Omega-3 fatty acid supplementation and cardiovascular disease

Journal of Lipid Research

Volumn 53, Issue 12, 2012, Pages 2525-2545

  Jump, Donald B ^a   Depner, Christopher M ^a   Tripathy, Sasmita ^a  

^a OREGON STATE UNIVERSITY   (United States)

Author keywords

Cardiomyocyte; Dyslipidemia; Endothelial cell; Inflammation; Pufa metabolism; Single nucleotide polymorphism

Indexed keywords

14,15 EPOXY 5,8,11 ICOSATRIENOIC ACID; 17,18 EPOXYEICOSATETRAENOIC ACID; 19,20 EPOXYDOCOSAPENTAENOIC ACID; ARACHIDONIC ACID; ARACHIDONIC ACID DERIVATIVE; DOCOSAHEXAENOIC ACID; DOCOSAPENTAENOIC ACID; ESSENTIAL FATTY ACID; FISH OIL; HEPATOCYTE NUCLEAR FACTOR 4ALPHA; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; ICOSAPENTAENOIC ACID; ICOSAPENTAENOIC ACID ETHYL ESTER; LINOLEIC ACID; LINSEED OIL; MATK 90; NEWHARVEST EPA; OLIVE OIL; OMEGA 3 ACID ETHYL ESTER; OMEGA 3 FATTY ACID; OMEGA 6 FATTY ACID; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR; PLACEBO; RETINOID X RECEPTOR; SOYAMEGA; STEARIDONIC ACID; UNCLASSIFIED DRUG; VITAMIN B GROUP; VITAMIN D;

ANTIARRHYTHMIC ACTIVITY; ANTIINFLAMMATORY ACTIVITY; CARDIOVASCULAR DISEASE; CARDIOVASCULAR RISK; DIET SUPPLEMENTATION; DIETARY INTAKE; DRUG PROTEIN BINDING; DRUG RECEPTOR BINDING; DRUG STRUCTURE; DRUG TARGETING; DYSLIPIDEMIA; FATTY ACID METABOLISM; FATTY ACID OXIDATION; FATTY ACID SYNTHESIS; HEART PROTECTION; HUMAN; HYPERCHOLESTEROLEMIA; HYPERTRIGLYCERIDEMIA; METABOLIC REGULATION; NONHUMAN; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; SINGLE NUCLEOTIDE POLYMORPHISM; STRUCTURE ANALYSIS;

CARDIOVASCULAR DISEASES; DIETARY SUPPLEMENTS; FATTY ACIDS, OMEGA-3; HUMANS;

EID: 84869043579     PISSN: 00222275     EISSN: 15397262     Source Type: Journal    
DOI: 10.1194/jlr.R027904     Document Type: Review

References (239)

1. Spector, A. A. 1999. Essentiality of fatty acids. Lipids. 34 (Suppl.): S1-S3.
2. Bang, H. O., J. Dyerberg, and A. B. Nielsen. 1971. Plasma lipid and lipoprotein pattern in Greenlandic West-coast Eskimos. Lancet. 1: 1143-1145.
3. Bang, H. O., and J. Dyerberg. 1972. Plasma lipids and lipoproteins in Greenlandic west coast Eskimos. Acta Med. Scand. 192: 85-94.
4. Dyerberg, J., H. O. Bang, and N. Hjorne. 1975. Fatty acid composition of the plasma lipids in Greenland Eskimos. Am. J. Clin. Nutr. 28: 958-966.
5. Bang, H. O., J. Dyerberg, and N. Hjorne. 1976. The composition of food consumed by Greenland Eskimos. Acta Med. Scand. 200: 69-73.
6. O'Keefe, J. H., Jr., and W. S. Harris. 2000. From Inuit to implementation: omega-3 fatty acids come of age. Mayo Clin. Proc. 75: 607-614.
7. Harris, W. S., D. Mozaffarian, M. Lefevre, C. D. Toner, J. Colombo, S. C. Cunnane, J. M. Holden, D. M. Klurfeld, M. C. Morris, and J. Whelan. 2009. Towards establishing dietary reference intakes for eicosapentaenoic and docosahexaenoic acids. J. Nutr. 139: 804S-819S.
8. Dyerberg, J., H. O. Bang, E. Stoffersen, S. Moncada, and J. R. Vane. 1978. Eicosapentaenoic acid and prevention of thrombosis and atherosclerosis? Lancet. 2: 117-119. (Pubitemid 8373454)
9. Harris, W. S., D. Mozaffarian, E. Rimm, P. Kris-Etherton, L. L. Rudel, L. J. Appel, M. M. Engler, M. B. Engler, and F. Sacks. 2009. Omega-6 fatty acids and risk for cardiovascular disease: a science advisory from the American Heart Association Nutrition Subcommittee of the Council on Nutrition, Physical Activity, and Metabolism; Council on Cardiovascular Nursing; and Council on Epidemiology and Prevention. Circulation. 119: 902-907.
10. Danaei, G., E. L. Ding, D. Mozaffarian, B. Taylor, J. Rehm, C. J. Murray, and M. Ezzati. 2009. The preventable causes of death in the United States: comparative risk assessment of dietary, lifestyle, and metabolic risk factors. PLoS Med. 6: e1000058.
11. Mozaffarian, D., and R. Clarke. 2009. Quantitative effects on cardiovascular risk factors and coronary heart disease risk of replacing partially hydrogenated vegetable oils with other fats and oils. Eur. J. Clin. Nutr. 63 (Suppl. 2): S22-S33.
12. Kris-Etherton, P., J. Flemming, and W. S. Harris. 2010. The debate about n-6 polyunsaturated fatty acid recommendatons for cardiovascular health. J. Am. Diet. Assoc. 110: 201-204.
13. Han, S. N., L. S. Leka, A. H. Lichtenstein, L. M. Ausman, E. J. Schaefer, and S. N. Meydani. 2002. Effect of hydrogenated and saturated, relative to polyunsaturated, fat on immune and inflammatory responses of adults with moderate hypercholesterolemia. J. Lipid Res. 43: 445-452. (Pubitemid 34252275)
14. Harris, W. S., and D. M. Klurfeld. 2011. Twentieth-century trends in essential fatty acid intakes and the predicted omega-3 index: evidence versus estimates. Am. J. Clin. Nutr. 93: 907-908.
15. Gebauer, S. K., T. L. Psota, W. S. Harris, and P. M. Kris-Etherton. 2006. n-3 fatty acid dietary recommendations and food sources to achieve essentiality and cardiovascular benefits. Am. J. Clin. Nutr. 83: 1526S-1535S. (Pubitemid 44713094)
16. Craig, W. J., and A. R. Mangels. 2009. Position of the American Dietetic Association: vegetarian diets. J. Am. Diet. Assoc. 109: 1266-1282.
17. Kris-Etherton, P. M., W. S. Harris, and L. J. Appel. 2002. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation. 106: 2747-2757. (Pubitemid 35364932)
18. Kris-Etherton, P. M., W. S. Harris, and L. J. Appel. 2003. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Arterioscler. Thromb. Vasc. Biol. 23: e20-e30.
19. Kris-Etherton, P. M., W. S. Harris, and L. J. Appel. 2003. Omega-3 fatty acids and cardiovascular disease: new recommendations from the American Heart Association. Arterioscler. Thromb. Vasc. Biol. 23: 151-152. (Pubitemid 36231919)
20. Mozaffarian, D., and J. H. Wu. 2011. Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events. J. Am. Coll. Cardiol. 58: 2047-2067.
21. Lee, J. H., J. H. O'Keef, C. J. Lavie, and W. S. Harris. 2009. Omega-3 fatty acids: cardiovascular benefits, sources and sustainability. Nat. Rev. Cardiol. 6: 753-758.
22. Saravanan, P., N. C. Davidson, E. B. Schmidt, and P. C. Calder. 2010. Cardiovascular effects of marine omega-3 fatty acids. Lancet. 376: 540-550.
23. Harris, W. S., and C. Von Schacky. 2004. The Omega-3 Index: a new risk factor for death from coronary heart disease? Prev. Med. 39: 212-220. (Pubitemid 38797975)
24. Harris, W. S., S. A. Sands, S. L. Windsor, H. A. Ali, T. L. Stevens, A. Magalski, C. B. Porter, and A. M. Borkon. 2004. Omega-3 fatty acids in cardiac biopsies from heart transplantation patients: correlation with erythrocytes and response to supplementation. Circulation. 110: 1645-1649. (Pubitemid 39297988)
25. Metcalf, R. G., M. J. James, R. A. Gibson, J. R. Edwards, J. Stubberfield, R. Stuklis, K. Roberts-Thomson, G. D. Young, and L. G. Cleland. 2007. Effects of fish-oil supplementation on myocardial fatty acids in humans. Am. J. Clin. Nutr. 85: 1222-1228. (Pubitemid 46740462)
26. Siscovick, D. S., T. E. Raghunathan, I. King, S. Weinmann, K. G. Wicklund, J. Albright, V. Bovbjerg, P. Arbogast, H. Smith, L. H. Kushi, et al. 1995. Dietary intake and cell membrane levels of long-chain n-3 polyunsaturated fatty acids and the risk of primary cardiac arrest. JAMA. 274: 1363-1367.
