Clinical Markers of the Zone

Clinical Intervention Studies

These studies have used the AA/EPA ratio to measure the levels of inflammation in various clinical intervention studies using omega-3 fatty acids.

McNamara RK, Jandacek R, Rider T, Tso P, Chu WJ, Weber WA, Welge JA, Strawn JR, Adler CM, and DelBello MP. “Effects of fish oil supplementation on prefrontal metabolite concentrations in adolescents with major depressive disorder: A preliminary 1H MRS study.” Nutr Neurosci 19:145-155 (2016)

Takahashi M, Myojo M, Watanabe A, Kiyosue A, Kimura K, Ando J, Hirata Y, and Komuro I. “Effect of purified eicosapentaenoic acid on red cell distribution width in patients with ischemic heart disease.” Heart Vessels 30:587-594 (2015)

Georgiou T and Prokopiou E. “The New Era of Omega-3 Fatty Acids Supplementation: Therapeutic Effects on Dry Age-Related Macular Degeneration.” J Stem Cells 10:205-215 (2015)

Georgiou T, Neokleous A, Nikolaou D, and Sears B. “Pilot study for treating dry age-related macular degeneration (AMD) with high-dose omega-3 fatty acids.” PharmaNutrition 2:8-11 (2014)

Tanaka N, Ishida T, Nagao M, Mori T, Monguchi T, Sasaki M, Mori K, Kondo K, Nakajima H, Honjo T, Irino Y, Toh R, Shinohara M, and Hirata K. “Administration of high dose eicosapentaenoic acid enhances anti-inflammatory properties of high-density lipoprotein in Japanese patients with dyslipidemia.” Atherosclerosis 237:577-583 (2014)

Sato T, Kameyama T, Ohori T, Matsuki A, and Inoue H. “Effects of eicosapentaenoic acid treatment on epicardial and abdominal visceral adipose tissue volumes in patients with coronary artery disease.” J Atheroscler Thromb 21:1031-1043 (2014)

Takada K, Ishikawa S, Yokoyama N, Hosogoe N, and Isshiki T. “Effects of eicosapentaenoic acid on platelet function in patients taking long-term aspirin following coronary stent implantation.” Int Heart J 55:228-233 (2014)

Toyama K, Nishioka T, Isshiki A, Ando T, Inoue Y, Kirimura M, Kamiyama T, Sasaki O, Ito H, Maruyama Y, and Yoshimoto N. “Eicosapentaenoic acid combined with optimal statin therapy improves endothelial dysfunction in patients with coronary artery disease.” Cardiovasc Drugs Ther 28:53-59 (2014)

Fukuoka Y, Nuruki N, Amiya S, Tofuku K, Aosaki S, and Tsubouchi H. “Effects of a fish-based diet and administration of pure eicosapentaenoic acid on brachial-ankle pulse wave velocity in patients with cardiovascular risk factors.” J Cardiol 63:211-217 (2014)

McNamara RK, Perry M, and Sears, B. “Dissociation of C-reactive protein levels from long-chain omega-3 fatty acid status and anti-depressant response in adolescents with major depressive disorder: an open-label dose-ranging trial.”  J Nutr Therapeutics 2:235-243 (2013)

Sears B, Bailes J, and Asselin B. “Therapeutic uses of high-dose omega-3 fatty acids to treat comatose patients with severe brain injury.” PharmaNutrition 1: 86-89 (2013)

Ohnishi H and Saito Y. “Eicosapentaenoic acid (EPA) reduces cardiovascular events: relationship with the EPA/arachidonic acid ratio.” J Atheroscler Thromb 20:861-877 (2013)

Tani S, Nagao K, Matsumoto M, and Hirayama A. “Highly purified eicosapentaenoic acid may increase low-density lipoprotein particle size by improving triglyceride metabolism in patients with hypertriglyceridemia.” Circ . 77:2349-2357 (2013)

Satoh-Asahara N, Shimatsu A, Sasaki Y, Nakaoka H, Himeno A, Tochiya M, Kono S, Takaya T, Ono K, Wada H, Suganami T, Hasegawa K, and Ogawa Y. “Highly purified eicosapentaenoic acid increases interleukin-10 levels of peripheral blood monocytes in obese patients with dyslipidemia.” Diabetes Care 35:2631-2539 (2012)

Rizzo AM, Corsetto PA, Montorfano G, Opizzi A, Faliva M, Giacosa A, Ricevuti G, Pelucchi C, Berra B, and Rondanelli M. “Comparison between the AA/EPA ratio in depressed and non depressed elderly females: omega-3 fatty acid supplementation correlates with improved symptoms but does not change immunological parameters.” Nutr J 11:82 (2012)

Itariu BK, Zeyda M, Hochbrugger EE, Neuhofer A, Prager G, Schindler K, Bohdjalian A, Mascher D, Vangala S, Schranz M, Krebs M, Bischof MG, and Stulnig TM. “Long-chain n-3 PUFAs reduce adipose tissue and systemic inflammation in severely obese nondiabetic patients: a randomized controlled trial.” Am J Clin Nutr 96:1137-1149 (2012)

Rizzo AM, Montorfano G, Negroni M, Adorni L,Berselli P, Corsetto P, Wahle K, and Berra B. “A rapid method for determining arachidonic:eicosapentaenoic acid ratios in whole blood lipids: correlation with erythrocyte membrane ratios and validation in a large Italian population of various ages and pathologies.” Lipids Health Dis 9:7 (2010)

Matsuzaki M, Yokoyama M, Saito Y, Origasa H, Ishikawa Y, Oikawa S, Sasaki J, Hishida H, Itakura H, Kita T, Kitabatake A, Nakaya N, Sakata T, Shimada K, Shirato K, and Matsuzawa Y. “Incremental effects of eicosapentaenoic acid on cardiovascular events in statin-treated patients with coronary artery disease.” Circ J 73:1283-1290 (2009)

Oikawa S, Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, Sasaki J, Hishida H, Itakura H, Kita T, Kitabatake A, Nakaya N, Sakata T, Shimada K, and Shirato K. “Suppressive effect of EPA on the incidence of coronary events in hypercholesterolemia with impaired glucose metabolism: Sub-analysis of the Japan EPA Lipid Intervention Study (JELIS).” Atherosclerosis 206:535-539 (2009)

