High dietary n6/n3 ratio decreases eicosapentaenoic to arachidonic acid ratios and upregulates NFκB/p50 expression in short-term low-dose streptozotocin and high-fructose rat model of diabetes


      • Diets with basal (6) and high n6/n3 ratio decrease 20:5n3 and 22:66n3 content in the plasma of diabetic rats.
      • Diets with basal (6) and high n6/n3 ratio decrease 20:5n3/20:4n6 ratio in plasma and liver neutral lipids of diabetic rats.
      • Diet with high n6/n3 ratio increases 4-HNE and NFκB/p50 expression in the liver tissue of diabetic rats.
      • Diet with low n6/n3 (1) ratio and supplemented with DHA and EPA can attenuate changes caused by the diets with basal (6) and high n6/n3 ratio in diabetic rats.


      We studied the influence of dietary n6/n3 ratio and docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids supplementation on fatty acid profile, lipid peroxidation and NFκ/p50 expression in diabetes type 2. Treatments consisted of three dietary n6/n3 ratios: 6 (Control), 50 (high n6) and 1 (DHA and EPA supplemented). Half of the rats in each of the dietary treatments were made diabetic using the fructose/low-streptozotocin model. The Control and high n6 diets decreased EPA/ARA (arachidonic acid) ratios in the plasma and in the hepatic tissue suggesting proinflammatory fatty acid profile. The high n6 diet additionally increased the 4-HNE and NFκ/p50 expression in the hepatic tissue. These changes were the consequence of a decrease in the plasma content of DHA and EPA and an increase in the content of arachidonic acid in the liver neutral lipids. The supplementation with the DHA and EPA attenuated the change in EPA/ARA ratios, which imply the importance of the n6/n3 ratio in diabetes type 2.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Prostaglandins, Leukotrienes and Essential Fatty Acids
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Brenner R.R.
        Hormonal modulation of Δ6 and Δ5 desaturases: case of diabetes, prostaglandins.
        Leukotrienes Essent. Fat Acid. 2003; 68: 151-162
        • Starcevic K.
        • Filipovic N.
        • Galan A.
        • Micek V.
        • Gudan Kurilj A.
        • Masek T.
        Hepatic lipogenesis and brain fatty acid profile in response to different dietary n6/n3 ratios and DHA/EPA supplementation in streptozotocin treated rats.
        Mol. Nutr. Food Res. 2018; 62e1701007
        • Ghebremeskel K.
        • Bitsanis D.
        • Koukkou E.
        • Lowy C.
        • Poston L.
        • Crawford M.A.
        Liver triacylglycerols and free fatty acids in streptozotocin-induced diabetic rats have atypical n-6 and n-3 pattern.
        Comparat. Biochem. Physiol. Part C Toxicol. Pharmacol. 2002; 132: 349-354
        • Comte C.
        • Bellenger S.
        • Bellenger J.
        • Tessier C.
        • Poisson J.P.
        • Narce M.
        Effects of streptozotocin and dietary fructose on delta-6 desaturation in spontaneously hypertensive rat liver.
        Biochimie. 2004; 86: 799-806
        • Malaisse W.J.
        • Zhang Y.
        • Louchami K.
        • Sener A.
        • Portois L.
        • Carpentier Y.A.
        Brain phospholipid and triglyceride fatty acid content and pattern in type 1 and type 2 diabetic rats.
        Neurosci. Lett. 2006; 409: 75-79
        • Montanaro M.A.
        • Bernasconi A.M.
        • González M.S.
        • Rimoldi O.J.
        • Brenner R.R.
        Effects of fenofibrate and insulin on the biosynthesis of unsaturated fatty acids in streptozotocin diabetic rats, prostaglandins.
        Leukotrienes Essent. Fat Acid. 2005; 73: 369-378
        • Mašek T.
        • Filipović N.
        • Hamzić L.F.
        • Puljak L.
        • Starčević K.
        Long-term streptozotocin diabetes impairs arachidonic and docosahexaenoic acid metabolism and ∆5 desaturation indices in aged rats.
        Exp. Gerontol. 2014; 60: 140-146
        • El Hafidi M.