27. Aarsetoey, H., V. Ponitz, H. Grundt, H. Staines, W. S. Harris, and D. W. Nilsen. 2009. (n-3) Fatty acid content of red blood cells does not predict risk of future cardiovascular events following an acute coronary syndrome. J. Nutr. 139: 507-513.
28. Myerburg, R. J., A. Interian, Jr., R. M. Mitrani, K. M. Kessler, and A. Castellanos. 1997. Frequency of sudden cardiac death and profi les of risk. Am. J. Cardiol. 80: 10F-19F. (Pubitemid 27377820)
29. Wilhelm, M., R. Tobias, F. Asskali, R. Kraehner, S. Kuly, L. Klinghammer, H. Boehles, and W. G. Daniel. 2008. Red blood cell omega-3 fatty acids and the risk of ventricular arrhythmias in patients with heart failure. Am. Heart J. 155: 971-977.
30. Myerburg, R. J., and J. Junttila. 2012. Sudden cardiac death caused by coronary heart disease. Circulation. 125: 1043-1052.
31. Streppel, M. T., M. C. Ocke, H. C. Boshuizen, F. J. Kok, and D. Kromhout. 2008. Long-term fish consumption and n-3 fatty acid intake in relation to (sudden) coronary heart disease death: the Zutphen study. Eur. Heart J. 29: 2024-2030.
32. Aarsetøy, H., V. Pönitz, O. B. Nilsen, H. Grundt, W. S. Harris, and D. W. Nilsen. 2008. Low levels of cellular omega-3 increase the risk of ventricular fibrillation during the acute ischaemic phase of a myocardial infarction. Resuscitation. 78: 258-264.
33. Aarsetoey, H., R. Aarsetoey, T. Lindner, H. Staines, W. S. Harris, and D. W. Nilsen. 2011. Low levels of the omega-3 index are associated with sudden cardiac arrest and remain stable in survivors in the subacute phase. Lipids. 46: 151-161.
34. Von Schacky, C. 2010. Omega-3 fatty acids vs. cardiac disease-the contribution of the omega-3 index. Cell Mol. Biol. (Noisy-le-grand). 56: 93-101.
35. Huikuri, H. V., A. Castellanos, and R. J. Myerburg. 2001. Sudden death due to cardiac arrhythmias. N. Engl. J. Med. 345: 1473-1482.
36. Von Schacky, C. 2008. Omega-3 fatty acids: anti-arrhythmic, pro-arrhythmic or both? Curr. Opin. Clin. Nutr. Metab. Care. 11: 94-99. (Pubitemid 351323168)
37. Raitt, M. H., W. E. Connor, C. Morris, J. Kron, B. Halperin, S. S. Chugh, J. McClelland, J. Cook, K. MacMurdy, R. Swenson, et al. 2005. Fish oil supplementation and risk of ventricular tachycardia and ventricular fibrillation in patients with implantable defibrillators: a randomized controlled trial. JAMA. 293: 2884-2891. (Pubitemid 41029142)
38. Brouwer, I. A., M. H. Raitt, C. Dullemeijer, D. F. Kraemer, P. L. Zock, C. Morris, M. B. Katan, W. E. Connor, J. A. Camm, E. G. Schouten, et al. 2009. Effect of fish oil on ventricular tachyarrhythmia in three studies in patients with implantable cardioverter defibrillators. Eur. Heart J. 30: 820-826.
39. Dávila-Román, V. G., G. Vedala, P. Herrero, L. de las Fuentes, J. G. Rogers, D. P. Kelly, and R. J. Gropler. 2002. Altered myocardial fatty acid and glucose metabolism in idiopathic dilated cardiomyopathy. J. Am. Coll. Cardiol. 40: 271-277. (Pubitemid 34756287)
40. Herrero, P., L. R. Peterson, J. B. McGill, S. Matthew, D. Lesniak, C. Dence, and R. J. Gropler. 2006. Increased myocardial fatty acid metabolism in patients with type 1 diabetes mellitus. J. Am. Coll. Cardiol. 47: 598-604. (Pubitemid 43170851)
41. Rijzewijk, L. J., R. W. van der Meer, H. J. Lamb, H. W. de Jong, M. Lubberink, J. A. Romijn, J. J. Bax, A. de Roos, J. W. Twisk, R. J. Heine, et al. 2009. Altered myocardial substrate metabolism and decreased diastolic function in nonischemic human diabetic cardiomyopathy: studies with cardiac positron emission tomography and magnetic resonance imaging. J. Am. Coll. Cardiol. 54: 1524-1532.
42. Goldberg, I. J., C. M. Trent, and P. C. Schulze. 2012. Lipid metabolism and toxicity in the heart. Cell Metab. 15: 805-812.
43. Jump, D. B. 2008. N-3 polyunsaturated fatty acid regulation of hepatic gene transcription. Curr. Opin. Lipidol. 19: 242-247. (Pubitemid 351653561)
44. Park, W. J., K. S. Kothapalli, P. Lawrence, C. Tyburczy, and J. T. Brenna. 2009. An alternate pathway to long chain polyunsaturates: the FADS2 gene product Delta8-desaturates 20:2n-6 and 20:3n-3. J. Lipid Res. 50: 1195-1202.
45. Gregory, M. K., R. A. Gibson, R. J. Cook-Johnson, L. G. Cleland, and M. J. James. 2011. Elongase reactions as control points in longchain polyunsaturated fatty acid synthesis. PLoS ONE. 6: e29662.
46. Stroud, C. K., T. Y. Nara, M. Roqueta-Rivera, E. C. Radlowski, P. Lawrence, Y. Zhang, B. H. Cho, M. Segre, R. A. Hess, J. T. Brenna, et al. 2009. Disruption of FADS2 gene in mice impairs male reproduction and causes dermal and intestinal ulceration. J. Lipid Res. 50: 1870-1880.
47. Jump, D. B., M. Torres-Gonzalez, and L. K. Olson. 2011. Soraphen A, a inhibitor of acetyl CoA carboxylase activity, interferes with fatty acid elongation. Biochem. Pharmacol. 81: 649-660.
48. Fan, Y. Y., J. M. Monk, T. Y. Hou, E. Callway, L. Vincent, B. Weeks, P. Yang, and R. S. Chapkin. 2012. Characterization of an arachidonic acid-deficient (Fads1 knockout) mouse model. J. Lipid Res. 53: 1287-1295.
49. Huang, Y. S., W. C. Huang, C. W. Li, and L. T. Chuang. 2011. Eicosadienoic acid differentially modulates production of inflammatory modulators in murine macrophages. Mol. Cell. Biochem. 358: 85-94.
50. Jakobsson, A., R. Westerberg, and A. Jacobsson. 2006. Fatty acid elongases in mammals: their regulation and role in metabolism. Prog. Lipid Res. 45: 237-249.
51. Guillou, H., D. Zadravec, P. G. Martin, and A. Jacobsson. 2010. The key roles of elongases and desaturases in mammalian fatty acid metabolism: insights from transgenic mice. Prog. Lipid Res. 49: 186-199.
52. Wang, Y., D. Botolin, B. Christian, J. Busik, J. Xu, and D. B. Jump. 2005. Tissue-specific, nutritional, and developmental regulation of rat fatty acid elongases. J. Lipid Res. 46: 706-715. (Pubitemid 43073280)
53. Wang, Y., D. Botolin, J. Xu, B. Christian, E. Mitchell, B. Jayaprakasam, M. G. Nair, J. M. Peters, J. V. Busik, L. K. Olson, et al. 2006. Regulation of hepatic fatty acid elongase and desaturase expression in diabetes and obesity. J. Lipid Res. 47: 2028-2041. (Pubitemid 44401991)
54. Tripathy, S., M. Torres-Gonzalez, and D. B. Jump. 2010. Elevated hepatic fatty acid elongase-5 (Elovl5) activity corrects dietary fat induced hyperglycemia in obese C57BL/6J mice. J. Lipid Res. 51: 2642-2654.
55. Igarashi, M., K. Ma, L. Chang, J. M. Bell, and S. I. Rapoport. 2008. Rat heart cannot synthesize docosahexaenoic acid from circulating alpha-linolenic acid because it lacks elongase-2. J. Lipid Res. 49: 1735-1745.