Buydens-Branchey L, Branchey M, and Hibbeln JR. “Associations between increases in plasma n-3 polyunsaturated fatty acids following supplementation and decreases in anger and anxiety in substance abusers.” Prog Neuropsychopharmacol Biol Psychiatry 32:568-575 (2008)

Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, Oikawa S, Sasaki J, Hishida H, Itakura H, Kita T, Kitabatake A, Nakaya N, Sakata T, Shimada K, and Shirato K. “Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomized open-label, blinded endpoint analysis.” Lancet 369:1090-1098 (2007)

Germano M, Meleleo D, Montorfano G, Adorni L, Negroni M, Berra B, and Rizzo AM. “Plasma, red blood cells phospholipids and clinical evaluation after long chain omega-3 supplementation in children with attention deficit hyperactivity disorder (ADHD).” Nutr Neurosci 10:1-9 (2007)

Sorgi PJ, Hallowell EM, Hutchins HL, Sears B. “Effects of an open-label pilot study with high-dose EPA/DHA concentrates on plasma phospholipids and behavior in children with attention deficit hyperactivity disorder.” Nutr J 6:16 (2007)

Johnston CS, Tjonn S, Swan PD, White A, Hutchins H, and Sears B. “Ketogenic low-carbohydrate diets have no metabolic advantage over nonketogenic low-carbohydrate diets.” Am J Clin Nutr 83: 1055-1061 (2006)

Fontani G, Corradeschi F, Felici A, Alfatti F, Bugarini R, Fiaschi AI, Cerretani D, Montorfano G, Rizzo AM, and Berra B. “Blood profiles, body fat and mood state in healthy subjects on different diets supplemented with omega-3 polyunsaturated fatty acids.” Eur J Clin Invest 35:499-507 (2005)

Stark KD, Mulvad G, Pedersen HS, Park EJ, Dewailly E, and Holub BJ. “Fatty acid compositions of serum phospholipids of postmenopausal women: a comparison between Greenland Inuit and Canadians before and after supplementation with fish oil.” Nutrition 18:627-630 (2002)

Endres S, Ghorbani R, Kelley VE, Georgilis K, Lonnemann G, van der Meer JW, Cannon JG, Rogers TS, Klempner MS, Weber PC, Schaefer EJ, Wolff SM, and Dinarello CA. “The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells.” N Engl J Med 320:265-271 (1989)


Fat- 1 Mice Studies

The fat-1 mouse is a genetically engineered animal so that much of the omega-6 fatty acids are converted to omega-3 fatty acids. The resulting AA/EPA ratio in these genetically altered animals is approximately 1.  These studies show the benefits of lowering the AA/EPA ratio in a wide number of chronic disease conditions.

Song MY, Wang J, Lee Y, Lee J, Kwon KS, Bae EJ, and Park BH. “Enhanced M2 macrophage polarization in high n-3 polyunsaturated fatty acid transgenic mice fed a high-fat diet.” Mol Nutr Food Res (2016) [Epub ahead of print]

Ren H, Yang Z, Luo C, Zeng H, Li P, Kang JX, Wan JB, He C, and Su H. “Enriched Endogenous Omega-3 Fatty Acids in Mice Ameliorate Parenchymal Cell Death After Traumatic Brain Injury.” Mol Neurobiol  (2016) [Epub ahead of print]

Ahn SH, Park SY, Baek JE, Lee SY, Baek WY, Lee SY, Lee YS, Ju Yoo H, Kim H, Lee SH, Im DS, Lee SK, Kim BJ, and Koh JM. “Free Fatty Acid Receptor 4 (GPR120) Stimulates Bone Formation and Suppresses Bone Resorption in the Presence of Elevated n-3 Fatty Acid Levels.” Endocrinology (2016) [Epub ahead of print]

Tan Y, Ren H, Shi Z, Yao X, He C, Kang JX, Wan JB, Li P, Yuan TF, and Su H. “Endogenous Docosahexaenoic Acid (DHA) Prevents Aβ1-42 Oligomer-Induced Neuronal Injury.” Mol Neurobiol 53:3146-53 (2016)

Kaliannan K, Wang B, Li XY, Bhan AK, and Kang JX. “Omega-3 fatty acids prevent early-life antibiotic exposure-induced gut microbiota dysbiosis and later-life obesity.” Int J Obes 40:1039-42 (2016)

Ma S, Ge Y, Gai X, Xue M, Li N, Kang J, Wan J, and Zhang J. “Transgenic n-3 PUFAs enrichment leads to weight loss via modulating neuropeptides in hypothalamus.” Neurosci Lett611:28-32 (2016)

Hwang WM, Bak DH, Kim DH, Hong JY, Han SY, Park KY, Lim K, Lim DM, and Kang JG.  “Omega-3 Polyunsaturated Fatty Acids May Attenuate Streptozotocin-Induced Pancreatic β-Cell Death via Autophagy Activation in Fat-1 Transgenic Mice.” Endocrinol Metab 30:569-75 (2015)

Huang W, Wang B, Li X, and Kang JX. “Endogenously elevated n-3 polyunsaturated fatty acids alleviate acute ethanol-induced liver steatosis.” Biofactors  41:453-62 (2015)

Shi Z, Ren H, Luo C, Yao X, Li P, He C, Kang JX, Wan JB, Yuan TF, and Su H. “Enriched Endogenous Omega-3 Polyunsaturated Fatty Acids Protect Cortical Neurons from Experimental Ischemic Injury.” Mol Neurobiol (2015) [Epub ahead of print]

Wang X, Ma DW, Kang JX, and Kulka M. “n-3 Polyunsaturated fatty acids inhibit Fc receptor I-mediated mast cell activation.” J Nutr Biochem 26:1580-1588 (2015)

Hwang WM, Bak DH, Kim DH, Hong JY, Han SY, Park KY, Lim K, and Lim DM. “Attenuation of streptozotocin-induced pancreatic beta cell death in transgenic fat-1 mice via autophagy activation.” Endocrinol Metab 2015 [Epub ahead of print]

Woo SJ, Lim K, Park SY, Jung MY, Lim HS, Jeon MG, Lee SI, and Park BH. “Endogenous conversion of n-6 to n-3 polyunsaturated fatty acids attenuates K/BxN serum-transfer arthritis in fat-1 mice.” J Nutr Biochem 26:713-720 (2015)

