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Flaxseed Oil Supplementation Improve Gene Expression Levels of PPAR-γ, LP(a), IL-1 and TNF-α in Type 2 Diabetic Patients with Coronary Heart Disease

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Lipids

Abstract

This study was carried out to determine the effects of flaxseed oil administration on gene expression levels related to insulin, lipid and inflammation in overweight diabetic patients with coronary heart disease (CHD). This randomized double-blind, placebo-controlled trial was conducted among 60 diabetic patients with CHD. Subjects were randomly allocated into two groups to intake either 1000 mg n-3 fatty acid from flaxseed oil containing 400 mg α-Linolenic acid [ALA (18:3n-3)] (n = 30) or placebo (n = 30) twice a day for 12 weeks. Gene expression related to insulin, lipid and inflammation were quantified in peripheral blood mononuclear cells (PBMC) of diabetic patients with CHD with RT-PCR method. Results of RT-PCR demonstrated that after the 12-week intervention, compared with the placebo, flaxseed oil supplementation could up-regulate gene expression of peroxisome proliferator-activated receptor gamma (PPAR-γ) (P = 0.02) in PBMC of diabetic patients with CHD. In addition, compared with the placebo, taking flaxseed oil supplements down-regulated gene expression levels of lipoprotein(a) [LP(a)] (P = 0.001), interleukin-1 (IL-1) (P = 0.001) and tumor necrosis factor alpha (TNF-α) (P = 0.02) in PBMC of diabetic patients with CHD. We did not observe any significant effect of flaxseed oil supplementation on gene expression levels of low-density lipoprotein receptor (LDLR), IL-8 and transforming growth factor beta (TGF-β) in PBMC of diabetic patients with CHD. Overall, flaxseed oil supplementation for 12 weeks in diabetic patients with CHD significantly improved gene expression levels of PPAR-γ, LP(a), IL-1 and TNF-α, but did not influence LDLR, IL-8 and TGF-β.

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Abbreviations

CHD:

Coronary heart disease

DHA:

Docosahexaenoic acid

IL-1:

Interleukin-1

IL-8:

Interleukin-8

Lp(a):

Lipoprotein(a)

LDLR:

Low-density lipoprotein receptor

NF-κB:

Nuclear factor-κB

PPAR-γ:

Peroxisome proliferator-activated receptor gamma

TNF-α:

Tumor necrosis factor alpha

TGF-β:

Transforming growth factor beta

T2DM:

Type 2 diabetes mellitus

References

  1. Lehrke M, Marx N (2017) Diabetes mellitus and heart failure. Am J Med 130:S40–S50

    Article  CAS  PubMed  Google Scholar 

  2. Thrainsdottir IS, Aspelund T, Hardarson T et al (2005) Glucose abnormalities and heart failure predict poor prognosis in the population-based Reykjavik Study. Eur J Cardiovasc Prev Rehabil 12:465–471

    Article  PubMed  Google Scholar 

  3. Thrainsdottir IS, Aspelund T, Thorgeirsson G et al (2005) The association between glucose abnormalities and heart failure in the population-based Reykjavik study. Diabetes Care 28:612–616

    Article  PubMed  Google Scholar 

  4. Deedwania P, Patel K, Fonarow GC et al (2013) Prediabetes is not an independent risk factor for incident heart failure, other cardiovascular events or mortality in older adults: findings from a population-based cohort study. Int J Cardiol 168:3616–3622

    Article  PubMed  PubMed Central  Google Scholar 

  5. Casella S, Bielli A, Mauriello A, Orlandi A (2015) Molecular pathways regulating macrovascular pathology and vascular smooth muscle cells phenotype in type 2 diabetes. Int J Mol Sci 16:24353–24368

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Barre DE, Mizier-Barre KA, Griscti O, Hafez K (2016) Flaxseed oil supplementation manipulates correlations between serum individual mol % free fatty acid levels and insulin resistance in type 2 diabetics. Insulin resistance and percent remaining pancreatic beta-cell function are unaffected. Endocr Regul 50:183–193

    Article  CAS  PubMed  Google Scholar 

  7. Taghizadeh M, Tamtaji OR, Dadgostar E et al (2017) The effects of omega-3 fatty acids and vitamin E co-supplementation on clinical and metabolic status in patients with Parkinson’s disease: a randomized, double-blind, placebo-controlled trial. Neurochem Int 108:183–189

    Article  CAS  PubMed  Google Scholar 

  8. Nasri K, Hantoushzadeh S, Aghadavod E, Taghizadeh M, Asemi Z (2017) The effects of omega-3 fatty acids supplementation on gene expression involved in the insulin and lipid signaling pathway in patients with polycystic ovary syndrome. Horm Metab Res 49:446–451