        • Cuéllar A.
        • Ramı́rez J.
        • Baños G.
        Effect of sucrose addition to drinking water, that induces hypertension in the rats, on liver microsomal Δ9 and Δ5-desaturase activities.
        J. Nutr. Biochem. 2001; 12: 396-403
        • Mašek T.
        • Filipović N.
        • Vuica A.
        • Starčević K.
        Effects of treatment with sucrose in drinking water on liver histology, lipogenesis and lipogenic gene expression in rats fed high-fiber diet, prostaglandins.
        Leukotrienes Essent. Fat Acid. 2017; 116: 1-8
        • Levant B.
        • Ozias M.K.
        • Guilford B.L.
        • Wright D.E.
        Streptozotocin-induced diabetes partially attenuates the effects of a high-fat diet on liver and brain fatty acid composition in mice.
        Lipids. 2013; 48: 939-948
        • da Silva-Santi L.G.
        • Antunes M.M.
        • Caparroz-Assef S.M.
        • Carbonera F.
        • Masi L.N.
        • Curi R.
        • Visentainer J.V.
        • Bazotte R.B.
        Liver fatty acid composition and inflammation in mice fed with high-carbohydrate diet or high-fat diet.
        Nutrients. 2016; 8: 682
        • Yao M.
        • Hou L.
        • Xie T.
        • Liu Y.
        • Dai D.
        • Shi Y.
        • Lian K.
        • Jiang L.
        The biosynthesis of DHA is increased in the liver of diabetic rats induced by high-fat diets and STZ, in correlation with increased activity of peroxisomal β-oxidation.
        Eur. J. Lipid Sci Technol. 2015; 118: 137-146
        • Donath M.Y.
        • Shoelson S.E.
        Type 2 diabetes as an inflammatory disease.
        Nat. Rev. Immunol. 2011; 11: 98
        • Wilson R.D.
        • Islam M.S.
        Fructose-fed streptozotocin-injected rat: an alternative model for type 2 diabetes.
        Pharmacol. Rep. 2012; 64: 129-139
        • Hawkins R.C.
        Evaluation of roche accu-chek go and medisense optium blood glucose meters.
        Clin. Chim. Acta. 2005; 353: 127-131
        • Livak K.J.
        • Schmittgen T.D.
        Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method.
        Methods. 2001; 25: 402-408
        • Folch J.
        • Lees M.
        • Stanley G.H.S.
        A simple method for the isolation and purification of total lipids from animal tissues.
        J. Biol. Chem. 1957; 226: 497-509
        • Quideau S.A.
        • McIntosh A.C.S.
        • Norris C.E.
        • Lloret E.
        • Swallow M.J.B.
        • Hannam K.
        Extraction and analysis of microbial phospholipid fatty acids in Soils.
        J. Vis. Exp. 2016; : 54360
        • Malik V.S.
        • Hu F.B.
        Fructose and cardiometabolic Health: what the evidence from sugar-sweetened beverages tells us.
        J. Am. Coll. Cardiol. 2015; 66: 1615-1624
        • Ludwig D.S.
        • Peterson K.E.
        • Gortmaker S.L.
        Relation between consumption of sugar-sweetened drinks and childhood obesity: a prospective, observational analysis.
        Lancet. 2001; 357: 505-508
        • Bray G.A.
        • Nielsen S.J.
        • Popkin B.M.
        Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity.
        Am. J. Clin. Nutr. 2004; 79: 537-543
        • Okoduwa S.I.R.
        • Umar I.A.
        • James D.B.
        • Inuwa H.M.
        Appropriate insulin level in selecting fortified diet-fed, streptozotocin-treated rat model of type 2 diabetes for anti-diabetic studies.
        PLoS ONE. 2017; 12e0170971
        • Calder P.C.
        Omega-3 fatty acids and inflammatory processes.
        Nutrients. 2010; 2: 355-374
        • Dennis E.A.
        • Norris P.C.
        Eicosanoid storm in infection and inflammation.
        Nat. Rev. Immunol. 2015; 15: 511-523
        • Ito R.
        • Satoh-Asahara N.
        • Yamakage H.
        • Sasaki Y.
        • Odori S.