Li X, Ballantyne LL, Che X, Mewburn JD, Kang JX, Barkley RM, Murphy RC, Yu Y, and Funk CD. “Endogenously generated omega-3 fatty acids attenuate vascular inflammation and neointimal hyperplasia by interaction with free fatty acid receptor 4 in mice.” J Am Heart Assoc 4(4) (2015)

Belchior T, Paschoal VA, Magdalon J, Chimin P, Farias TM, Chaves-Filho AB, Gorjão R, St-Pierre P, Miyamoto S, Kang JX, Deshaies Y, Marette A, and Festuccia W. “Omega-3 fatty acids protect from diet-induced obesity, glucose intolerance, and adipose tissue inflammation through PPARγ-dependent and PPARγ-independent actions.”  Mol Nutr Food Res 59:957-67 (2015)

Delpech JC, Madore C, Joffre C, Aubert A, Kang JX, Nadjar A, and Layé S. “Transgenic increase in n-3/n-6 fatty acid ratio protects against cognitive deficits induced by an immune challenge through decrease of neuroinflammation.” Neuropsychopharmacology40:525-536 (2015)

Algamas-Dimantov A, Yehuda-Shnaidman E, Hertz R, Peri I, Bar-Tana J, and Schwartz B. “Prevention of diabetes-promoted colorectal cancer by (n-3) polyunsaturated fatty acids and (n-3) PUFA mimetic.” Oncotarget 5:9851-9863 (2014)

Li J, Li FR, Wei D, Jia W, Kang JX, Stefanovic-Racic M, Dai Y, and Zhao AZ. “Endogenous ω-3 polyunsaturated fatty acid production confers resistance to obesity, dyslipidemia, and diabetes in mice.”  Mol Endocrinol 28:1316-1328 (2014)

Gao Z, Wang Y, Ren Z, Li Q, Wang Y, and Dai Y. “Genome-wide screen for serum microRNA expression profile in mfat-1 transgenic mice.” Tumour Biol 35:9717-9723 (2014)

Luo C, Ren H, Wan JB, Yao X, Zhang X, He C, So KF, Kang JX, Pei Z, and Su H. “Enriched endogenous omega-3 fatty acids in mice protect against global ischemia injury.” J Lipid Res 55:1288-1297 (2014)

Wang J, Shi Y, Zhang L, Zhang F, Hu X, Zhang W, Leak RK, Gao Y, Chen L, and Chen J. “Omega-3 polyunsaturated fatty acids enhance cerebral angiogenesis and provide long-term protection after stroke.” Neurobiol Dis 68:91-103 (2014)

Liu Q, Wu D, Ni N, Ren H, Luo C, He C, Kang JX, Wan JB, and Su H. “Omega-3 polyunsaturated fatty acids protect neural progenitor cells against oxidative injury.” Mar Drugs 12:2341-2356 (2014)

Koren N, Simsa-Maziel S, Shahar R, Schwartz B, and Monsonego-Ornan E. “Exposure to omega-3 fatty acids at early age accelerate bone growth and improve bone quality.” J Nutr Biochem 25:623-633 (2014)

Qin S, Wen J, Bai XC, Chen TY, Zheng RC, Zhou GB, Ma J, Feng JY, Zhong BL, and Li YM. “Endogenous n-3 polyunsaturated fatty acids protect against imiquimod-induced psoriasis-like inflammation via the IL-17/IL-23 axis.” Mol Med Rep 9:2097-2104 (2014)

Huang MJ, Wang L, Jin DD, Zhang ZM, Chen TY, Jia CH, Wang Y, Zhen XC, Huang B, Yan B, Chen YH, Li SF, Yang JC, Dai YF, and Bai XC. “Enhancement of the synthesis of n-3 PUFAs in fat-1 transgenic mice inhibits mTORC1 signaling and delays surgically induced osteoarthritis in comparison with wild-type mice.” Ann Rheum Dis 73:1719-1727 (2014)

Taguchi A, Kawana K, Tomio K, Yamashita A, Isobe Y, Nagasaka K, Koga K, Inoue T, Nishida H, Kojima S, Adachi K, Matsumoto Y, Arimoto T, Wada-Hiraike O, Oda K, Kang JX, Arai H, Arita M, Osuga Y, and Fujii T. “Matrix metalloproteinase (MMP)-9 in cancer-associated fibroblasts (CAFs) is suppressed by omega-3 polyunsaturated fatty acids in vitro and in vivo.” PLoS One9:e89605 (2014)

Romanatto T, Fiamoncini J, Wang B, Curi R, and Kang JX. “Elevated tissue omega-3 fatty acid status prevents age-related glucose intolerance in fat-1 transgenic mice.” Biochim Biophys Acta 1842:186-191 (2014)

Chen Z, Zhang Y, Jia C, Wang Y, Lai P, Zhou X, Wang Y, Song Q, Lin J, Ren Z, Gao Q, Zhao Z, Zheng H, Wan Z, Gao T, Zhao A, Dai Y, and Bai X. “mTORC1/2 targeted by n-3 polyunsaturated fatty acids in the prevention of mammary tumorigenesis and tumor progression.” Oncogene 33:4548-4557 (2014)

Yamashita A, Kawana K, Tomio K, Taguchi A, Isobe Y, Iwamoto R, Masuda K, Furuya H, Nagamatsu T, Nagasaka K, Arimoto T, Oda K, Wada-Hiraike O, Yamashita T, Taketani Y, Kang JX, Kozuma S, Arai H, Arita M, Osuga Y, and Fujii T. “Increased tissue levels of omega-3 polyunsaturated fatty acids prevents pathological preterm birth.” Sci Rep 3:3113 (2013)

Zou Z, Bellenger S, Massey KA, Nicolaou A, Geissler A, Bidu C, Bonnotte B, Pierre AS, Minville-Walz M, Rialland M, Seubert J, Kang JX, Lagrost L, Narce M, and Bellenger J. “Inhibition of the HER2 pathway by n-3 polyunsaturated fatty acids prevents breast cancer in fat-1 transgenic mice.” J Lipid Res 54:3453-3463 (2013)