    Article  CAS  PubMed  Google Scholar 

  9. Zhao Y, Joshi-Barve S, Barve S, Chen LH (2004) Eicosapentaenoic acid prevents LPS-induced TNF-alpha expression by preventing NF-kappaB activation. J Am Coll Nutr 23:71–78

    Article  CAS  PubMed  Google Scholar 

  10. Mansoori A, Sotoudeh G, Djalali M et al (2015) Effect of DHA-rich fish oil on PPARgamma target genes related to lipid metabolism in type 2 diabetes: a randomized, double-blind, placebo-controlled clinical trial. J Clin Lipidol 9:770–777

    Article  PubMed  Google Scholar 

  11. Hung AM, Booker C, Ellis CD et al (2015) Omega-3 fatty acids inhibit the up-regulation of endothelial chemokines in maintenance hemodialysis patients. Nephrol Dial Transpl 30:266–274

    Article  CAS  Google Scholar 

  12. American Diabetes Association (2014) Diagnosis and classification of diabetes mellitus. Diabetes Care 37(Suppl 1):S81–90

    Article  Google Scholar 

  13. Welles CC, Whooley MA, Karumanchi SA et al (2014) Vitamin D deficiency and cardiovascular events in patients with coronary heart disease: data from the Heart and Soul Study. Am J Epidemiol 179:1279–1287

    Article  PubMed  PubMed Central  Google Scholar 

  14. Dunkley PR, Jarvie PE, Robinson PJ (2008) A rapid Percoll gradient procedure for preparation of synaptosomes. Nat Protoc 3:1718–1728

    Article  CAS  PubMed  Google Scholar 

  15. Francis GA, Fayard E, Picard F, Auwerx J (2003) Nuclear receptors and the control of metabolism. Annu Rev Physiol 65:261–311

    Article  CAS  PubMed  Google Scholar 

  16. Hsueh WA, Jackson S, Law RE (2001) Control of vascular cell proliferation and migration by PPAR-gamma: a new approach to the macrovascular complications of diabetes. Diabetes Care 24:392–397

    Article  CAS  PubMed  Google Scholar 

  17. Bruemmer D, Yin F, Liu J et al (2003) Regulation of the growth arrest and DNA damage-inducible gene 45 (GADD45) by peroxisome proliferator-activated receptor gamma in vascular smooth muscle cells. Circ Res 93:e38–47

    Article  CAS  PubMed  Google Scholar 

  18. Gan Q, Huang J, Zhou R et al (2008) PPAR{gamma} accelerates cellular senescence by inducing p16INK4{alpha} expression in human diploid fibroblasts. J Cell Sci 121:2235–2245

    Article  CAS  PubMed  Google Scholar 

  19. Meher AP, Joshi AA, Joshi SR (2014) Maternal micronutrients, omega-3 fatty acids, and placental PPARgamma expression. Appl Physiol Nutr Metab 39:793–800

    Article  CAS  PubMed  Google Scholar 

  20. Meher A, Joshi A, Joshi S (2014) Differential regulation of hepatic transcription factors in the Wistar rat offspring born to dams fed folic acid, vitamin B12 deficient diets and supplemented with omega-3 fatty acids. PLoS One 9:e90209

    Article  PubMed  PubMed Central  Google Scholar 

  21. Coyne GS, Kenny DA, Childs S, Sreenan JM, Waters SM (2008) Dietary n-3 polyunsaturated fatty acids alter the expression of genes involved in prostaglandin biosynthesis in the bovine uterus. Theriogenology 70:772–782

    Article  CAS  PubMed  Google Scholar 

  22. UK Prospective Diabetes Study (UKPDS) Group (1998) Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:854–865

    Article  Google Scholar 

  23. Strakova N, Ehrmann J, Bartos J, Malikova J, Dolezel J, Kolar Z (2005) Peroxisome proliferator-activated receptors (PPAR) agonists affect cell viability, apoptosis and expression of cell cycle related proteins in cell lines of glial brain tumors. Neoplasma 52:126–136

    CAS  PubMed  Google Scholar 

  24. Chistyakov DV, Aleshin SE, Astakhova AA, Sergeeva MG, Reiser G (2015) Regulation of peroxisome proliferator-activated receptors (PPAR) alpha and -gamma of rat brain astrocytes in the course of activation by toll-like receptor agonists. J Neurochem 134:113–124

    Article  CAS  PubMed  Google Scholar 

  25. Hwang DH, Kim JA, Lee JY (2016) Mechanisms for the activation of Toll-like receptor 2/4 by saturated fatty acids and inhibition by docosahexaenoic acid. Eur J Pharmacol 785:24–35

    Article  CAS  PubMed  Google Scholar 

  26. Vitseva OI, Tanriverdi K, Tchkonia TT et al (2008) Inducible Toll-like receptor and NF-kappaB regulatory pathway expression in human adipose tissue. Obesity (Silver Spring) 16:932–937

    Article  CAS  Google Scholar 

  27. Alexopoulou L, Thomas V, Schnare M et al (2002) Hyporesponsiveness to vaccination with Borrelia burgdorferi OspA in humans and in TLR1- and TLR2-deficient mice. Nat Med 8:878–884

    CAS  PubMed  Google Scholar 

  28. Lee JY, Ye J, Gao Z et al (2003) Reciprocal modulation of Toll-like receptor-4 signaling pathways involving MyD88 and phosphatidylinositol 3-kinase/AKT by saturated and polyunsaturated fatty acids. J Biol Chem 278:37041–37051

    Article  CAS  PubMed  Google Scholar 

  29. Itoh T, Fairall L, Amin K et al (2008) Structural basis for the activation of PPARgamma by oxidized fatty acids. Nat Struct Mol Biol 15:924–931

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Gani OA (2008) Are fish oil omega-3 long-chain fatty acids and their derivatives peroxisome proliferator-activated receptor agonists? Cardiovasc Diabetol 7:6

    Article  PubMed  PubMed Central  Google Scholar 

  31. Remels AH, Langen RC, Gosker HR et al (2009) PPARgamma inhibits NF-kappaB-dependent transcriptional activation in skeletal muscle. Am J Physiol Endocrinol Metab 297:E174–183

    Article  CAS  PubMed  Google Scholar 

  32. Colussi GL, Baroselli S, Sechi L (2004) Omega-3 polyunsaturated fatty acids decrease plasma lipoprotein(a) levels in hypertensive subjects. Clin Nutr 23:1246–1247

    Article  CAS  PubMed  Google Scholar 

  33. Herrmann W, Biermann J, Kostner GM (1995) Comparison of effects of N-3 to N-6 fatty acids on serum level of lipoprotein(a) in patients with coronary artery disease. Am J Cardiol 76:459–462

    Article  CAS  PubMed  Google Scholar 

  34. Beavers KM, Beavers DP, Bowden RG, Wilson RL, Gentile M (2009) Effect of over-the-counter fish-oil administration on plasma Lp(a) levels in an end-stage renal disease population. J Ren Nutr 19:443–449

    Article  CAS  PubMed  Google Scholar 

  35. Svensson M, Schmidt EB, Jorgensen KA, Christensen JH (2008) The effect of n-3 fatty acids on lipids and lipoproteins in patients treated with chronic haemodialysis: a randomized placebo-controlled intervention study. Nephrol Dial Transpl 23:2918–2924

    Article  CAS  Google Scholar 

  36. Nordestgaard BG, Chapman MJ, Ray K et al (2010) Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J 31:2844–2853

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kamstrup PR, Tybjaerg-Hansen A, Nordestgaard BG (2011) Lipoprotein(a) and risk of myocardial infarction–genetic epidemiologic evidence of causality. Scand J Clin Lab Investig 71:87–93

    Article  CAS  Google Scholar 

  38. Steinberg D, Witztum JL (2010) Oxidized low-density lipoprotein and atherosclerosis. Arterioscler Thromb Vasc Biol 30:2311–2316

    Article  CAS  PubMed  Google Scholar 

  39. Chen H, Li D, Chen J, Roberts GJ, Saldeen T, Mehta JL (2003) EPA and DHA attenuate ox-LDL-induced expression of adhesion molecules in human coronary artery endothelial cells via protein kinase B pathway. J Mol Cell Cardiol 35:769–775

    Article  CAS  PubMed  Google Scholar 

  40. Huang ZG, Liang C, Han SF, Wu ZG (2012) Vitamin E ameliorates ox-LDL-induced foam cells formation through modulating the activities of oxidative stress-induced NF-kappaB pathway. Mol Cell Biochem 363:11–19

    Article  CAS  PubMed  Google Scholar 

  41. Hosseinzadeh A, Ardebili SM (2016) Efficacy of omega fatty acid supplementation on mrna expression level of tumor necrosis factor alpha in patients with gastric adenocarcinoma. J Gastrointest Cancer 47:287–293