        • Kono S.
        • Wada H.
        • Suganami T.
        • Ogawa Y.
        • Hasegawa K.
        • Shimatsu A.
        An increase in the EPA/AA ratio is associated with improved arterial stiffness in obese patients with dyslipidemia.
        J. Atheroscler. Thromb. 2014; 21: 248-260
        • Nagahara Y.
        • Motoyama S.
        • Sarai M.
        • Ito H.
        • Kawai H.
        • Takakuwa Y.
        • Miyagi M.
        • Shibata D.
        • Takahashi H.
        • Naruse H.
        • Ishii J.
        • 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. 2016; 250: 30-37
        • Nielsen F.
        • Mikkelsen B.B.
        • Nielsen J.B.
        • Andersen H.R.
        • Grandjean P.
        Plasma malondialdehyde as biomarker for oxidative stress: reference interval and effects of life-style factors.
        Clin. Chem. 1997; 43: 1209-1214
        • Inoguchi T.
        • Li P.
        • Umeda F.
        • Yu H.Y.
        • Kakimoto M.
        • Imamura M.
        • Aoki T.
        • Etoh T.
        • Hashimoto T.
        • Naruse M.
        • Sano H.
        • Utsumi H.
        • Nawata H.
        High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C–dependent activation of NAD(P)H oxidase in cultured vascular cells.
        Diabetes. 2000; 49: 1939-1945
        • Reis J.S.
        • Veloso C.A.
        • Volpe C.M.
        • Fernandes J.S.
        • Borges E.A.
        • Isoni C.A.
        • Dos Anjos P.M.
        • Nogueira-Machado J.A.
        Soluble RAGE and malondialdehyde in type 1 diabetes patients without chronic complications during the course of the disease.
        Diabetes Vasc. Dis. Res. 2012; 9: 309-314
        • Matsuda M.
        • Tamura R.
        • Kanno K.
        • Segawa T.
        • Kinoshita H.
        • Nishimoto O.
        • Nishiyama H.
        • Kawamoto T.
        Impact of dyslipidemic components of metabolic syndrome, adiponectin levels, and anti-diabetes medications on malondialdehyde-modified low-density lipoprotein levels in statin-treated diabetes patients with coronary artery disease.
        Diabetol. Metab. Syndr. 2013; 5: 77
        • Csala M.
        • Kardon T.
        • Legeza B.
        • Lizák B.
        • Mandl J.
        • Margittai É.
        • Puskás F.
        • Száraz P.
        • Szelényi P.
        • Bánhegyi G.
        On the role of 4-hydroxynonenal in health and disease.
        Biochimica et Biophysica Acta (BBA) - Mol. Basis Dis. 1852; 1852: 826-838
        • Zhong H.
        • Yin H.
        Role of lipid peroxidation derived 4-hydroxynonenal (4-HNE) in cancer: focusing on mitochondria.
        Redox Biol. 2015; 4: 193-199
        • Dalleau S.
        • Baradat M.
        • Guéraud F.
        • Huc L.
        Cell death and diseases related to oxidative stress:4-hydroxynonenal (HNE) in the balance.
        Cell Death Differ. 2013; 20: 1615
        • Mattson M.P.
        Roles of the lipid peroxidation product 4-hydroxynonenal in obesity, the metabolic syndrome, and associated vascular and neurodegenerative disorders.
        Exp. Gerontol. 2009; 44: 625-633
        • Pillon N.J.
        • Croze M.L.
        • Vella R.E.
        • Soulère L.
        • Lagarde M.
        • Soulage C.O.
        The lipid peroxidation by-product 4-Hydroxy-2-Nonenal (4-HNE) induces insulin resistance in skeletal muscle through both carbonyl and oxidative stress.
        Endocrinology. 2012; 153: 2099-2111
        • Castro J.P.
        • Jung T.
        • Grune T.
        • Siems W.
        4-Hydroxynonenal (HNE) modified proteins in metabolic diseases.
        Free Radic. Biol. Med. 2017; 111: 309-315
        • Silverstein R.L.
        • Febbraio M.
        CD36, a scavenger receptor involved in immunity, metabolism, angiogenesis, and behavior.