Tomio K, Kawana K, Taguchi A, Isobe Y, Iwamoto R, Yamashita A, Kojima S, Mori M, Nagamatsu T, Arimoto T, Oda K, Osuga Y, Taketani Y, Kang JX, Arai H, Arita M, Kozuma S, and Fujii T. “Omega-3 polyunsaturated fatty acids suppress the cystic lesion formation of peritoneal endometriosis in transgenic mouse models.” PLoS One 8:e73085 (2013)

Hu X, Zhang F, Leak RK, Zhang W, Iwai M, Stetler RA, Dai Y, Zhao A, Gao Y, and Chen J. “Transgenic overproduction of omega-3 polyunsaturated fatty acids provides neuroprotection and enhances endogenous neurogenesis after stroke.” Curr Mol Med 13:1465-1473 (2013)

Heerwagen MJ, Stewart MS, de la Houssaye BA, Janssen RC, and Friedman JE. “Transgenic increase in N-3/n-6 fatty acid ratio reduces maternal obesity-associated inflammation and limits adverse developmental programming in mice.” PLoS One 8:e67791 (2013)

Kang JX and Gleason ED. “Omega-3 fatty acids and hippocampal neurogenesis in depression.” CNS Neurol Disord Drug Targets. 12:460-465 (2013)

Lim SN, Gladman SJ, Dyall SC, Patel U, Virani N, Kang JX, Priestley JV, and Michael-Titus AT. “Transgenic mice with high endogenous omega-3 fatty acids are protected from spinal cord injury.” Neurobiol Dis 51:104-112 (2013)

MacLennan MB, Clarke SE, Perez K, Wood GA, Muller WJ, Kang JX, and Ma DW. “Mammary tumor development is directly inhibited by lifelong n-3 polyunsaturated fatty acids.” J Nutr Biochem 24:388-395 (2013)

Kim EH, Bae JS, Hahm KB, and Cha JY. “Endogenously synthesized n-3 polyunsaturated fatty acids in fat-1 mice ameliorate high-fat diet-induced non-alcoholic fatty liver disease.” Biochem Pharmacol 84:1359-1365 (2013)

An L, Pang YW, Gao HM, Tao L, Miao K, Wu ZH, and Tian JH. “Heterologous expression of C. elegans fat-1 decreases the n-6/n-3 fatty acid ratio and inhibits adipogenesis in 3T3-L1 cells.” Biochem Biophys Res Commun 428:405-10 (2012)

Gladman SJ, Huang W, Lim SN, Dyall SC, Boddy S, Kang JX, Knight MM, Priestley JV, and Michael-Titus AT. “Improved outcome after peripheral nerve injury in mice with increased levels of endogenous ω-3 polyunsaturated fatty acids.”  J Neurosci 32:563-571 (2012)

Monk JM, Jia Q, Callaway E, Weeks B, Alaniz RC, McMurray DN, and Chapkin RS. “Th17 cell accumulation is decreased during chronic experimental colitis by (n-3) PUFA in fat-1 mice.” J Nutr 142:117-124 (2012)

Song KS, Jing K, Kim JS, Yun EJ, Shin S, Seo KS, Park JH, Heo JY, Kang JX, Suh KS, Wu T, Park JI, Kweon GR, Yoon WH, Hwang BD, and Lim K. “Omega-3-polyunsaturated fatty acids suppress pancreatic cancer cell growth in vitro and in vivo via downregulation of Wnt/Beta-catenin signaling.” Pancreatology 11:574-584 (2011)

Lebbadi M, Julien C, Phivilay A, Tremblay C, Emond V, Kang JX, and Calon F. “Endogenous conversion of omega-6 into omega-3 fatty acids improves neuropathology in an animal model of Alzheimer’s disease.” J Alzheimers Dis 27:853-869 (2011)

Weylandt KH, Krause LF, Gomolka B, Chiu CY, Bilal S, Nadolny A, Waechter SF, Fischer A, Rothe M, and Kang JX. “Suppressed liver tumorigenesis in fat-1 mice with elevated omega-3 fatty acids is associated with increased omega-3 derived lipid mediators and reduced TNF-α.”  Carcinogenesis32:897-903 (2011)

Bellenger J, Bellenger S, Bataille A, Massey KA, Nicolaou A, Rialland M, Tessier C, Kang JX, and Narce M. “High pancreatic n-3 fatty acids prevent STZ-induced diabetes in fat-1 mice: inflammatory pathway inhibition.” Diabetes 60:1090-1099 (2011)

Bousquet M, Gue K, Emond V, Julien P, Kang JX, Cicchetti F, and Calon F. “Transgenic conversion of omega-6 into omega-3 fatty acids in a mouse model of Parkinson’s disease.” J Lipid Res 52:263-271 (2011)

Gravaghi C, La Perle KM, Ogrodwski P, Kang JX, Quimby F, Lipkin M, and Lamprecht SA. “Cox-2 expression, PGE(2) and cytokines production are inhibited by endogenously synthesized n-3 PUFAs in inflamed colon of fat-1 mice.” J Nutr Biochem 22:360-365 (2011)

Smith BK, Holloway GP, Reza-Lopez S, Jeram SM, Kang JX, and Ma DW. “A decreased n-6/n-3 ratio in the fat-1 mouse is associated with improved glucose tolerance.” Appl Physiol Nutr Metab 35:699-706 (2010)

White PJ, Arita M, Taguchi R, Kang JX, and Marette A. “Transgenic restoration of long-chain n-3 fatty acids in insulin target tissues improves resolution capacity and alleviates obesity-linked inflammation and insulin resistance in high-fat-fed mice.” Diabetes 59:3066-3073 (2010)

Wan JB, Huang LL, Rong R, Tan R, Wang J, and Kang JX. “Endogenously decreasing tissue n-6/n-3 fatty acid ratio reduces atherosclerotic lesions in apolipoprotein E-deficient mice by inhibiting systemic and vascular inflammation.” Arterioscler Thromb Vasc Biol 30:2487-2494 (2010).