    Article  CAS  PubMed  Google Scholar 

  42. Rees D, Miles EA, Banerjee T et al (2006) Dose-related effects of eicosapentaenoic acid on innate immune function in healthy humans: a comparison of young and older men. Am J Clin Nutr 83:331–342

    CAS  PubMed  Google Scholar 

  43. Meydani SN, Lichtenstein AH, Cornwall S et al (1993) Immunologic effects of national cholesterol education panel step-2 diets with and without fish-derived N-3 fatty acid enrichment. J Clin Investig 92:105–113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Haghiac M, Yang XH, Presley L et al (2015) Dietary omega-3 fatty acid supplementation reduces inflammation in obese pregnant women: a randomized double-blind controlled clinical trial. PLoS One 10:e0137309

    Article  PubMed  PubMed Central  Google Scholar 

  45. Cheshmehkani A, Senatorov IS, Kandi P et al (2015) Fish oil and flax seed oil supplemented diets increase FFAR4 expression in the rat colon. Inflamm Res 64:809–815

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Cormier H, Rudkowska I, Lemieux S, Couture P, Vohl MC (2016) Expression and sequence variants of inflammatory genes; effects on plasma inflammation biomarkers following a 6-week supplementation with fish oil. Int J Mol Sci 17:375

    Article  PubMed  PubMed Central  Google Scholar 

  47. McNelis JC, Olefsky JM (2014) Macrophages, immunity, and metabolic disease. Immunity 41:36–48

    Article  CAS  PubMed  Google Scholar 

  48. Trayhurn P, Wood IS (2004) Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr 92:347–355

    Article  CAS  PubMed  Google Scholar 

  49. Ajuwon KM, Spurlock ME (2005) Palmitate activates the NF-kappaB transcription factor and induces IL-6 and TNFalpha expression in 3T3-L1 adipocytes. J Nutr 135:1841–1846

    CAS  PubMed  Google Scholar 

  50. Sarbolouki S, Javanbakht MH, Derakhshanian H et al (2013) Eicosapentaenoic acid improves insulin sensitivity and blood sugar in overweight type 2 diabetes mellitus patients: a double-blind randomised clinical trial. Singap Med J 54:387–390

    Article  Google Scholar 

  51. Woodman RJ, Mori TA, Burke V, Puddey IB, Watts GF, Beilin LJ (2002) Effects of purified eicosapentaenoic and docosahexaenoic acids on glycemic control, blood pressure, and serum lipids in type 2 diabetic patients with treated hypertension. Am J Clin Nutr 76:1007–1015

    CAS  PubMed  Google Scholar 

  52. Farsi PF, Djazayery A, Eshraghian MR et al (2014) Effects of supplementation with omega-3 on insulin sensitivity and non-esterified free fatty acid (NEFA) in type 2 diabetic patients. Arq Bras Endocrinol Metabol 58:335–340

    Article  PubMed  Google Scholar 

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Acknowledgements

This study was founded by a Grant from the Vice-chancellor for Research, KUMS, and Iran. We are grateful to the Research and Development Division of Barij Essence Company, Kashan, Iran that provided flaxseed oil supplements and placebo capsules for the present study.

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Authors and Affiliations

  1. Department of Molecular and Cellular Sciences, Faculty of Advanced Sciences and Technology, Pharmaceutical Sciences Branch, Islamic Azad University (IAUPS), Tehran, Iran

    Ali Akbar Hashemzadeh & Nikoo Nasoohi

  2. Department of Cardiology, School of Medicine, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran

    Fariba Raygan

  3. Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran

    Esmat Aghadavod, Elmira Akbari, Mohsen Taghizadeh & Zatollah Asemi

  4. Barij Medicinal Plants Research Center, Kashan, Islamic Republic of Iran

    Mohammad Reza Memarzadeh

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  1. Ali Akbar Hashemzadeh
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  2. Nikoo Nasoohi
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  3. Fariba Raygan
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  4. Esmat Aghadavod
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Contributions

ZA contributed in conception, design, statistical analysis and drafting of the manuscript. A-AH, NN, FR, EA, EA, MT and M-RM contributed in data collection and manuscript drafting. All authors approved the final version for submission. ZA supervised the study.

Corresponding author

Correspondence to Zatollah Asemi.

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Hashemzadeh, A.A., Nasoohi, N., Raygan, F. et al. Flaxseed Oil Supplementation Improve Gene Expression Levels of PPAR-γ, LP(a), IL-1 and TNF-α in Type 2 Diabetic Patients with Coronary Heart Disease. Lipids 52, 907–915 (2017). https://doi.org/10.1007/s11745-017-4295-5

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