respond to changes in PUFA composition. In this minireview I will highlight some of the recent advances in our understanding of n-3 PUFA effects on cells with an emphasis on those mechanisms likely to have a broad physiological impact. n-3 and n-6 PUFA are the two major classes of PUFA encountered in the diet, and both classes of fatty acids are required for normal human health (15Spector A.A. Lipids. 1999; 34: S1-S3Crossref PubMed Google Scholar). Linoleic acid (18:2n-6) is the predominant plant-derived dietary PUFA and is a precursor for arachidonic acid (20:4n-6) and eicosanoids (see Fig. 1, supplemental material). α-Linolenic acid (18:3n-3) is the predominant plant-derived dietary n-3 PUFA and is a precursor for 22:6n-3. Linoleic acid, 20:4n-6 and 22:6n-3, are prominent PUFA in cellular phospholipids (11Salem Jr., N. Litman B. Kim H-Y. Gawrisch K. Lipids. 2001; 36: 945-959Crossref PubMed Scopus (772) Google Scholar). Non-esterified fatty acids (NEFA) enter cells via fatty acid transporters and are rapidly converted to fatty acyl-CoA thioesters (FA-CoA) by acyl-CoA synthetases (see Fig. 2, supplemental material). Intracellular NEFA and FA-CoA are low (<10 μm), and a major fraction of these lipids is bound to specific proteins, i.e. fatty acid-binding protein and FA-CoA-binding protein. FA-CoAs are substrates for neutral lipid (triglycerides, cholesterol esters) and polar lipid (phospholipids (PS, PE, PC), sphingolipids, and plasmalogens) synthesis as well as elongation, desaturation, β-oxidation, and protein acylation reactions. 22:6n-3 is the most abundant n-3 PUFA in most tissues and is found at the sn-2 position of phospholipids (11Salem Jr., N. Litman B. Kim H-Y. Gawrisch K. Lipids. 2001; 36: 945-959Crossref PubMed Scopus (772) Google Scholar, 16Salem Jr., N. Curr. Top. Nutr. Dis. 1989; 22: 109-228Google Scholar). Deficiencies of n-3 PUFA lead to a loss of 22:6n-3 from brain and retina rod outer segment (ROS) phospholipids with a compensatory replacement by 22:5n-6 (11Salem Jr., N. Litman B. Kim H-Y. Gawrisch K. Lipids. 2001; 36: 945-959Crossref PubMed Scopus (772) Google Scholar, 17Moriguchi T. Greiner R.S. Salem Jr., N. J. Neurochem. 2000; 75: 2563-2573Crossref PubMed Scopus (361) Google Scholar, 18Salem Jr., N. Moriguchi T. Greiner R.S. McBride K. Ahmad A. Catalan J. Slotnick B. J. Mol. Neurosci. 2001; 16: 299-307Crossref PubMed Scopus (101) Google Scholar, 19Contreras M.A. Greiner R.S. Chang M.C. Myers C.S. Salem Jr., N. Rapoport S.I. J. Neurochem. 2000; 75: 2392-2400Crossref PubMed Scopus (103) Google Scholar). This minor change in membrane phospholipid structure is sufficient to lead to memory loss, learning disabilities, and impaired visual acuity. Metabolic studies with healthy humans have shown that in contrast to 20:5n-3, 18:3n-3 is not efficiently converted to 22:6n-3. 18:3n-3 is preferentially utilized by the skin and is more rapidly oxidized than the 20- and 22-carbon n-3 PUFA (20Pawlosky R.J. Hibbeln J.R. Novotny J.A. Salem Jr., N. J. Lipid Res. 2001; 42: 1257-1265Abstract Full Text Full Text PDF PubMed Google Scholar). 22-Carbon PUFA requires prior peroxisomal β-oxidation before entering the mitochondrial β-oxidation spiral (21Sprecher H. Biochim. Biophys. Acta. 2000; 1486: 219-231Crossref PubMed Scopus (662) Google Scholar). This metabolic partitioning decreases the availability of 18:3n-3 for conversion to the 20- and 22-carbon PUFA in the liver (20Pawlosky R.J. Hibbeln J.R. Novotny J.A. Salem Jr., N. J. Lipid Res. 2001; 42: 1257-1265Abstract Full Text Full Text PDF PubMed Google Scholar). In rodents maintained on chow diets, 18:3n-3 and 20:5n-3 are minor PUFAs in the phospholipid fraction. However, supplementing diets with fish oil, a rich source of 20:5n-3 and 22:6n-3, significantly increases tissue levels of 20:5n-3, 22:5n-3, and 22:6n-3; these changes occur at the expense of 20:4n-6. Such diets also induce hepatic microsomal, peroxisomal, and mitochondrial fatty acid oxidation while suppressing fatty acid synthesis (12Jump D.B. Clarke S.D. Annu. Rev. Nutr. 1999; 19: 63-90Crossref PubMed Scopus (549) Google Scholar). Differences in how 18- versus 20- and 22-carbon n-3 PUFA are metabolized in cells likely contribute to their effects on cellular regulatory processes. These effects extend beyond differential β-oxidation to include PUFA assimilation into neutral lipids. CoA thioesters of 20:5n-3 are poor substrates for diacylglycerol acyltransferase, the last step in triglyceride synthesis (22Froyland L. Madsen L. Vaagenes H. Totland G.K. Auwerx J. Kryvi H. Staels B. Berge R.K. J. Lipid Res. 1997; 38: 1851-1858Abstract Full Text PDF PubMed Google Scholar, 23Madsen L. Rustan A.C. Vaagenes H. Berg K. Dyroy E. Berge R.K. Lipids. 