56. Rapoport, S. I., M. Igarashi, and F. Gao. 2010. Quantitative contributions of diet and liver synthesis to docosahexaenoic acid homeostasis. Prostaglandins Leukot. Essent. Fatty Acids. 82: 273-276.
57. Green, C. D., C. G. Ozguden-Akkoc, Y. Wang, D. B. Jump, and L. A. Olson. 2010. Role of fatty acid elongases in determination of de novo synthesized monounsaturated fatty acid species. J. Lipid Res. 51: 1871-1877.
58. Wu, J. H., R. N. Lemaitre, F. Imamura, I. B. King, X. Song, D. Spiegelman, D. S. Siscovick, and D. Mozaffarian. 2011. Fatty acids in the de novo lipogenesis pathway and risk of coronary heart disease: the Cardiovascular Health Study. Am. J. Clin. Nutr. 94: 431-438.
59. Matsuzaka, T., H. Shimano, N. Yahagi, M. Amemiya-Kudo, T. Yoshikawa, A. H. Hasty, Y. Tamura, J. Osuga, H. Okazaki, Y. Iizuka, et al. 2002. Dual regulation of mouse Delta(5)-and Delta(6)- desaturase gene expression by SREBP-1 and PPARalpha. J. Lipid Res. 43: 107-114. (Pubitemid 34117224)
60. Matsuzaka, T., and H. Shimano. 2009. Elovl6: a new player in fatty acid metabolism and insulin sensitivity. J. Mol. Med. 87: 379-384.
61. Sprecher, H. 2000. Metabolism of highly unsaturated n-3 and n-6 fatty acids. Biochim. Biophys. Acta. 1486: 219-231. (Pubitemid 30618862)
62. Pawar, A., and D. B. Jump. 2003. Unsaturated fatty acid regulation of peroxisome proliferator-activated receptor alpha activity in rat primary hepatocytes. J. Biol. Chem. 278: 35931-35939. (Pubitemid 37139911)
63. Ryan, A. S., E. Bailey-Hall, E. B. Nelson, and N. Salem, Jr. 2009. The hypolipidemic effect of an ethyl ester of algal-docosahexaenoic acid in rats fed a high-fructose diet. Lipids. 44: 817-826.
64. Brossard, N., M. Croset, C. Pachiaudi, J. P. Riou, J. L. Tayot, and M. Lagarde. 1996. Retroconversion and metabolism of [13C] 22:6,n-3 triacylglycerols. Am. J. Clin. Nutr. 64: 577-586.
65. Plourde, M., R. Chouinard-Watkins, M. Vandal, Y. Zhang, P. Lawrence, J. T. Brenna, and S. C. Cunnane. 2011. Plasma incorporation, apparent retroconversion and beta-oxidation of 13C-docosahexaenoic acid in the elderly. Nutr. Metab. (Lond). 8: 5-9.
66. Jump, D. B. 2011. Fatty acid regulation of hepatic gene expression. Curr. Opin. Clin. Nutr. Metab. Care. 14: 115-120.
67. Gao, F., H. W. Kim, M. Igarashi, D. Kiesewetter, L. Chang, K. Ma, and S. I. Rapoport. 2011. Liver conversion of docosahexaenoic and arachidonic acids from their 18-carbon precursors in rats on a DHA-free but alpha-LNA-containing n-3 PUFA adequate diet. Biochim. Biophys. Acta. 1811: 484-489.
68. Depner, C. M., M. Torres-Gonzalez, S. Tripathy, G. Milne, and D. B. Jump. 2012. Menhaden oil decreases high-fat diet-induced markers of hepatic damage, steatosis, inflammation, and fibrosis in obese ldlr-/-mice. J. Nutr. 142: 1495-1503.
69. Mohrhauer, H., and R. T. Holman. 1963. The effect of dose level of essential fatty acids upon fatty acid composition of the rat liver. J. Lipid Res. 4: 151-159.
70. Qin, Y., K. T. Dalen, J. A. Gustafsson, and H. I. Nebb. 2009. Regulation of hepatic fatty acid elongase 5 by LXRalpha-SREBP-1c. Biochim. Biophys. Acta. 1791: 140-147.
71. Tu, W. C., R. J. Cook-Johnson, M. J. James, B. S. Muhlhausler, and R. A. Gibson. 2010. Omega-3 long chain fatty acid synthesis is regulated more by substrate levels than gene expression. Prostaglandins Leukot. Essent. Fatty Acids. 83: 61-68.
72. Saggerson, D. 2008. Malonyl-CoA, a key signaling molecule in mammalian cells. Annu. Rev. Nutr. 28: 253-272.
73. Muoio, D. M., and C. B. Newgard. 2008. Fatty acid oxidation and insulin action: when less is more. Diabetes. 57: 1455-1456.
74. Warensjö, E., M. Rosell, M. L. Hellenius, B. Vessby, U. De Faire, and U. Riserus. 2009. Associations between estimated fatty acid desaturase activities in serum lipids and adipose tissue in humans: links to obesity and insulin resistance. Lipids Health Dis. 8: 37.
75. Kawashima, A., S. Sugawara, M. Okita, T. Akahane, K. Fukui, M. Hashiuchi, C. Kataoka, and I. Tsukamoto. 2009. Plasma fatty acid composition, estimated desaturase activities and intakes of energy and nutrient in Japanese men with abdominal obesity or metabolic syndrome. J. Nutr. Sci. Vitaminol. (Tokyo). 55: 400-406.
76. Pachikian, B. D., A. Essaghir, J. B. Demoulin, A. M. Neyrinck, E. Catry, F. C. De Backer, N. Dejeans, E. M. Dewulf, F. M. Sohet, L. Portois, et al. 2011. Hepatic n-3 polyunsaturated fatty acid depletion promotes steatosis and insulin resistance in mice: genomic analysis of cellular targets. PLoS ONE. 6: e23365.
77. Glaser, C., E. Lattka, P. Rzehak, C. Steer, and B. Koletzko. 2011. Genetic variation in polyunsaturated fatty acid metabolism and its potential relevance for human development and health. Matern. Child Nutr. 7 (Suppl. 2): 27-40.
78. Blanchard, H., P. Legrand, and F. Pedrono. 2011. Fatty Acid Desaturase 3 (Fads3) is a singular member of the Fads cluster. Biochimie. 93: 87-90.
79. Sergeant, S., C. E. Hugenschmidt, M. E. Rudock, J. T. Ziegler, P. Ivester, H. C. Ainsworth, D. Vaidya, L. Douglas Case, C. D. Langefeld, B. I. Freedman, et al. 2012. Differences in arachidonic acid levels and fatty acid desaturase (FADS) gene variants in African Americans and European Americans with diabetes or the metabolic syndrome. Br. J. Nutr. 107: 547-555.
80. Lattka, E., T. Illig, B. Koletzko, and J. Heinrich. 2010. Genetic variants of the FADS1 FADS2 gene cluster as related to essential fatty acid metabolism. Curr. Opin. Lipidol. 21: 64-69.
81. Glaser, C., J. Heinrich, and B. Koletzko. 2010. Role of FADS1 and FADS2 polymorphisms in polyunsaturated fatty acid metabolism. Metabolism. 59: 993-999.
82. Bokor, S., J. Dumont, A. Spinneker, M. Gonzalez-Gross, E. Nova, K. Widhalm, G. Moschonis, P. Stehle, P. Amouyel, S. De Henauw, et al. 2010. Single nucleotide polymorphisms in the FADS gene cluster are associated with delta-5 and delta-6 desaturase activities estimated by serum fatty acid ratios. J. Lipid Res. 51: 2325-2333.
83. Mathias, R. A., C. Vergara, L. Gao, N. Rafaels, T. Hand, M. Campbell, C. Bickel, P. Ivester, S. Sergeant, K. C. Barnes, et al. 2010. FADS genetic variants and omega-6 polyunsaturated fatty acid metabolism in a homogeneous island population. J. Lipid Res. 51: 2766-2774.
84. Lemaitre, R. N., T. Tanaka, W. Tang, A. Manichaikul, M. Foy, E. K. Kabagambe, J. A. Nettleton, I. B. King, L. C. Weng, S. Bhattacharya, et al. 2011. Genetic loci associated with plasma phospholipid n-3 fatty acids: a meta-analysis of genome-wide association studies from the CHARGE Consortium. PLoS Genet. 7: e1002193.
85. Lattka, E., S. Eggers, G. Moeller, K. Heim, M. Weber, D. Mehta, H. Prokisch, T. Illig, and J. Adamski. 2010. A common FADS2 promoter polymorphism increases promoter activity and facilitates binding of transcription factor ELK1. J. Lipid Res. 51: 182-191.
