Effects of DHA-rich n-3 fatty acid supplementation on gene expression in blood mononuclear leukocytes: the OmegAD study

Inger Vedin, Tommy Cederholm, Yvonne Freund-Levi, Hans Basun, Anita Garlind, Gerd Faxén Irving, Maria Eriksdotter-Jönhagen, Lars-Olof Wahlund, Ingrid Dahlman, Jan Palmblad, Inger Vedin, Tommy Cederholm, Yvonne Freund-Levi, Hans Basun, Anita Garlind, Gerd Faxén Irving, Maria Eriksdotter-Jönhagen, Lars-Olof Wahlund, Ingrid Dahlman, Jan Palmblad

Abstract

Background: Dietary fish oil, rich in n-3 fatty acids (n-3 FAs), e.g. docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), regulate inflammatory reactions by various mechanisms, e.g. gene activation. However, the effects of long-term treatment with DHA and EPA in humans, using genome wide techniques, are poorly described. Hence, our aim was to determine the effects of 6 mo of dietary supplementation with an n-3 FA preparation rich in DHA on global gene expression in peripheral blood mononuclear cells.

Methods and findings: In the present study, blood samples were obtained from a subgroup of 16 patients originating from the randomized double-blind, placebo-controlled OmegAD study, where 174 Alzheimer disease (AD) patients received daily either 1.7 g of DHA and 0.6 g EPA or placebo for 6 months. In blood samples obtained from 11 patients receiving n-3 FA and five placebo, expressions of approximately 8000 genes were assessed by gene array. Significant changes were confirmed by real-time PCR. At 6 months, the n-3 FAs group displayed significant rises of DHA and EPA plasma concentrations, as well as up- and down-regulation of nine and ten genes, respectively, was noticed. Many of these genes are involved in inflammation regulation and neurodegeneration, e.g. CD63, MAN2A1, CASP4, LOC399491, NAIP, and SORL1 and in ubiqutination processes, e.g. ANAPC5 and UBE2V1. Down-regulations of ANAPC5 and RHOB correlated to increases of plasma DHA and EPA levels.

Conclusions: We suggest that 6 months of dietary n-3 FA supplementation affected expression of genes that might influence inflammatory processes and could be of significance for AD.

Trial registration: ClinicalTrials.gov NCT00211159.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. CONSORT flowchart. Study design at…
Figure 1. CONSORT flowchart. Study design at baseline and after n-3 FA or placebo supplementation to AD patients for 6 months.
AD = Alzheimer's disease, n-3 FA = Omega-3 fatty acid treatment, Placebo = Placebo treatment.
Figure 2. Plasma values for docosahexaenoic acid…
Figure 2. Plasma values for docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) at baseline and after 6 months.
Individual values are flanked by mean and SD values. Significant increases of DHA and EPA were noted in the n-3 fatty acids (n-3 FAs) group after 6 months, but not in the placebo group.
Figure 3. Correlation between changes of plasma…
Figure 3. Correlation between changes of plasma docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) and gene expression.
Changes of plasma DHA, left, and EPA, right, and changes of expression (signal log ratio units) for the ANAPC5 (left) and CASP4 (right) genes.