1999; 34: 951-963Crossref PubMed Scopus (156) Google Scholar, 24Berge R.K. Madsen L. Vaagenes H. Tronstad K.J. Rustan A.C. J. 1999; PubMed Scopus Google Scholar). 20- PUFAs are substrates for cholesterol B. the of 20:5n-3 and likely NEFA CoA thioester factors that will regulatory mechanisms (see Fig. 2, supplemental material). these mechanisms of the major in this retina levels of 22:6n-3. In of in the phospholipids and are 22:6n-3 PE, and and acid, 20:4n-6 Res. PubMed Scopus Google Scholar). an to the role of 22:6n-3 in membrane structure and is an membrane protein in the by a two i.e. and Litman J. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, Litman J. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, S.L. A. J. Neurosci. 2001; 16: PubMed Scopus Google Scholar). and the and a that and of the to of the plasma membrane and the visual Litman and Litman J. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, Litman J. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, S.L. A. J. Neurosci. 2001; 16: PubMed Scopus Google Scholar) that the for the of is to the of phospholipid with more 22:6n-3 both the of and to phospholipids the of cholesterol on both the of and membrane composition plays a role in the of the signaling system in the retina n-3 PUFA is with memory loss and function (11Salem Jr., N. Litman B. Kim H-Y. Gawrisch K. Lipids. 2001; 36: 945-959Crossref PubMed Scopus (772) Google Scholar, 17Moriguchi T. Greiner R.S. Salem Jr., N. J. Neurochem. 2000; 75: 2563-2573Crossref PubMed Scopus (361) Google Scholar, 18Salem Jr., N. Moriguchi T. Greiner R.S. McBride K. Ahmad A. Catalan J. Slotnick B. J. Mol. Neurosci. 2001; 16: 299-307Crossref PubMed Scopus (101) Google Scholar, 19Contreras M.A. Greiner R.S. Chang M.C. Myers C.S. Salem Jr., N. Rapoport S.I. J. Neurochem. 2000; 75: 2392-2400Crossref PubMed Scopus (103) Google Scholar, R.J. Hibbeln J.R. Novotny J.A. Salem Jr., N. J. Lipid Res. 2001; 42: 1257-1265Abstract Full Text Full Text PDF PubMed Google Scholar). for this in neuronal cells J. T. 2000; PubMed Scopus Google Scholar). is a to nuclear some of have a major on not 22:6n-3, a source of 22:6n-3 to (15Spector A.A. Lipids. 1999; 34: S1-S3Crossref PubMed Google Scholar). n-3 PUFA is with a in and neuronal (11Salem Jr., N. Litman B. Kim H-Y. Gawrisch K. Lipids. 2001; 36: 945-959Crossref PubMed Scopus (772) Google Scholar, L. Greiner Salem Jr., N. Kim Lipids. 2000; PubMed Scopus Google Scholar, H-Y. A. L. J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). is to and plasma membrane cells with 22:6n-3 in the of the plasma membrane and to the with the plasma membrane and cell H-Y. A. L. J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). the and 22:6n-3 of the fatty acid in membrane 20:5n-3 and are at However, cells with 20:5n-3 increases 20:5n-3, 22:5n-3, and 22:6n-3 in both the phospholipid and protein of are for n-3 PUFA effects on membrane Lipid are the of the plasma membrane that are in cholesterol and E. Curr. Opin. 2001; PubMed Scopus Google Scholar). and and These membrane contribute to the structure and function of plasma membrane and cholesterol as well as kinase and cell with fatty acids into the of the plasma membrane with for of the on J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). In some of requires prior and is required for membrane of in cell signaling are found in lipid of the kinase and Lipid are to by These occur to both the phospholipid as well as to with well for PUFA effects on lipid is T-cell activation J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, L. J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, T. D. H. J. 1998; PubMed Scopus Google Scholar, J. N. J. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, A. H. J. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). n-3 and n-6 PUFAs composition and function an T. D. H. J. 1998; PubMed Scopus Google Scholar). n-3 PUFAs and are as rapidly cellular phospholipid eicosanoid PUFA (see N. J. PubMed Scopus Google Scholar). T-cell activation requires the T-cell receptor These are to the plasma membrane via in lipid T. D. H. J. 1998; PubMed Scopus Google Scholar). kinase of protein plays an important role in T-cell have an at a at position of the protein. of the are also at a and are required for to L. J. 2000; Full Text Full Text PDF PubMed Scopus Google A. H. J. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). two and are on the of lipid of the and activation that to and signaling L. J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, T. D. H. J. 1998; PubMed Scopus Google Scholar, J. N. J. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, A. H. J. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). Lipid from with 20:4n-6 20:5n-3 and and a in both signaling and In the proteins, and the and in PUFA of with PUFA both outer and phospholipids with 20- and 22-carbon more lipid of in the for the of from in J. N. J. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). PUFA of also in PUFA acylation of L. J. 2000; Full Text Full Text PDF PubMed Scopus Google A. H. J. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). In the of acylation the fatty acid composition to the and polyunsaturated fatty acids bound to is a that will a broad of fatty acids to of with PUFA in the of to with of to with the from signaling signaling These studies how changes in membrane phospholipid composition as well as protein acylation signaling from the plasma In the of PUFA on membrane protein acylation and protein to the membrane and is likely to have a broad on signaling will important to n-3 PUFA acylation of membrane beyond to include effects on membrane Non-esterified PUFAs from the sn-2 position of the membrane phospholipids by the action of specific are substrates for a an cytochrome P450 A. Hrboticky N. Weber P.C. Lipids. 1999; 34: S13-S18Crossref PubMed Google Scholar, D. Annu. Rev. Nutr. 2000; 20: 431-456Crossref PubMed Scopus (177) Google Scholar, 14Dubois R.N. Abramson S.B. Crofford L. Gupta R.A. Simon L.S. Van De Putte L.B.A. Lipsky P.E. 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J. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). However, studies with the have shown that is not the transcription factor in fatty acid effects on gene In to the and transcription factors have as for fatty acid hepatic nuclear and and A. Hrboticky N. Weber P.C. Lipids. 1999; 34: S13-S18Crossref PubMed Google Scholar, 12Jump D.B. Clarke S.D. Annu. Rev. Nutr. 1999; 19: 63-90Crossref PubMed Scopus (549) Google Scholar, 13Duplus, E., Glorian, M., and Forest, C. (2000) 275,30749–30752Google Scholar, J. T. 2000; PubMed Scopus Google Scholar, J. J. 1997; Scopus Google Scholar, S.L. T. R.J. J. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Clarke S.D. J. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, J. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, D.B. J. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, A. M., and N. Scholar, J. H. B. A. R.A. 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This with lipid 20- and 22-carbon n-3 PUFAs are lipids that to the to cells membrane phospholipid eicosanoid synthesis and and transcription factor and n-3 PUFAs diverse physiological processes and visual and and and with major effects on body and lipid metabolism (see Table I, supplemental material). is important to those effects that are specific for n-3 PUFA from those effects that are with fatty acids in n-6 PUFAs n-3 PUFAs eicosanoid synthesis and signaling and This for the and action of n-3 is also a for 22:6n-3 22:5n-6 for normal development and In PUFA effects on membrane composition as well as the regulation of transcription factors are more by changes in cellular levels of fatty acids than specific effects of n-3 of n-3 PUFA to β-oxidation assimilation into neutral lipids sufficient to NEFA levels these factors to as regulatory for transcription factors substrates for protein to this effects of n-3 PUFA on physiological processes of in with n-3 PUFA changes in the of membrane A. J. Nutr. Health Aging. 2001; 5: 173-178PubMed Google Scholar, A. J. Lipid Res. 2001; 42: Full Text Full Text PDF PubMed Google Scholar). this changes in membrane phospholipid composition of membrane to specific is in understanding how n-3 PUFAs cell mechanisms have and mechanisms are likely to that will how these lipids human health and I for of the have in this I Salem at the of Health and at for and for a of the with