86. Ohno, Y., S. Suto, M. Yamanaka, Y. Mizutani, S. Mitsutake, Y. Igarashi, T. Sassa, and A. Kihara. 2010. ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis. Proc. Natl. Acad. Sci. USA. 107: 18439-18444.
87. Tanaka, T., J. Shen, G. R. Abecasis, A. Kisialiou, J. M. Ordovas, J. M. Guralnik, A. Singleton, S. Bandinelli, A. Cherubini, D. Arnett, et al. 2009. Genome-wide association study of plasma polyunsaturated fatty acids in the InCHIANTI Study. PLoS Genet. 5: e1000338.
88. Aslibekyan, S., M. K. Jensen, H. Campos, C. D. Linkletter, E. B. Loucks, J. M. Ordovas, R. Deka, E. B. Rimm, and A. Baylin. 2012. Genetic variation in fatty acid elongases is not associated with intermediated cardiovascular phenotypes or myocardial infarction. Eur. J. Clin. Nutr. 66: 353-359.
89. Stoffel, W., B. Holz, B. Jenke, E. Binczek, R. H. Gunter, C. Kiss, I. Karakesisoglou, M. Thevis, A. A. Weber, S. Arnhold, et al. 2008. Delta-6 desaturase (FADS2) deficiency unveils the role of omega-3 and omega-6 polyunsaturated fatty acids. EMBO J. 27: 2281-2292.
90. Nakamura, M. T., and T. Y. Nara. 2004. Structure, function, and dietary regulation of delta6, delta5, and delta9 desaturases. Annu. Rev. Nutr. 24: 345-376.
91. Moon, Y. A., R. E. Hammer, and J. D. Horton. 2009. Deletion of ELOVL5 leads to fatty liver through activation of SREBP-1c in mice. J. Lipid Res. 50: 412-423.
92. Jump, D. B. 2002. The biochemistry of n-3 polyunsaturated fatty acids. J. Biol. Chem. 277: 8755-8758. (Pubitemid 34952937)
93. Wassall, S. R., and W. Stillwell. 2009. Polyunsaturated fatty acid-cholesterol interactions: domain formation in membranes. Biochim. Biophys. Acta. 1788: 24-32.
94. Soni, S. P., D. S. LoCascio, Y. Liu, J. A. Williams, R. Bittman, W. Stillwell, and S. R. Wassall. 2008. Docosahexaenoic acid enhances segregation of lipids between: 2H-NMR study. Biophys. J. 95: 203-214.
95. Hsueh, H. W., Z. Zhou, J. Whelan, K. G. Allen, N. Moustaid- Moussa, H. Kim, and K. J. Claycombe. 2011. Stearidonic and eicosapentaenoic acids inhibit interleukin-6 expression in ob/ob mouse adipose stem cells via Toll-like receptor-2-mediated pathways. J. Nutr. 141: 1260-1266.
96. Lee, J. Y., L. Zhao, and D. H. Hwang. 2010. Modulation of pattern recognition receptor-mediated inflammation and risk of chronic diseases by dietary fatty acids. Nutr. Rev. 68: 38-61.
97. Lee, J. Y., A. Plakidas, W. H. Lee, A. Heikkinen, P. Chanmugam, G. Bray, and D. H. Hwang. 2003. Differential modulation of Toll-like receptors by fatty acids: preferential inhibition by n-3 poly-unsaturated fatty acids. J. Lipid Res. 44: 479-486. (Pubitemid 37279695)
98. Stulnig, T. M., M. Berger, T. Sigmund, D. Raederstorff, H. Stockinger, and W. Waldhausl. 1998. Polyunsaturated fatty acids inhibit T cell signal transduction by modification of detergent-insoluble membrane domains. J. Cell Biol. 143: 637-644. (Pubitemid 28512560)
99. Chen, W., W. J. Esselman, D. B. Jump, and J. V. Busik. 2005. Anti-inflammatory effect of docosahexaenoic acid on cytokine-induced adhesion molecule expression in human retinal vascular endothelial cells. Invest. Ophthalmol. Vis. Sci. 46: 4342-4347. (Pubitemid 44264641)
100. Chen, W., D. B. Jump, W. J. Esselman, and J. V. Busik. 2007. Inhibition of cytokine signaling in human retinal endothelial cells through modification of caveolae/lipid rafts by docosahexaenoic acid. Invest. Ophthalmol. Vis. Sci. 48: 18-26. (Pubitemid 47251381)
101. Nilsson, N. E., K. Kotarsky, C. Owman, and B. Olde. 2003. Identification of a free fatty acid receptor, FFA2R, expressed on leukocytes and activated by short-chain fatty acids. Biochem. Biophys. Res. Commun. 303: 1047-1052. (Pubitemid 36390250)
102. Brown, A. J., S. Jupe, and C. P. Briscoe. 2005. A family of fatty acid binding receptors. DNA Cell Biol. 24: 54-61. (Pubitemid 40096170)
103. Oh, D. Y., S. Talukdar, E. J. Bae, T. Imamura, H. Morinaga, W. Fan, P. Li, W. J. Lu, S. M. Watkins, and J. M. Olefsky. 2010. GPR120 is an omega-3 fatty acid receptor mediating potent antiinfl ammatory and insulin-sensitizing effects. Cell. 142: 687-698.
104. Talukdar, S., J. M. Olefsky, and O. Osborn. 2011. Targeting GPR120 and other fatty acid-sensing GPCRs ameliorates insulin resistance and inflammatory diseases. Trends Pharmacol. Sci. 32: 543-550.
105. Fredriksson, R., P. J. Hoglund, D. E. Gloriam, M. C. Lagerstrom, and H. B. Schioth. 2003. Seven evolutionarily conserved human rhodopsin G protein-coupled receptors lacking close relatives. FEBS Lett. 554: 381-388. (Pubitemid 37412518)
106. Burns, R. N., and N. H. Moniri. 2010. Agonism with the omega-3 fatty acids alpha-linolenic acid and docosahexaenoic acid mediates phosphorylation of both the short and long isoforms of the human GPR120 receptor. Biochem. Biophys. Res. Commun. 396: 1030-1035.
107. Oh, D. Y., and W. S. Lagakos. 2011. The role of G-protein-coupled receptors in mediating the effect of fatty acids on inflammation and insulin sensitivity. Curr. Opin. Clin. Nutr. Metab. Care. 14: 322-327
108. Saltiel, A. R. 2010. Fishing out a sensor for anti-inflammatory oils. Cell. 142: 672-674.
109. Wada, M., C. J. DeLong, Y. H. Hong, C. J. Rieke, I. Song, R. S. Sidhu, C. Yuan, M. Warnock, A. H. Schmaier, C. Yokoyama, et al. 2007. Enzymes and receptors of prostaglandin pathways with arachidonic acid-derived versus eicosapentaenoic acid-derived substrates and products. J. Biol. Chem. 282: 22254-22266. (Pubitemid 47267340)
110. Smith, W. L. 2008. Nutritionally essential fatty acids and biologically indispensable cyclooxygenases. Trends Biochem. Sci. 33: 27-37.
111. Calder, P. C. 2006. n-3 polyunsaturated fatty acids, inflammation, and inflammatory diseases. Am. J. Clin. Nutr. 83: 1505S-1519S. (Pubitemid 44713092)
112. Spite, M., and C. N. Serhan. 2010. Novel lipid mediators promote resolution of acute inflammation: impact of aspirin and statins. Circ. Res. 107: 1170-1184.
113. Serhan, C. N., R. Yang, K. Martinod, K. Kasuga, P. S. Pillai, T. F. Porter, S. F. Oh, and M. Spite. 2009. Maresins: novel macrophage mediators with potent antiinflammatory and proresolving actions. J. Exp. Med. 206: 15-23.
114. Zhang, C., and N. G. Bazan. 2010. Lipid-mediated cell signaling protects agains injury and neurodegeneration. J. Nutr. 140: 858-863.
115. Arnold, C., M. Markovic, K. Blossey, G. Wallukat, R. Fisher, R. Dechend, A. Konkel, C. Von Schaky, F. C. Luft, D. N. Muller, et al. 2010. Arachidonic acid-metabolizing cytochrome P450 enzymes are targets of omega-3 fatty acids. J. Biol. Chem. 285: 32720-32733.
116. Arnold, C., A. Konkel, R. Fischer, and W-H. Schunck. 2010. Cytochrome P450-dependent metabolism of omega-6 and omega-3 long-chain polyunsaturated fatty acids. Pharmacol. Rep. 62: 536-547.