Griffitts J, Saunders D, Tesiram YA, Reid GE, Salih A, Liu S, Lydic TA, Busik JV, Kang JX, and Towner RA. “Non-mammalian fat-1 gene prevents neoplasia when introduced to a mouse hepatocarcinogenesis model: Omega-3 fatty acids prevent liver neoplasia.” Biochim Biophys Acta 1801:1133-1144 (2010)

Banu J, Bhattacharya A, Rahman M, Kang JX, and Fernandes G. “Endogenously produced n-3 fatty acids protect against ovariectomy induced bone loss in fat-1 transgenic mice.” J Bone Miner Metab 28:617-626 (2010)

Orr SK, Tong JY, Kang JX, Ma DW, and Bazinet RP. “The fat-1 mouse has brain docosahexaenoic acid levels achievable through fish oil feeding.” Neurochem Res 35:811-819 (2010)

Boudrault C, Bazinet RP, Kang JX, and Ma DW. “Cyclooxygenase-2 and n-6 PUFA are lower and DHA is higher in the cortex of fat-1 mice.” Neurochem Int 56:585-589 (2010)

Wei D, Li J, Shen M, Jia W, Chen N, Chen T, Su D, Tian H, Zheng S, Dai Y, and Zhao A. “Cellular production of n-3 PUFAs and reduction of n-6-to-n-3 ratios in the pancreatic beta-cells and islets enhance insulin secretion and confer protection against cytokine-induced cell death.” Diabetes 59:471-478 (2010)

Rahman M, Halade GV, Bhattacharya A, and Fernandes G. “The fat-1 transgene in mice increases antioxidant potential, reduces pro-inflammatory cytokine levels, and enhances PPAR-gamma and SIRT-1 expression on a calorie restricted diet.” Oxid Med Cell Longev 2:307-316 (2009)

Rahman MM, Bhattacharya A, Banu J, Kang JX, and Fernandes G. “Endogenous n-3 fatty acids protect ovariectomy induced bone loss by attenuating osteoclastogenesis.” J Cell Mol Med 13:1833-1844 (2009)

He C, Qu X, Cui L, Wang J, and Kang JX. “Improved spatial learning performance of fat-1 mice is associated with enhanced neurogenesis and neuritogenesis by docosahexaenoic acid.” Proc Natl Acad Sci USA 106:11370-11375 (2009)

Ji S, Hardy RW, and Wood PA. “Transgenic expression of n-3 fatty acid desaturase (fat-1) in C57/BL6 mice: Effects on glucose homeostasis and body weight.” J Cell Biochem 107:809-817 (2009)

Mayer K, Kiessling A, Ott J, Schaefer MB, Hecker M, Henneke I, Schulz R, Günther A, Wang J, Wu L, Roth J, Seeger W, and Kang JX. “Acute lung injury is reduced in fat-1 mice endogenously synthesizing n-3 fatty acids.” Am J Respir Crit Care Med179:474-483 (2009)

Lau BY, Ward WE, Kang JX, and Ma DW. “Femur EPA and DHA are correlated with femur biomechanical strength in young fat-1 mice.” J Nutr Biochem 20:453-461 (2009)

Jia Q, Lupton JR, Smith R, Weeks BR, Callaway E, Davidson LA, Kim W, Fan YY, Yang P, Newman RA, Kang JX, McMurray DN, and Chapkin RS. “Reduced colitis-associated colon cancer in Fat-1 (n-3 fatty acid desaturase) transgenic mice.” Cancer Res 68:3985-3991 (2008)

Weylandt KH, Nadolny A, Kahlke L, Köhnke T, Schmöcker C, Wang J, Lauwers GY, Glickman JN, and Kang JX. “Reduction of inflammation and chronic tissue damage by omega-3 fatty acids in fat-1 transgenic mice with pancreatitis.” Biochim Biophys Acta 1782:634-641 (2008)

Taha AY, Huot PS, Reza-López S, Prayitno NR, Kang JX, Burnham WM, and Ma DW. “Seizure resistance in fat-1 transgenic mice endogenously synthesizing high levels of omega-3 polyunsaturated fatty acids.” J Neurochem 105:380-388 (2008)

Nowak J, Weylandt KH, Habbel P, Wang J, Dignass A, Glickman JN, and Kang JX. “Colitis-associated colon tumorigenesis is suppressed in transgenic mice rich in endogenous n-3 fatty acids.” Carcinogenesis 28:1991-1995 (2007)

Connor KM1, SanGiovanni JP, Lofqvist C, Aderman CM, Chen J, Higuchi A, Hong S, Pravda EA, Majchrzak S, Carper D, Hellstrom A, Kang JX, Chew EY, Salem N Jr, Serhan CN, and Smith LE. “Increased dietary intake of omega-3-polyunsaturated fatty acids reduces pathological retinal angiogenesis.” Nat Med 13:868-873 (2007)

Kang JX. “Fat-1 transgenic mice: a new model for omega-3 research.” Prostaglandins Leukot Essent Fatty Acids 77:263-267 (2007)

Xia S, Lu Y, Wang J, He C, Hong S, Serhan CN, and Kang JX. “Melanoma growth is reduced in fat-1 transgenic mice: impact of omega-6/omega-3 essential fatty acids.” Proc Natl Acad Sci U S A 103:12499-12504 (2006)

Hudert CA, Weylandt KH, Lu Y, Wang J, Hong S, Dignass A, Serhan CN, and Kang JX. “Transgenic mice rich in endogenous omega-3 fatty acids are protected from colitis.” Proc Natl Acad Sci U S A 103:11276-11281 (2006)

Kang JX, Wang J, Wu L, and Kang ZB. “Transgenic mice: fat-1 mice convert n-6 to n-3 fatty acids.” Nature 427:504 (2004)

 Epidemiological or Observational Studies

These studies have demonstrated differences in the AA/EPA ratios in different populations or chronic disease conditions.

LaChance L, McKenzie K, Taylor VH, and Vigod SN. “Omega-6 to Omega-3 Fatty Acid Ratio in Patients with ADHD: A Meta-Analysis.” J Can Acad Child Adolesc Psychiatry25:87-96 (2016)

Nakanishi S, Nagano C, Miyahara M, and Sawano F. “Sex differences in the association between the eicosapentaenoic acid/arachidonic acid ratio and the visceral fat area among patients with type 2 diabetes.” Intern Med 55:1269-74 (2016)

Nagahara Y, Motoyama S, Sarai M, Ito H, Kawai H, Takakuwa Y, Miyagi M, Shibata D, Takahashi H, Naruse H, Ishii J, and Ozaki Y. “Eicosapentaenoic acid to arachidonic acid (EPA/AA) ratio as an associated factor of high risk plaque on coronary computed tomography in patients without coronary artery disease.” Atherosclerosis 250:30-37 (2016)

Watanabe S, Yoshihisa A, Kanno Y, Takiguchi M, Yokokawa T, Sato A, Miura S, Shimizu T, Abe S, Sato T, Suzuki S, Oikawa M, Sakamoto N, Yamaki T, Sugimoto K, Kunii H, Nakazato K, Suzuki H, Saitoh SI, and Takeishi Y. “Associations with eicosapentaenoic acid to arachidonic acid ratio and mortality in hospitalized heart failure fatients.” J Card Failure 16:30062-30068 (2016)

Todoroki K, Ikeya Y, Fukui S, Tanaka C, Sekine K, Shizuma T, Fukuyama N, and Mori H. “Nutrition-dependent eicosapentaenoic acid deficiency in care house residents.” Nutrition 32:806-810 (2016)

Umemoto N, Ishii H, Kamoi D, Aoyama T, Sakakibara T, Takahashi H, Tanaka A, Yasuda Y, Suzuki S, Matsubara T, and Murohara T. “Reverse association of omega-3/omega-6 polyunsaturated fatty acids ratios with carotid atherosclerosis in patients on hemodialysis.” Atherosclerosis 249:65-69 (2016)

Okada K, Kotani K, and Ishibashi S. “Ankle-brachial index and eicosapentaenoic acid/arachidonic acid ratio in smokers with type 2 diabetes mellitus.” Tob Induc Dis 14:2 (2016)

Nagai K, Koshiba H, Shibata S, Matsui T, Kozaki K. “Correlation between the serum eicosapentanoic acid-to-arachidonic acid ratio and the severity of cerebral white matter hyperintensities in older adults with memory disorder.” Geriatr Gerontol Int 1:48-52 (2015)

Hikita H, Shigeta T, Kimura S, Takahashi A, Isobe M. “Coronary artery disease severity and cardiovascular biomarkers in patients with peripheral artery disease.” Int J Angiol 24:278-282 (2015)

Lotrich FE, Sears B, and McNamara RK. “Polyunsaturated fatty acids moderate the effect of poor sleep on depression risk.” Prostaglandins Leukot Essent Fatty Acids 106:19-25 (2016)

Suwa M, Yamaguchi S, Komori T, Kajimoto S, and Kino M. “The association between cerebral white matter lesions and plasma omega-3 to omega-6 polyunsaturated fatty acids ratio to cognitive impairment development.” Biomed Res Int 2015:153437 (2015)

Nodera M, Suzuki H, Yamada S, Kamioka M, Kaneshiro T, Kamiyama Y, and Takeishi Y. “Association of serum n-3/n-6 polyunsaturated fatty acid ratio with T-Wave alternans in patients with ischemic heart disease.” Int Heart J 56:613-617 (2015)

Sakamoto A, Saotome M, Hosoya N, Kageyama S, Yoshizaki T, Takeuchi R, Murata K, Nawada R, Onodera T, Takizawa A, Satoh H, and Hayashi H. “Aberrant serum polyunsaturated fatty acids profile is relevant with acute coronary syndrome.” Heart Vessels (2015)

Tani S, Takahashi A, Nagao K, and Hirayama A. “Association of fish consumption-derived ratio ofs n-3 to n-6 polyunsaturated fatty acids and cardiovascular risk with the prevalence of coronary artery disease.” Int Heart J 56:260-268 (2015)

Wakabayashi Y, Funayama H, Ugata Y, Taniguchi Y, Hoshino H, Ako J, and Momomura S. “Low eicosapentaenoic acid to arachidonic acid ratio is associated with thin-cap fibroatheroma determined by optical coherence tomography.” J Cardiol 66:482-488 (2015)

Pareja-Galeano H, Sanchis-Gomar F, Santos-Lozano A, Garatachea N, Fiuza-Luces C, Lucia A, Emanuele E. “Serum eicosapentaenoic acid to arachidonic acid ratio is associated with cardio-healthy exceptional longevity.” Int J Cardiol 184:655-656 (2015)

Fukami A, Adachi H, Hirai Y, Enomoto M, Otsuka M, Kumagai E, Nakamura S, Yoshimura A, Obuchi A, Nohara Y, Nakao E, Hori K, and Fukumoto Y. “Association of serum eicosapentaenoic acid to arachidonic acid ratio with microalbuminuria in a population of community-dwelling Japanese.” Atherosclerosis 239:577-582 (2015)

Hishikari K, Kimura S, Yamakami Y, Kojima K, Sagawa Y, Otani H, Sugiyama T, Kuwahara T, Hikita H, Takahashi A, and Isobe M. “The prognostic value of the serum eicosapentaenoic acid to arachidonic acid ratio in relation to clinical outcomes after endovascular therapy in patients with peripheral artery disease caused by femoropopliteal artery lesions.” Atherosclerosis 239:583-588 (2015)

Ikeya Y, Fukuyama N, and Mori H. “Low plasma eicosapentaenoic acid concentration as a possible risk factor for intracerebral hemorrhage.” Nutr Res. 35:214-220 (2015)

Ishitobi T, Hyogo H, Kan H, Hiramatsu A, Arihiro K, Aikata H, and Chayama K. “Eicosapentaenoic acid/arachidonic acid ratio as a possible link between non-alcoholic fatty liver disease and cardiovascular disease.” Hepatol Res 45:533-539 (2015)

Yagi S, Hara T, Ueno R, Aihara K, Fukuda D, Takashima A, Hotchi J, Ise T, Yamaguchi K, Tobiume T, Iwase T, Yamada H, Soeki T, Wakatsuki T, Shimabukuro M, Akaike M, and Sata M. “Serum concentration of eicosapentaenoic acid is associated with cognitive function in patients with coronary artery disease.” Nutr J 13:112 (2014)

Okada K, Kotani K, Yagyu H, and Ishibashi S. “Eicosapentaenoic acid/arachidonic acid ratio and smoking status in elderly patients with type 2 diabetes mellitus.” Diabetol Metab Syndr 6:85 (2014)