        Sci. Signal. 2009; 2 (re3): re3
        • Ohgami N.
        • Nagai R.
        • Ikemoto M.
        • Arai H.
        • Miyazaki A.
        • Hakamata H.
        • Horiuchi S.
        • Nakayama H.
        CD36, serves as a receptor for advanced glycation endproducts (AGE).
        J. Diabetes Complicat. 2002; 16: 56-59
        • Steneberg P.
        • Sykaras A.G.
        • Backlund F.
        • Straseviciene J.
        • Soderstrom I.
        • Edlund H.
        Hyperinsulinemia enhances hepatic expression of the fatty acid transporter Cd36 and provokes hepatosteatosis and hepatic insulin resistance.
        J. Biol. Chem. 2015; 290: 19034-19043
        • Buque X.
        • Cano A.
        • Miquilena-Colina M.E.
        • Garcia-Monzon C.
        • Ochoa B.
        • Aspichueta P.
        High insulin levels are required for FAT/CD36 plasma membrane translocation and enhanced fatty acid uptake in obese Zucker rat hepatocytes.
        Am. J. Physiol. Endocrinol. Metab. 2012; 303: E504-E514
        • Baeuerle P.A.
        • Henkel T.
        Function and activation of NF-kappa B in the immune system.
        Annu. Rev. Immunol. 1994; 12: 141-179
        • Barkett M.
        • Gilmore T.D.
        Control of apoptosis by Rel/NF-kappaB transcription factors.
        Oncogene. 1999; 18: 6910-6924
        • Allam-Ndoul B.
        • Guénard F.
        • Barbier O.
        • Vohl M.-C.
        Effect of n-3 fatty acids on the expression of inflammatory genes in THP-1 macrophages.
        Lipids Health Dis. 2016; 15 (69-): 69
        • Zwart S.R.
        • Pierson D.
        • Mehta S.
        • Gonda S.
        • Smith S.M.
        Capacity of omega-3 fatty acids or eicosapentaenoic acid to counteract weightlessness-induced bone loss by inhibiting NF-kappaB activation: from cells to bed rest to astronauts.
        J. Bone Mineral Res. Off. J. Am. Soc. Bone Mineral Res. 2010; 25: 1049-1057
        • Netsu S.
        • Konno R.
        • Odagiri K.
        • Soma M.
        • Fujiwara H.
        • Suzuki M.
        Oral eicosapentaenoic acid supplementation as possible therapy for endometriosis.
        Fertil. Steril. 2008; 90: 1496-1502
        • Hommelberg P.P.
        • Plat J.
        • Langen R.C.
        • Schols A.M.
        • Mensink R.P.
        Fatty acid-induced NF-kappaB activation and insulin resistance in skeletal muscle are chain length dependent.
        Am. J. Physiol. Endocrinol. Metab. 2009; 296: E114-E120
        • Poletto A.C.
        • Furuya D.T.
        • David-Silva A.
        • Ebersbach-Silva P.
        • Santos C.L.
        • Correa-Giannella M.L.
        • Passarelli M.
        • Machado U.F.
        Oleic and linoleic fatty acids downregulate Slc2a4/GLUT4 expression via NFKB and SREBP1 in skeletal muscle cells.
        Mol. Cell Endocrinol. 2015; 401: 65-72
        • Hennig B.
        • Toborek M.
        • Joshi-Barve S.
        • Barger S.W.
        • Barve S.
        • Mattson M.P.
        • McClain C.J.
        Linoleic acid activates nuclear transcription factor-kappa B (NF-kappa B) and induces NF-kappa B-dependent transcription in cultured endothelial cells.
        Am. J. Clin. Nutr. 1996; 63: 322-328
        • Toborek M.
        • Barger S.W.
        • Mattson M.P.
        • Barve S.
        • McClain C.J.
        • Hennig B.
        Linoleic acid and TNF-alpha cross-amplify oxidative injury and dysfunction of endothelial cells.
        J. Lipid Res. 1996; 37: 123-135
        • Brenner R.
        Antagonism between type 1 and type 2 diabetes in unsaturated fatty acid biosynthesis.
        Future Lipidol. 2006; 1: 631-640