The Biochemistry of n-3 Polyunsaturated Fatty Acids

Abstract

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: 945-9