Ito H, Ohira H, Chinen T, Omoto T, Shinozaki M, Nishio S, Abe M, Antoku S, Mifune M, and Toagane M. “The ratio of serum eicosapentaenoic acid to arachidonic acid is associated with renal impairment and diabetic macroangiopathies in elderly patients with type 2 diabetes.” Diabetes Care 37:e7-8 (2014)

Nishizaki Y, Shimada K, Tani S, Ogawa T, Ando J, Takahashi M, Yamamoto M, Shinozaki T, Miyauchi K, Nagao K, Hirayama A, Yoshimura M, Komuro I, Nagai R, and Daida H. “Significance of imbalance in the ratio of serum n-3 to n-6 polyunsaturated fatty acids in patients with acute coronary syndrome.” Am J Cardiol 113:441-445 (2014)

Ito R, Satoh-Asahara N, Yamakage H, Sasaki Y, Odori S, Kono S, Wada H, Suganami T, Ogawa Y, Hasegawa K, and Shimatsu A. “An increase in the EPA/AA ratio is associated with improved arterial stiffness in obese patients with dyslipidemia.” J Atheroscler Thromb 21:248-60 (2014)

Hasegawa T, Otsuka K, Iguchi T, Matsumoto K, Ehara S, Nakata S, Nishimura S, Kataoka T, Shimada K, and Yoshiyama M. “Serum n-3 to n-6 polyunsaturated fatty acids ratio correlates with coronary plaque vulnerability: an optical coherence tomography study.“ Heart Vessels 29:596-602 (2014)

Serikawa T, Miura S, Okabe M, Hongo H, Tokutome M, Yoshikawa T, Takesue K, Adachi S, Osaka K, Matsukawa R, Yanagi D, Nozoe M, Kozai T, Hironaga K, Saku K, and Yamamoto Y. “Ratio of eicosapentaenoic acid to arachidonic acid is a critical risk factor for acute coronary syndrome in middle-aged older patients as well as younger adult patients.” J Cardiol 63:35-40 (2014)

Fukuda S, Fujioka S, Hosaka S, Akita S, Kimura S, Kurotani K, and Mizoue T. “Relationship between arteriosclerosis obliterans and the ratio of serum eicosapentaenoic acid to arachidonic acid.” Ann Thorac Cardiovasc Surg 20:44-47 (2014)

Ninomiya T, Nagata M, Hata J, Hirakawa Y, Ozawa M, Yoshida D, Ohara T, Kishimoto H, Mukai N, Fukuhara M, Kitazono T, and Kiyohara Y. “Association between ratio of serum eicosapentaenoic acid to arachidonic acid and risk of cardiovascular disease: the Hisayama Study.” Atherosclerosis 231:261-7 (2013)

Oshima Y, Niki K, Hiramoto Y, Morimoto S, Takami H, and Izumi M. “Serum eicosapentaenoic acid/arachidonic acid ratio is low in patients with pulmonary thromboembolism.” J Nutr Sci Vitaminol 59:474-477 (2013)

Suda S, Katsumata T, Okubo S, Kanamaru T, Suzuki K, Watanabe Y, Katsura K, Katayama Y. “Low serum n-3 polyunsaturated fatty acid/n-6 polyunsaturated fatty acid ratio predicts neurological deterioration in Japanese patients with acute ischemic stroke.” Cerebrovasc Dis 36:388-393 (2013)

Lotrich FE, Sears B, and McNamara RK. “Anger induced by interferon-alpha is moderated by ratio of arachidonic acid to omega-3 fatty acids.” J Psychosom Res 75:475-483 (2013)

Inoue K, Kishida K, Hirata A, Funahashi T, and Shimomura I. “Low serum eicosapentaenoic acid / arachidonic acid ratio in male subjects with visceral obesity.” Nutr Metab 10:25 (2013)

Fujihara M, Fukata M, Odashiro K, Maruyama T, Akashi K, and Yokoi Y. “Reduced plasma eicosapentaenoic acid-arachidonic acid ratio in peripheral artery disease.” Angiology 64:112-118 (2013)

Ikeya Y, Fukuyama N, Kitajima W, Ogushi Y, and Mori H. “Comparison of eicosapentaenoic acid concentrations in plasma between patients with ischemic stroke and control subjects.” Nutrition 29:127-131 (2013)

Lotrich FE, Sears B, and McNamara RK. “Elevated ratio of arachidonic acid to long-chain omega-3 fatty acids predicts depression development following interferon-alpha treatment: relationship with interleukin-6.” Brain Behav Immun 31:48-53 (2013)

Mishina M, Kim K, Kominami S, Mizunari T, Kobayashi S, and Katayama Y. “Impact of polyunsaturated fatty acid consumption prior to ischemic stroke.” Acta Neurol Scand 127:181-185 (2013)

Harris WS, Pottala JV, Varvel SA, Borowski JJ, Ward JN, and McConnell JP. “Erythrocyte omega-3 fatty acids increase and linoleic acid decreases with age: observations from 160,000 patients.” Prostaglandins Leukot Essent Fatty Acids 88:257-263 (2013)

Sekikawa A, Steingrimsdottir L, Ueshima H, Shin C, Curb JD, Evans RW, Hauksdottir AM, Kadota A, Choo J, Masaki K, Thorsson B, Launer LJ, Garcia ME, Maegawa H, Willcox BJ, Eiriksdottir G, Fujiyoshi A, Miura K, Harris TB, Kuller LH, and Gudnason V. “Serum levels of marine-derived n-3 fatty acids in Icelanders, Japanese, Koreans, and Americans–a descriptive epidemiologic study.” Prostaglandins Leukot Essent Fatty Acids 87:11-16 (2012)

Hayakawa S, Yoshikawa D, Ishii H, Tanaka M, Kumagai S, Matsumoto M, Hayashi M, Sugiura T, Hayashi K, Ando H, Amano T, and Murohara T. “Association of plasma ω-3 to ω-6 polyunsaturated fatty acid ratio with complexity of coronary artery lesion.” Intern Med 51:1009-1014 (2012)