References

    1. Simopoulos AP. Omega-3 fatty acids in inflammation and autoimmune diseases. J Am Coll Nutr. 2002;21:495–505.
    1. Mori TA, Beilin LJ. Omega-3 fatty acids and inflammation. Curr Atheroscler Rep. 2004;6:461–467.
    1. Jacobson TA. Secondary prevention of coronary artery disease with omega-3 fatty acids. Am J Cardiol. 2006;98:61i–70i.
    1. Barberger-Gateau P, Letenneur L, Deschamps V, Peres K, Dartigues JF, et al. Fish, meat, and risk of dementia: cohort study. BMJ. 2002;325:932–933.
    1. Schaefer EJ, Bongard V, Beiser AS, Lamon-Fava S, Robins SJ, et al. Plasma phosphatidylcholine docosahexaenoic acid content and risk of dementia and Alzheimer disease: the Framingham Heart Study. Arch Neurol. 2006;63:1545–1550.
    1. Morris MC, Evans DA, Bienias JL, Tangney CC, Bennett DA, et al. Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease. Arch Neurol. 2003;60:940–946.
    1. Freund-Levi Y, Eriksdotter-Jonhagen M, Cederholm T, Basun H, Faxen-Irving G, et al. Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: a randomized double-blind trial. Arch Neurol. 2006;63:1402–1408.
    1. Calder PC. Polyunsaturated fatty acids and inflammation. Prostaglandins Leukot Essent Fatty Acids. 2006;75:197–202.
    1. de Urquiza AM, Liu S, Sjoberg M, Zetterstrom RH, Griffiths W, et al. Docosahexaenoic acid, a ligand for the retinoid X receptor in mouse brain. Science. 2000;290:2140–2144.
    1. Zhao G, Etherton TD, Martin KR, Vanden Heuvel JP, Gillies PJ, et al. Anti-inflammatory effects of polyunsaturated fatty acids in THP-1 cells. Biochem Biophys Res Commun. 2005;336:909–917.
    1. Kitajka K, Puskas LG, Zvara A, Hackler L, Jr, Barcelo-Coblijn G, et al. The role of n-3 polyunsaturated fatty acids in brain: modulation of rat brain gene expression by dietary n-3 fatty acids. Proc Natl Acad Sci U S A. 2002;99:2619–2624.
    1. Puskas LG, Kitajka K, Nyakas C, Barcelo-Coblijn G, Farkas T. Short-term administration of omega 3 fatty acids from fish oil results in increased transthyretin transcription in old rat hippocampus. Proc Natl Acad Sci U S A. 2003;100:1580–1585.
    1. Barcelo-Coblijn G, Hogyes E, Kitajka K, Puskas LG, Zvara A, et al. Modification by docosahexaenoic acid of age-induced alterations in gene expression and molecular composition of rat brain phospholipids. Proc Natl Acad Sci U S A. 2003;100:11321–11326.
    1. Rojas CV, Martinez JI, Flores I, Hoffman DR, Uauy R. Gene expression analysis in human fetal retinal explants treated with docosahexaenoic acid. Invest Ophthalmol Vis Sci. 2003;44:3170–3177.
    1. Narayanan BA, Narayanan NK, Reddy BS. Docosahexaenoic acid regulated genes and transcription factors inducing apoptosis in human colon cancer cells. Int J Oncol. 2001;19:1255–1262.
    1. Narayanan BA, Narayanan NK, Simi B, Reddy BS. Modulation of inducible nitric oxide synthase and related proinflammatory genes by the omega-3 fatty acid docosahexaenoic acid in human colon cancer cells. Cancer Res. 2003;63:972–979.
    1. Verlengia R, Gorjao R, Kanunfre CC, Bordin S, Martins De Lima T, et al. Comparative effects of eicosapentaenoic acid and docosahexaenoic acid on proliferation, cytokine production, and pleiotropic gene expression in Jurkat cells. J Nutr Biochem. 2004;15:657–665.
    1. Verlengia R, Gorjao R, Kanunfre CC, Bordin S, de Lima TM, et al. Effects of EPA and DHA on proliferation, cytokine production, and gene expression in Raji cells. Lipids. 2004;39:857–864.
    1. Kothapalli KS, Anthony JC, Pan BS, Hsieh AT, Nathanielsz PW, et al. Differential cerebral cortex transcriptomes of baboon neonates consuming moderate and high docosahexaenoic acid formulas. PLoS One. 2007;2:e370.
    1. Berger A, Mutch DM, German JB, Roberts MA. Dietary effects of arachidonate-rich fungal oil and fish oil on murine hepatic and hippocampal gene expression. Lipids Health Dis. 2002;1:2.
    1. Davidson LA, Nguyen DV, Hokanson RM, Callaway ES, Isett RB, et al. Chemopreventive n-3 polyunsaturated fatty acids reprogram genetic signatures during colon cancer initiation and progression in the rat. Cancer Res. 2004;64:6797–6804.
    1. Bouwens M, van de Rest O, Dellschaft N, Bromhaar MG, de Groot LC, et al. Fish-oil supplementation induces antiinflammatory gene expression profiles in human blood mononuclear cells. Am J Clin Nutr. 2009;90:415–424.
    1. Vedin I, Cederholm T, Lindén J, Freund-Levi Y, Basun H, et al. Inflammatory gene expression changes by omega-3 fatty acids in patients with Alzheimer's disease. FASEB Journal. 2004;18:A501.
    1. Vedin I, Cederholm T, Freund Levi Y, Basun H, Garlind A, et al. Effects of docosahexaenoic acid-rich n-3 fatty acid supplementation on cytokine release from blood mononuclear leukocytes: the OmegAD study. Am J Clin Nutr. 2008;87:1616–1622.
    1. Tusher VG, Tibshirani R, Chu G. Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci U S A. 2001;98:5116–5121.
    1. Boberg M, Croon LB, Gustafsson IB, Vessby B. Platelet fatty acid composition in relation to fatty acid composition in plasma and to serum lipoprotein lipids in healthy subjects with special reference to the linoleic acid pathway. Clin Sci (Lond) 1985;68:581–587.