117. Falck, J. R., G. Wallukat, N. Puli, M. Goli, C. Arnold, A. Konkel, M. Rothe, R. Fischer, D. N. Muller, and W. H. Schunck. 2011. 17(R),18(S)- epoxyeicosatetraenoic acid, a potent eicosapentaenoic acid (EPA) derived regulator of cardiomyocyte contraction: structure-activity relationships and stable analogues. J. Med. Chem. 54: 4109-4118.
118. Spector, A. A. 2009. Arachidonic acid cytochrome P450 epoxygenase pathway. J. Lipid Res. 50 (Suppl.): S52-S56.
119. Hoff, U., I. Lukitsch, L. Chaykovska, M. Ladwig, C. Arnold, V. L. Manthati, T. F. Fuller, W. Schneider, M. Gollasch, D. N. Muller, et al. 2011. Inhibition of 20-HETE synthesis and action protects the kidney from ischemia/reperfusion injury. Kidney Int. 79: 57-65.
120. Milne, G. L., H. Yin, and J. D. Morrow. 2008. Human biochemistry of the isoprostane pathway. J. Biol. Chem. 283: 15533-15537.
121. Saraswathi, V., J. D. Morrow, and A. H. Hasty. 2009. Dietary fish oil exerts hypolipidemic effects in lean and insulin sensitizing effect in obese LDLR-/-mice. J. Nutr. 139: 2380-2386.
122. Saraswathi, V., L. Gao, J. D. Morrow, A. Chait, K. D. Niswender, and A. H. Hasty. 2007. Fish oil increases cholesterol storage in white adipose tissue with concomitant decreases in inflammation, hepatic steatosis, and atherosclerosis in mice. J. Nutr. 137: 1776-1782. (Pubitemid 47037706)
123. Milne, G. L., H. Yin, K. D. Hardy, S. S. Davies, and L. J. Roberts 2nd. 2011. Isoprostane generation and function. Chem. Rev. 111: 5973-5996.
124. Song, W. L., G. Paschos, S. Fries, M. P. Reilly, Y. Yu, J. Rokach, C. T. Chang, P. Patel, J. A. Lawson, and G. A. Fitzgerald. 2009. Novel eicosapentaenoic acid-derived F3-isoprostanes as biomarkers of lipid peroxidation. J. Biol. Chem. 284: 23636-23643.
125. Jump, D. B., D. Botolin, Y. Wang, J. Xu, O. Demeure, and B. Christian. 2008. Docosahexaenoic acid (DHA) and hepatic gene transcription. Chem. Phys. Lipids. 153: 3-13.
126. Xu, H. E., M. H. Lambert, V. G. Montana, D. J. Parks, S. G. Blanchard, P. J. Brown, D. D. Sternbach, J. M. Lehmann, G. B. Wisely, T. M. Willson, et al. 1999. Molecular recognition of fatty acids by peroxisome proliferator-activated receptors. Mol. Cell. 3: 397-403. (Pubitemid 29290680)
127. Horton, J. D., J. L. Goldstein, and M. S. Brown. 2002. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J. Clin. Invest. 109: 1125-1131. (Pubitemid 34496588)
128. Postic, C., R. Dentin, P. D. Denechaud, and J. Girard. 2007. ChREBP, a transcriptional regulator of glucose and lipid metabolism. Annu. Rev. Nutr. 27: 179-192. (Pubitemid 351373354)
129. Botolin, D., Y. Wang, B. Christian, and D.B. Jump. 2006. Docosahexaenoic acid (22:6,n-3) regulates rat hepatocyte SREBP-1 nuclear abundance by Erk-and 26S proteasome-dependent pathways. J. Lipid Res. 47: 181-192. (Pubitemid 43107461)
130. Ben-Neriah, Y., and M. Karin. 2011. Inflammation meets cancer, with NF-kappaB as the matchmaker. Nat. Immunol. 12: 715-723.
131. Jump, D. B. 2004. Fatty acid regulation of gene transcription. Crit. Rev. Clin. Lab. Sci. 41: 41-78. (Pubitemid 38299789)
132. Austin, M. A., J. E. Hokanson, and K. L. Edwards. 1998. Hypertriglyceridemia as a cardiovascular risk factor. Am. J. Cardiol. 81: 7B-12B. (Pubitemid 28113939)
133. Hokanson, J. E., and M. A. Austin. 1996. Plasma triglyceride level is a risk factor for cardiovascular disease independent of highdensity lipoprotein cholesterol level: a meta-analysis of population- based prospective studies. J. Cardiovasc. Risk. 3: 213-219. (Pubitemid 26266496)
134. Sarwar, N., J. Danesh, G. Eiriksdottir, G. Sigurdsson, N. Wareham, S. Bingham, S. M. Boekholdt, K. T. Khaw, and V. Gudnason. 2007. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies. Circulation. 115: 450-458. (Pubitemid 46184196)
135. Goldberg, I. J., R. H. Eckel, and R. McPherson. 2011. Triglycerides and heart disease: still a hypothesis? Arterioscler. Thromb. Vasc. Biol. 31: 1716-1725.
136. Miller, M., N. J. Stone, C. Ballantyne, V. Bittner, M. H. Criqui, H. N. Ginsberg, A. C. Goldberg, W. J. Howard, M. S. Jacobson, P. M. Kris-Etherton, et al. 2011. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 123: 2292-2333.
137. Cottin, S. C., T. A. Sanders, and W. L. Hall. 2011. The differential effects of EPA and DHA on cardiovascular risk factors. Proc. Nutr. Soc. 70: 215-231.
138. Mozaffarian, D., and J. H. Wu. 2012. (n-3) Fatty acids and cardiovascular health: are effects of EPA and DHA shared or complementary? J. Nutr. 142: 614S-625S.
139. Jacobson, T. A., S. B. Glickstein, J. D. Rowe, and P. N. Soni. 2012. Effects of eicosapentaenoic acid and docosahexaenoic acid on low-density lipoprotein cholesterol and other lipids: a review. J. Clin. Lipidol. 6: 5-18.
140. Harris, W. S. 1997. n-3 fatty acids and serum lipoproteins: human studies. Am. J. Clin. Nutr. 65: 1645S-1654S. (Pubitemid 27187958)
141. Davidson, M. H., E. A. Stein, H. E. Bays, K. C. Maki, R. T. Doyle, R. A. Shalwitz, C. M. Ballantyne, and H. N. Ginsberg. 2007. Efficacy and tolerability of adding prescription omega-3 fatty acids 4 g/d to simvastatin 40 mg/d in hypertriglyceridemic patients: an 8-week, randomized, double-blind, placebo-controlled study. Clin. Ther. 29: 1354-1367. (Pubitemid 47348116)
142. Bays, H. E., K. C. Maki, R. T. Doyle, and E. Stein. 2009. The effect of prescription omega-3 fatty acids on body weight after 8 to 16 weeks of treatment for very high triglyceride levels. Postgrad. Med. 121: 145-150.
143. Bays, H. E., C. M. Ballantyne, J. J. Kastelein, J. L. Isaacsohn, R. A. Braeckman, and P. N. Soni. 2011. Eicosapentaenoic acid ethyl ester (AMR101) therapy in patients with very high triglyceride levels (from the Multi-center, plAcebo-controlled, Randomized, double- blInd, 12-week study with an open-label Extension [MARINE] trial). Am. J. Cardiol. 108: 682-690.
144. Pan, M., A. I. Cederbaum, Y. L. Zhang, H. N. Ginsberg, K. J. Williams, and E. A. Fisher. 2004. Lipid peroxidation and oxidant stress regulate hepatic apolipoprotein B degradation and VLDL production. J. Clin. Invest. 113: 1277-1287. (Pubitemid 39069927)
145. Shearer, G. C., O. V. Savinova, and W. S. Harris. 2012. Fish oil-how does it reduce plasma triglycerides? Biochim. Biophys. Acta. 1821: 843-851.
146. Ginsberg, H. N., and E. A. Fisher. 2009. The ever-expanding role of degradation in the regulation of apolipoprotein B metabolism. J. Lipid Res. 50 (Suppl.): S162-S166.
147. Weitz, D., H. Weintraub, E. Fisher, and A. Z. Schwartzbard. 2010. Fish oil for the treatment of cardiovascular disease. Cardiol. Rev. 18: 258-263.
148. Andreo, U., J. Elkind, C. Blachford, A. I. Cederbaum, and E. A. Fisher. 2011. Role of superoxide radical anion in the mechanism of apoB100 degradation
149. Qi, K., C. Fan, J. Jiang, H. Zhu, H. Jiao, Q. Meng, and R. J. Deckelbaum. 2008. Omega-3 fatty acid containing diets decrease plasma triglyceride concentrations in mice by reducing endogenous triglyceride synthesis and enhancing the blood clearance of triglyceride-rich particles. Clin. Nutr. 27: 424-430.
150. Parks, E. J., and M. K. Hellerstein. 2006. Thematic review series: patient-oriented research. Recent advances in liver triacylglycerol and fatty acid metabolism using stable isotope labeling techniques. J. Lipid Res. 47: 1651-1660. (Pubitemid 44222817)
151. Puglisi, M. J., A. H. Hasty, and V. Saraswathi. 2011. The role of adipose tissue in mediating the beneficial effects of dietary fish oil. J. Nutr. Biochem. 22: 101-108.
152. McConathy, W. J., J. C. Gesquiere, H. Bass, A. Tartar, J. C. Fruchart, and C. S. Wang. 1992. Inhibition of lipoprotein lipase activity by synthetic peptides of apolipoprotein C-III. J. Lipid Res. 33: 995-1003.
153. Ginsberg, H. N., N. A. Le, I. J. Goldberg, J. C. Gibson, A. Rubinstein, P. Wang-Iverson, R. Norum, and W. V. Brown. 1986. Apolipoprotein B metabolism in subjects with deficiency of apolipoproteins CIII and AI. Evidence that apolipoprotein CIII inhibits catabolism of triglyceride-rich lipoproteins by lipoprotein lipase in vivo. J. Clin. Invest. 78: 1287-1295. (Pubitemid 17181567)
154. Schoonjans, K., B. Staels, and J. Auwerx. 1996. Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression. J. Lipid Res. 37: 907-925. (Pubitemid 26182326)
155. Ren, B., A. P. Thelen, J. M. Peters, F. J. Gonzalez, and D. B. Jump. 1997. Polyunsaturated fatty acid suppression of hepatic fatty acid synthase and S14 gene expression does not require peroxisome proliferator-activated receptor alpha. J. Biol. Chem. 272: 26827-26832. (Pubitemid 27452629)
156. Zhang, J., C. Wang, L. Li, Q. Man, P. Song, L. Meng, Z. Y. Du, and L. Froyland. 2010. Inclusion of Atlantic salmon in the Chinese diet reduces cardiovascular disease risk markers in dyslipidemic adult men. Nutr. Res. 30: 447-454.
157. Zhang, J., C. Wang, L. Li, Q. Man, L. Meng, P. Song, L. Froyland, and Z. Y. Du. 2012. Dietary inclusion of salmon, herring and pompano as oily fish reduces CVD risk markers in dyslipidaemic middle-aged and elderly Chinese women. Br. J. Nutr. 6: 1-11.
158. Olivieri, O., N. Martinelli, M. Sandri, A. Bassi, P. Guarini, E. Trabetti, F. Pizzolo, D. Girelli, S. Friso, P. F. Pignatti, et al. 2005. Apolipoprotein C-III, n-3 polyunsaturated fatty acids, and "insulin- resistant" T-455C APOC3 gene polymorphism in heart disease patients: example of gene-diet interaction. Clin. Chem. 51: 360-367. (Pubitemid 40175806)
159. Flammer, A. J., and T. F. Luscher. 2010. Human endothelial dysfunction: EDRFs. Pflugers Arch. 459: 1005-1013.
160. Egert, S., and P. Stehle. 2011. Impact of n-3 fatty acids on endothelial function: results from human interventions studies. Curr. Opin. Clin. Nutr. Metab. Care. 14: 121-131.
161. Bonetti, P. O., L. O. Lerman, and A. Lerman. 2003. Endothelial dysfunction, a marker of atherosclerotic risk. Arterioscler. Thromb. Vasc. Biol. 23: 168-175. (Pubitemid 36231924)
162. Lusis, A. J. 2000. Atherosclerosis. Nature. 407: 233-241.
163. Ross, R. 1999. Atherosclerosis: an inflammatory disease. N. Engl. J. Med. 340: 115-126.
164. Stebbins, C. L., J. P. Stice, C. M. Hart, F. N. Mbai, and A. A. Knowlton. 2008. Effects of dietary docosahexaenoic acid (DHA) on eNOS in human coronary artery endothelial cells. J. Cardiovasc. Pharmacol. Ther. 13: 261-268.
165. Shibata, N., and C. K. Glass. 2009. Regulation of macrophage function in inflammation and atherosclerosis. J. Lipid Res. 50 (Suppl.): S277-S281.
166. Olefsky, J. M., and C. K. Glass. 2010. Macrophages, inflammation and insulin resistance. Annu. Rev. Physiol. 72: 219-246.
167. Serhan, C. N., S. Yacoubian, and R. Yang. 2008. Anti-inflammatory and proresolving lipid mediators. Annu. Rev. Pathol. 3: 279-312. (Pubitemid 351488283)
168. Yamada, H., M. Yoshida, Y. Nakano, T. Suganami, N. Satoh, T. Mita, K. Azuma, M. Itoh, Y. Yamamoto, Y. Kamei, et al. 2008. In vivo and in vitro inhibition of monocyte adhesion to endothelial cells and endothelial adhesion molecules by eicosapentaenoic acid. Arterioscler. Thromb. Vasc. Biol. 28: 2173-2179.
169. Chen, W., D. B. Jump, M. B. Grant, W. J. Esselman, and J. V. Busik. 2003. Dyslipidemia, but not hyperglycemia, induces inflammatory adhesion molecules in human retinal vascular endothelial cells. Invest. Ophthalmol. Vis. Sci. 44: 5016-5022. (Pubitemid 37315320)
170. Opreanu, M., T. A. Lydic, G. E. Reid, K. M. McSorley, W. J. Esselman, and J. V. Busik. 2010. Inhibition of cytokine signaling in human retinal endothelial cells through downregulation of sphingomyelinases by docosahexaenoic acid. Invest. Ophthalmol. Vis. Sci. 51: 3253-3263.
171. Burr, M. L., A. M. Fehily, J. F. Gilbert, S. Rogers, R. M. Holliday, P. M. Sweetnam, P. C. Elwood, and N. M. Deadman. 1989. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART). Lancet. 2: 757-761. (Pubitemid 19234807)
172. GISSI-Prevenzione Investigators. 1999. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico. Lancet. 354: 447-455.
173. London, B., C. Albert, M. E. Anderson, W. R. Giles, D. R. Van Wagoner, E. Balk, G. E. Billman, M. Chung, W. Lands, A. Leaf, et al. 2007. Omega-3 fatty acids and cardiac arrhythmias: prior studies and recommendations for future research: a report from the National Heart, Lung, and Blood Institute and Office of Dietary Supplements Omega-3 Fatty Acids and their Role in Cardiac Arrhythmogenesis Workshop. Circulation. 116: e320-e335. (Pubitemid 47360222)
174. Billman, G. E. 2012. Effect of dietary omega-3 polyunsaturated fatty acids on heart rate and heart rate variability in animals susceptible or resistant to ventricular fibrillation. Front. Physiol. 3: 71.
175. Richardson, E. S., P. A. Iaizzo, and Y-F. Xiao. 2011. Electrophysiological mechanisms and the anti-arrhythmic effects of omega-3 fatty acids. J. Cardiovasc. Transl. Res. 4: 42-52.
176. Billman, G. E., J. X. Kang, and A. Leaf. 1997. Prevention of ischemia-induced cardiac sudden death by n-3 polyunsaturated fatty acids in dogs. Lipids. 32: 1161-1168. (Pubitemid 27508108)
177. Stanley, W. C., R. J. Khairallah, and E. R. Dabkowski. 2012. Update on lipids and mitochondrial function: impact of dietary n-3 poly-unsaturated fatty acids. Curr. Opin. Clin. Nutr. Metab. Care. 15: 122-126.
178. Leaf, A., J. X. Kang, Y. F. Xiao, and G. E. Billman. 1998. Dietary n-3 fatty acids in the prevention of cardiac arrhythmias. Curr. Opin. Clin. Nutr. Metab. Care. 1: 225-228. (Pubitemid 128539448)
179. Khairallah, R. J., G. C. Sparagna, N. Khanna, K. M. O'Shea, P. A. Hecker, T. Kristian, G. Fiskum, C. Des Rosiers, B. M. Polster, and W. C. Stanley. 2010. Dietary supplementation with docosahexaenoic acid, but not eicosapentaenoic acid, dramatically alters cardiac mitochondrial phospholipid fatty acid composition and prevents permeability transition. Biochim. Biophys. Acta. 1797: 1555-1562.
180. O'Shea, K. M., R. J. Khairallah, G. C. Sparagna, W. Xu, P. A. Hecker, I. Robillard-Frayne, C. Des Rosiers, T. Kristian, R. C. Murphy, G. Fiskum, et al. 2009. Dietary omega-3 fatty acids alter cardiac mitochondrial phospholipid composition and delay Ca2+- induced permeability transition. J. Mol. Cell. Cardiol. 47: 819-827.
181. Duda, M. K., K. M. O'Shea, B. Lei, B. R. Barrows, A. M. Azimzadeh, T. E. McElfresh, B. D. Hoit, W. J. Kop, and W. C. Stanley. 2007. Dietary supplementation with omega-3 PUFA increases adiponectin and attenuates ventricular remodeling and dysfunction with pressure overload. Cardiovasc. Res. 76: 303-310. (Pubitemid 350198598)
182. Yamagishi, K., J. A. Nettleton, and A. R. Folsom. 2008. ARIC study investigators: plasma fatty acid composition and incident heart failure in middle-adge adults: the atherosclerosis risk in communities (ARIC) study. Am. Heart J. 156: 965-974.
183. Virtanen, J. K., J. Mursu, S. Voutilainen, and T. P. Tuomainen. 2009. Serum long-chain n-3 polyunsaturated fatty acids and risk of hospital diagnosis of atrial fibrillation in men. Circulation. 120: 2315-2321.
184. Pottala, J. V., S. Garg, B. E. Cohen, M. A. Whooley, and W. S. Harris. 2010. Blood eicosapentaenoic and docosahexaenoic acids predict all-cause mortality in patients with stable coronary heart disease: the Heart and Soul study. Circ. Cardiovasc. Qual. Outcomes. 3: 406-412.
185. de Goede, J., W. M. Verschuren, J. M. Boer, D. Kromhout, and J. M. Geleijnse. 2011. Alpha-linolenic acid intake and 10-year incidence of coronary heart disease and stroke in 20,000 middle-aged men and women in the Netherlands. PLoS ONE. 6: e17967.
186. Heine-Bröring, R. C., I. A. Brouwer, R. V. Proenca, F. J. van Rooij, A. Hofman, M. Oudkerk, J. C. Witteman, and J. M. Geleijnse. 2010. Intake of fish and marine n-3 fatty acids in relation to coronary calcification: the Rotterdam Study. Am. J. Clin. Nutr. 91: 1317-1323.
187. Mozaffarian, D., R. N. Lemaitre, I. B. King, X. Song, D. Spiegelman, F. M. Sacks, E. B. Rimm, and D. S. Siscovick. 2011. Circulating long-chain omega-3 fatty acids and incidence of congestive heart failure in older adults: the cardiovascular health study: a cohort study. Ann. Intern. Med. 155: 160-170.
188. Burr, M. L. 2007. Secondary prevention of CHD in UK men: the Diet and Reinfarction Trial and its sequel. Proc. Nutr. Soc. 66: 9-15. (Pubitemid 46748239)
189. Burr, M. L., P. A. Ashfield-Watt, F. D. Dunstan, A. M. Fehily, P. Breay, T. Ashton, P. C. Zotos, N. A. Haboubi, and P. C. Elwood. 2003. Lack of benefit of dietary advice to men with angina: results of a controlled trial. Eur. J. Clin. Nutr. 57: 193-200. (Pubitemid 36240469)
190. Gissi-HF Investigators, L. Tavazzi, A. P. Maggioni, R. Marchioli, S. Barlera, M. G. Franzosi, R. Latini, D. Lucci, G. L. Nicolosi, M. Porcu, et al. 2008. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomized, double-blind, placebo-controlled trial. Lancet. 372: 1223-1230.
191. Yokoyama, M., H. Origasa, M. Matsuzaki, Y. Matsuzawa, Y. Saito, Y. Ishikawa, S. Oikawa, J. Sasaki, H. Hishida, H. Itakura, et al. 2007. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet. 369: 1090-1098. (Pubitemid 46483662)
192. Itakura, H., M. Yokoyama, M. Matsuzaki, Y. Saito, H. Origasa, Y. Ishikawa, S. Oikawa, J. Sasaki, H. Hishida, T. Kita, et al. 2011. Relationships between plasma fatty acid composition and coronary artery disease. J. Atheroscler. Thromb. 18: 99-107.
193. Rauch, B., R. Schiele, S. Schneider, F. Diller, N. Victor, H. Gohlke, M. Gottwik, G. Steinbeck, U. Del Castillo, R. Sack, et al. 2010. OMEGA, a randomized, placebo-controlled trial to test the effect of highly purified omega-3 fatty acids on top of modern guideline- adjusted therapy after myocardial infarction. Circulation. 122: 2152-2159.
194. Kromhout, D., E. J. Giltay, and J. M. Geleijnse. 2010. n-3 fatty acids and cardiovascular events after myocardial infarction. N. Engl. J. Med. 363: 2015-2026.
195. Galan, P., E. Kesse-Guyot, S. Czernichow, S. Braincon, J. Blacher, and S. Hercberg. 2010. Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: a randomized placebo controlled trial. BMJ. 341: c6273.
196. Jacobson, T. A. 2007. Beyond lipids: the role of omega-3 fatty acids from fish oil in the prevention of coronary heart disease. Curr. Atheroscler. Rep. 9: 145-153. (Pubitemid 47381173)
197. Burr, M. L., F. D. Dunstan, and C. H. George. 2005. Is fish oil good or bad for heart disease? Two trials with apparently conflicting results. J. Membr. Biol. 206: 155-163. (Pubitemid 43199148)
198. Marik, P. E., and J. Varon. 2009. Omega-3 dietary supplements and the risk of cardiovascular events: a systematic review. Clin. Cardiol. 32: 365-372.
199. Delgado-Lista, J., P. Perez-Martinez, J. Lopez-Miranda, and F. Perez-Jimenez. 2012. Long chain omega-3 fatty acids and cardiovascular disease: a systematic review. Br. J. Nutr. 107(Suppl. 2) : S201-S213.
200. Deckelbaum, R. J., and P. C. Calder. 2012. Different outcomes for omega-3 heart trials: why? Curr. Opin. Clin. Nutr. Metab. Care. 15: 97-98.
201. Kwak, S. M., S.-K. Myung, Y. J. Lee, and H. G. Seo. 2012. Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease. A meta-analysis of randomized, double-blind, placebocontrol trials. Arch. Intern. Med. 172: 686-694.
202. Hu, F. B., and J. E. Manson. 2012. Omega-3 fatty acids and secondary prevention of cardiovascular disease - is it just a fish tail? Arch. Intern. Med. 172: 694-696.
203. Eussen, S. R., J. M. Geleijnse, E. J. Giltay, C. J. Rompelberg, O. H. Klungel, and D. Kromhout. 2012. Effects of n-3 fatty acids on major cardiovascular events in statin users and non-users with a history of myocardial infarction. Eur. Heart J. 33: 1582-1588.
204. Manson, J. E., S. S. Bassuk, I. M. Lee, N. R. Cook, M. A. Albert, D. Gordon, E. Zaharris, J. G. Macfadyen, E. Danielson, J. Lin, et al. 2012. The VITamin D and OmegA-3 TrialL (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease. Contemp. Clin. Trials. 33: 159-171.
205. Trikalinos, T. A., J. Lee, D. Moorthy, W. W. Yu, J. Lau, A. H. Lichtenstein, and M. Chung. 2012. Effects of Eicosapentanoic Acid and Docosahexanoic Acid on Mortality Across Diverse Settings: Systematic Review and Meta-Analysis of Randomized Trials and Prospective Cohorts. Nutritional Research Series, Vol. 4. Report No. 12-EHC040-EF. US Agency for Healthcare Research and Quality, Rockville, MD.
206. Burr, M. L., A. M. Fehily, S. Rogers, E. Welsby, S. King, and S. Sandham. 1989. Diet and reinfarction trial (DART): design, recruitment, and compliance. Eur. Heart J. 10: 558-567. (Pubitemid 19183796)
207. Burr, M. L., R. M. Holliday, A. M. Fehily, and P. J. Whitehead. 1992. Haematological prognostic indices after myocardial infarction: evidence from the diet and reinfarction trial (DART). Eur. Heart J. 13: 166-170.
208. Yokoyama, M., and H. Origasa. 2003. Effects of eicosapentaenoic acid on cardiovascular events in Japanese patients with hypercholesterolemia: rationale, design, and baseline characteristics of the Japan EPA Lipid Intervention Study (JELIS). Am. Heart J. 146: 613-620. (Pubitemid 37281704)
209. Jenkins, D. J., J. L. Sievenpiper, D. Pauly, U. R. Sumaila, C. W. Kendall, and F. M. Mowat. 2009. Are dietary recommendations for the use of fish oils sustainable? CMAJ. 180: 633-637.
210. Miller, M. R., A. R. Bridle, P. D. Nichols, and C. G. Carter. 2008. Increased elongase and desaturase gene expression with stearidonic acid enriched diet does not enhance long-chain (n-3) content of seawater Atlantic salmon (Salmo salar L.). J. Nutr. 138: 2179-2185.
211. Dyerberg, J., P. Madsen, J. M. Moller, I. Aardestrup, and E. B. Schmidt. 2010. Bioavailability of marine n-3 fatty acid formulations. Prostaglandins Leukot. Essent. Fatty Acids. 83: 137-141.
212. Gillies, P. J., W. S. Harris, and P. M. Kris-Etherton. 2011. Omega-3 fatty acids in food and pharma: the enabling role of biotechnology. Curr. Atheroscler. Rep. 13: 467-473.
213. Brenna, J. T. 2002. Efficiency of conversion of alpha-linolenic acid to long chain n-3 fatty acids in man. Curr. Opin. Clin. Nutr. Metab. Care. 5: 127-132.
214. Plourde, M., and S. C. Cunnane. 2007. Extremely limited synthesis of long chain polyunsaturates in adults: implications for their dietary essentiality and use as supplements. Appl. Physiol. Nutr. Metab. 32: 619-634.
215. Hussein, N., E. Ah-Sing, P. Wilkinson, C. Leach, B. A. Griffin, and D. J. Millward. 2005. 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. 46: 269-280. (Pubitemid 40271091)
216. Williams, C. M., and G. Burdge. 2006. Long-chain n-3 PUFA: plant v. marine sources. Proc. Nutr. Soc. 65: 42-50. (Pubitemid 43259983)
217. Pawlosky, R. J., J. R. Hibbeln, J. A. Novotny, and N. Salem, Jr. 2001. Physiological compartmental analysis of alpha-linolenic acid metabolism in adult humans. J. Lipid Res. 42: 1257-1265. (Pubitemid 32744249)
218. Egert, S., M. Lindenmeier, K. Harnack, K. Krome, H. F. Erbersdobler, U. Wahrburg, and V. Somoza. 2012. Margarines fortified with alpha-linolenic acid, eicosapentaenoic acid, or docosahexaenoic acid alter the fatty acid composition of erythrocytes but do not affect the antioxidant status of healthy adults. J. Nutr. 142: 1638-1644.
219. Geleijnse, J. M., J. de Goede, and I. A. Brouwer. 2010. Alphalinolenic acid: is it essential to cardiovascular health? Curr. Atheroscler. Rep. 12: 359-367.
220. Zhao, G., T. D. Etherton, K. R. Martin, S. G. West, P. J. Gillies, and P. M. Kris-Etherton. 2004. Dietary alpha-linolenic acid reduces inflammatory and lipid cardiovascular risk factors in hypercholesterolemic men and women. J. Nutr. 134: 2991-2997. (Pubitemid 39470074)
221. Dewell, A., F. F. Marvasti, W. S. Harris, P. Tsao, and C. D. Gardner. 2011. Low-and high-dose plant and marine (n-3) fatty acids do not affect plasma inflammatory markers in adults with metabolic syndrome. J. Nutr. 141: 2166-2171.
222. James, M. J., V. M. Ursin, and L. G. Cleland. 2003. Metabolism of stearidonic acid in human subjects: comparison with the metabolism of other n-3 fatty acids. Am. J. Clin. Nutr. 77: 1140-1145. (Pubitemid 44858428)
223. Harris, W. S., S. L. Lemke, S. N. Hansen, D. A. Goldstein, M. A. DiRienzo, H. Su, M. A. Nemeth, M. L. Taylor, G. Ahmed, and C. George. 2008. Stearidonic acid-enriched soybean oil increased the omega-3 index, an emerging cardiovascular risk marker. Lipids. 43: 805-811.
224. Whelan, J. 2009. Dietary stearidonic acid is a long chain (n-3) polyunsaturated fatty acids with potential health benefits. J. Nutr. 139: 5-10.
225. Banz, W. J., J. E. Davis, R. W. Clough, and J. L. Cheatwood. 2012. Stearidonic acid: is there a role in the prevention and management of type 2 diabetes mellitus. J. Nutr. 142: 635S-640S.
226. Deckelbaum, R. J., P. C. Calder, W. S. Harris, C. C. Akoh, K. C. Maki, J. Whelan, W. J. Banz, and E. Kennedy. 2012. Conclusions and recommendations from the symposium, Heart Healthy Omega-3s for Food: Stearidonic Acid (SDA) as a Sustainable Choice. J. Nutr. 142: 641S-643S.
227. Krul, E. S., S. L. Lemke, R. Mukherjea, M. L. Taylor, D. A. Goldstein, H. Su, P. Liu, A. Lawless, W. S. Harris, and K. C. Maki. 2012. Effects of duration of treatment and dosage of eicosapentaenoic acid and stearidonic acid on red blood cell eicosapentaenoic acid content. Prostaglandins Leukot. Essent. Fatty Acids. 86: 51-59.
228. Lemke, S. L., J. L. Vicini, H. Su, D. A. Goldstein, M. A. Nemeth, E. S. Krul, and W. S. Harris. 2010. Dietary intake of stearidonic acid-enriched soybean oil increases the omega-3 index: randomized, double-blind clinical study of efficacy and safety. Am. J. Clin. Nutr. 92: 766-775.
229. Maki, K. C., and T. M. Rains. 2012. Stearidonic acid raises red blood cell membrane eicosapentaenoic acid. J. Nutr. 142: 626S-629S.
230. Stanley, W. C., E. R. Dubkowski, R. F. Ribeiro, Jr., and K. A. O'Connell. 2012. Dietary fat and heart failure: moving from lipotoxicity to lipoprotection. Circ. Res. 110: 764-776.
231. Duda, M. K., K. M. O'Shea, A. Tintinu, W. Xu, R. J. Khairallah, B. R. Barrows, D. J. Chess, A. M. Azimzadeh, W. S. Harris, V. G. Sharov, et al. 2009. Fish oil, but not flaxseed oil, decreases inflammation and prevents pressure overload-induced cardiac dysfunction. Cardiovasc. Res. 81: 319-327.
232. Shah, K. B., M. K. Duda, K. M. O'Shea, G. C. Sparagna, D. J. Chess, R. J. Khairallah, I. Robillard-Frayne, W. Xu, R. C. Murphy, C. Des Rosiers, et al. 2009. The cardioprotective effects of fish oil during pressure overload are blocked by high fat intake: role of cardiac phospholipid remodeling. Hypertension. 54: 605-611.
233. Kelley, D. S., D. Siegel, M. Vemuri, and B. E. Mackey. 2007. Docosahexaenoic acid supplementation improves fasting and postprandial lipid profiles in hypertriglycemic men. Am. J. Clin. Nutr. 86: 324-333. (Pubitemid 47256914)
234. Khairallah, R. J., J. Kim, K. M. O'Shea, K. A. O'Connell, B. H. Brown, T. Galvao, C. Daneault, C. Des Rosiers, B. M. Polster, C. L. Hoppel, et al. 2012. Improved mitochondrial function with diet-induced increase in either docosahexaenoic acid or arachidonic acid in membrane phospholipids. PLoS ONE. 7: e34402.
235. Kromhout, D., J. M. Geleijnse, A. Menotti, and D. R. Jacobs, Jr. 2011. The confusion about dietary fatty acids recommendations for CHD prevention. Br. J. Nutr. 106: 627-632.
236. Jinno, Y., M. Nakakuki, H. Kawano, T. Notsu, K. Mizuguchi, and K. Imada. 2011. Eicosapentaenoic acid administration attenuates the pro-inflammatory properties of VLDL by decreasing its susceptibility to lipoprotein lipase in macrophages. Atherosclerosis. 219: 566-572.
237. Murthy, M., J. Hamilton, R. S. Greiner, T. Moriguchi, N. Salem, Jr., and H. Y. Kim. 2002. Differential effects of n-3 fatty acid defi- ciency on phospholipid molecular species composition in the rat hippocampus. J. Lipid Res. 43: 611-617.
238. Rojas, C. V., R. S. Greiner, L. C. Fuenzalida, J. I. Martinez, N. Salem, Jr., and R. Uauy. 2002. Long-term n-3 FA deficiency modifi es peroxisome proliferator-activated receptor beta mRNA abundance in rat ocular tissues. Lipids. 37: 367-374. (Pubitemid 34441799)
239. Catalan, J., T. Moriguchi, B. Slotnick, M. Murthy, R. S. Greiner, and N. Salem, Jr. 2002. Cognitive deficits in docosahexaenoic acid-deficient rats. Behav. Neurosci. 116: 1022-1031. (Pubitemid 35429637)