Khanaki K, Nouri M, Ardekani AM, Ghassemzadeh A, Shahnazi V, Sadeghi MR, Darabi M, Mehdizadeh A, Dolatkhah H, Saremi A, Imani AR, and Rahimipour A. “Evaluation of the relationship between endometriosis and omega-3 and omega-6 polyunsaturated fatty acids.” Iran Biomed J 16:38-43 (2012)

Domei T, Yokoi H, Kuramitsu S, Soga Y, Arita T, Ando K, Shirai S, Kondo K, Sakai K, Goya M, Iwabuchi M, Ueeda M, and Nobuyoshi M. “Ratio of serum n-3 to n-6 polyunsaturated fatty acids and the incidence of major adverse cardiac events in patients undergoing percutaneous coronary intervention.” Circ J 76:423-439 (2012)

Caspar-Bauguil S, Fioroni A, Galinier A, Allenbach S, Pujol MC, Salvayre R, Cartier A, Lemieux I, Richard D, Biron S, Marceau P, Casteilla L, Penicaud L, and Mauriege P. “Pro-inflammatory phospholipid arachidonic acid/eicosapentaenoic acid ratio of dysmetabolic severely obese women.” Obes Surg 22:935-944 (2012)

Ueeda M, Doumei T, Takaya Y, Ohnishi N, Takaishi A, Hirohata S, Miyoshi T, Shinohata R, Usui S, and Kusachi S. “Association of serum levels of arachidonic acid and eicosapentaenoic acid with prevalence of major adverse cardiac events after acute myocardial infarction.” Heart Vessels 26:145-152 (2011)

Kawabata T, Hirota S, Hirayama T, Adachi N, Kaneko Y, Iwama N, Kamachi K, Araki E, Kawashima H, and Kiso Y. “Associations between dietary n-6 and n-3 fatty acids and arachidonic acid compositions in plasma and erythrocytes in young and elderly Japanese volunteers.” Lipids Health Dis 10:138 (2011)

Kawabata T, Hirota S, Hirayama T, Adachi N, Hagiwara C, Iwama N, Kamachi K, Araki E, Kawashima H, and Kiso Y. “Age-related changes of dietary intake and blood eicosapentaenoic acid, docosahexaenoic acid, and arachidonic acid levels in Japanese men and women.” Prostaglandins Leukot Essent Fatty Acids 84:131-137 (2011)

Kashiyama T, Ueda Y, Nemoto T, Wada M, Masumura Y, Matsuo K, Nishio M, Hirata A, Asai M, Kashiwase K, and Kodama K. “Relationship between coronary plaque vulnerability and serum n-3/n-6 polyunsaturated fatty acid ratio.” Circ J 75:2432-2438 (2011)

Itakura H, Yokoyama M, Matsuzaki M, Saito Y, Origasa H, Ishikawa Y, Oikawa S, Sasaki J, Hishida H, Kita T, Kitabatake A, Nakaya N, Sakata T, Shimada K, Shirato K, and Matsuzawa Y. “Relationships between plasma fatty acid composition and coronary artery disease.” J Atheroscler Thromb 18:99-107 (2011)

Yanagisawa N, Shimada K, Miyazaki T, Kume A, Kitamura Y, Ichikawa R, Ohmura H, Kiyanagi T, Hiki M, Fukao K, Sumiyoshi K, Hirose K, Matsumori R; Takizawa H, Fujii K, Mokuno H, Inoue N, and Daida H. “Polyunsaturated fatty acid levels of serum and red blood cells in apparently healthy Japanese subjects living in an urban area.” J Atheroscler Thromb 17:285-294 (2010)

Schins A, Crijns HJ, Brummer RJ, Wichers M, Lousberg R, Celis S, and Honig A. “Altered omega-3 polyunsaturated fatty acid status in depressed post-myocardial infarction patients.” Acta Psychiatr Scand 115:35-40 (2007)

Conklin SM, Manuck SB, Yao JK, Flory JD, Hibbeln JR, Muldoon MF. “High omega-6 and low omega-3 fatty acids are associated with depressive symptoms and neuroticism.” Psychosom Med 69:932-934 (2007)

Nakamura T, Azuma A, Kuribayashi T, Sugihara H, Okuda S, and Nakagawa M. “Serum fatty acid levels, dietary style and coronary heart in three neighbouring areas in Japan.” Brit J Nutr 89:267-272 (2003)

Hirai K, Horiuchi R, Ohno Y, Higuchi H, and Asano Y. “Lower eicosapentaenoic acid and higher arachidonic acid levels in sera of young adults in the Netherlands than in Japan.” Environ Health Prev Med 5:60-65 (2000)

Yamada T, Strong JP, Ishii T, Ueno T, Koyama M, Wagayama H, Shimizu A, Sakai T, Malcom GT, and Guzman MA. “Atherosclerosis and omega-3 fatty acids in the populations of fishing village and a farming village in Japan.” Athero 153: 469-481 (2000)

Maes M, Smith R, Christophe A, Cosyns P, Desnyder R, and Meltzer H. “Fatty acid composition in major depression: decreased omega 3 fractions in cholesteryl esters and increased C20: 4 omega 6/C20:5 omega 3 ratio in cholesteryl esters and phospholipids.” J Affect Disord 38:35-46 (1996)

Adams PB. Lawson S, Sanigorski A, and Sinclair AJ. “Arachidonic acid to eicosapentaenoic acid ratio in blood correlates positively with clinical symptoms of depression.” Lipids 31:S157-61 (1996)

Iso H, Sato S, Falsm AR, Shimamoto T, terao A, Munger RG, Kitamure A, Konishi M, Iida M, and Komachi Y. “Serum fatty acids and fish intake in rural Japanese, urban Japanese, Japanese American and Caucasian American men.” Int J Epidemiol 18:374-381 (1989)

Kondo T, Ogawa K, Satake T, Kitazawa M, Taki K, Sugiyama S, and Ozawa T. “Plasma-free eicosapentaenoic acid/arachidonic acid ratio: a possible new coronary risk factor.” Clin Cardiol 9:413-416 (1986)

Kagawa Y, Nishizawa M, Suzuki M, Miyatake T, Hamamoto T, Goto K, Motonaga E, Izumikawa H, Hirata H, and Ebihara A. “Eicosapolyenoic acid of serum lipids of Japanese islanders with low incidence of cardiovascular diseases.” J Nutr Sci Vitaminol 28:441-453 (1982)