    1. Christie LA, Su JH, Tu CH, Dick MC, Zhou J, et al. Differential regulation of inhibitors of apoptosis proteins in Alzheimer's disease brains. Neurobiol Dis. 2007;26:165–173.
    1. Hartl D, Krauss-Etschmann S, Koller B, Hordijk PL, Kuijpers TW, et al. Infiltrated neutrophils acquire novel chemokine receptor expression and chemokine responsiveness in chronic inflammatory lung diseases. J Immunol. 2008;181:8053–8067.
    1. Trottestam H, Beutel K, Meeths M, Carlsen N, Heilmann C, et al. Pediatr Blood Cancer; 2008. Treatment of the X-linked lymphoproliferative, Griscelli and Chediak-Higashi syndromes by HLH directed therapy.
    1. Lakshmanan U, Porter AG. Caspase-4 interacts with TNF receptor-associated factor 6 and mediates lipopolysaccharide-induced NF-kappaB-dependent production of IL-8 and CC chemokine ligand 4 (macrophage-inflammatory protein-1). J Immunol. 2007;179:8480–8490.
    1. Yukioka F, Matsuzaki S, Kawamoto K, Koyama Y, Hitomi J, et al. Presenilin-1 mutation activates the signaling pathway of caspase-4 in endoplasmic reticulum stress-induced apoptosis. Neurochem Int. 2008;52:683–687.
    1. Rodriguez PL, Sahay S, Olabisi OO, Whitehead IP. ROCK I-mediated activation of NF-kappaB by RhoB. Cell Signal. 2007;19:2361–2369.
    1. Kaleem M, Zhao A, Hamshere M, Myers AJ. Identification of a novel valosin-containing protein polymorphism in late-onset Alzheimer's disease. Neurodegener Dis. 2007;4:376–381.
    1. Andersen OM, Reiche J, Schmidt V, Gotthardt M, Spoelgen R, et al. Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein. Proc Natl Acad Sci U S A. 2005;102:13461–13466.
    1. Scherzer CR, Offe K, Gearing M, Rees HD, Fang G, et al. Loss of apolipoprotein E receptor LR11 in Alzheimer disease. Arch Neurol. 2004;61:1200–1205.
    1. Chiarugi A, Moskowitz MA. Poly(ADP-ribose) polymerase-1 activity promotes NF-kappaB-driven transcription and microglial activation: implication for neurodegenerative disorders. J Neurochem. 2003;85:306–317.
    1. Infante J, Llorca J, Mateo I, Rodriguez-Rodriguez E, Sanchez-Quintana C, et al. Interaction between poly(ADP-ribose) polymerase 1 and interleukin 1A genes is associated with Alzheimer's disease risk. Dement Geriatr Cogn Disord. 2007;23:215–218.
    1. Jakobsen CH, Storvold GL, Bremseth H, Follestad T, Sand K, et al. DHA induces ER stress and growth arrest in human colon cancer cells: associations with cholesterol and calcium homeostasis. J Lipid Res. 2008;49:2089–2100.
    1. Gorjao R, Verlengia R, Lima TM, Soriano FG, Boaventura MF, et al. Effect of docosahexaenoic acid-rich fish oil supplementation on human leukocyte function. Clin Nutr. 2006;25:923–938.
    1. Mutch DM, Berger A, Mansourian R, Rytz A, Roberts MA. The limit fold change model: a practical approach for selecting differentially expressed genes from microarray data. BMC Bioinformatics. 2002;3:17.
    1. Endres S, Ghorbani R, Kelley VE, Georgilis K, Lonnemann G, et al. 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. 1989;320:265–271.
    1. Meydani SN, Lichtenstein AH, Cornwall S, Meydani M, Goldin BR, et al. Immunologic effects of national cholesterol education panel step-2 diets with and without fish-derived N-3 fatty acid enrichment. J Clin Invest. 1993;92:105–113.
    1. Trebble T, Arden NK, Stroud MA, Wootton SA, Burdge GC, et al. Inhibition of tumour necrosis factor-alpha and interleukin 6 production by mononuclear cells following dietary fish-oil supplementation in healthy men and response to antioxidant co-supplementation. Br J Nutr. 2003;90:405–412.
    1. Hernandez D, Guerra R, Milena A, Torres A, Garcia S, et al. Dietary fish oil does not influence acute rejection rate and graft survival after renal transplantation: a randomized placebo-controlled study. Nephrol Dial Transplant. 2002;17:897–904.
    1. Blok WL, Deslypere JP, Demacker PN, van der Ven-Jongekrijg J, Hectors MP, et al. Pro- and anti-inflammatory cytokines in healthy volunteers fed various doses of fish oil for 1 year. Eur J Clin Invest. 1997;27:1003–1008.
    1. Kew S, Mesa MD, Tricon S, Buckley R, Minihane AM, et al. Effects of oils rich in eicosapentaenoic and docosahexaenoic acids on immune cell composition and function in healthy humans. Am J Clin Nutr. 2004;79:674–681.
    1. Ma QL, Teter B, Ubeda OJ, Morihara T, Dhoot D, et al. Omega-3 fatty acid docosahexaenoic acid increases SorLA/LR11, a sorting protein with reduced expression in sporadic Alzheimer's disease (AD): relevance to AD prevention. J Neurosci. 2007;27:14299–14307.
    1. Perez SE, Berg BM, Moore KA, He B, Counts SE, et al. DHA diet reduces AD pathology in young APPswe/PS1 Delta E9 transgenic mice: possible gender effects. J Neurosci Res. 2010;88:1026–1040.
    1. Dahlman I, Linder K, Arvidsson Nordstrom E, Andersson I, Liden J, et al. Changes in adipose tissue gene expression with energy-restricted diets in obese women. Am J Clin Nutr. 2005;81:1275–1285.
    1. Farzaneh-Far R, Lin J, Epel ES, Harris WS, Blackburn EH, et al. Association of marine omega-3 fatty acid levels with telomeric aging in patients with coronary heart disease. JAMA. 2010;303:250–257.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever