Abnormal lipid metabolism in metabolic syndrome: an epigenetic perspective

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Metabolic syndrome is a complex pathology including central obesity, impaired glucose tolerance/diabetes, an atherogenic dyslipidemia and a prothrombotic state.

A new perspective on understanding the mechanisms underlying metabolic syndrome is provided by the epigenetic changes (mainly DNA methylation and histone covalent modifications), which influence gene expression without changing of the DNA sequence.

DNA methylation (mainly in carnitine palmitoyltransferase 1A gene) and histone modifications were shown to be associated with VLDL and LDL phenotypes, with hyperglycemia and reduced level of HDL cholesterol, with hypertriglyceridemic waist phenotype and with progression of atherosclerotic occlusion in peripheral arteries. The epigenetic changes can occur in the prenatal period, throughout the life span, and can be transmitted to the offspring. Both poor maternal nutrition and maternal obesity, diabetes and overfeeding can result in epigenetic alterations that amplify the risk of metabolic syndrome for the offspring.

Throughout life span, environmental factors, such as nutrition and exercise can induce epigenetic changes influencing the evolution of the metabolic syndrome (through adipocyte metabolism and insulin signaling pathway). The epigenetic modifications are not completely erased during gametogenesis and embryogensis, resulting in a transgenerational transmission of an epigenetic state up to the fifth generation.

Epigenetic mechanisms are an interface between environmental stimuli and resulting phenotype by inducing a certain transcriptional state, which may be also transmitted to the next generation(s) and which may predispose to an increased risk for developing metabolic syndrome in the context of a mismatched environment.

Elucidating epigenetic modulation might provide additional information about risk evaluation and more targeted therapeutical intervention.

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  • 1. Kraja AT Vaidya D Pankow JS Goodarzi MO Assimes TL Kullo IJ et al. A bivariate genome-wide approach to metabolic syndrome: STAMPEED consortium. Diabetes. 2011;60:1329-39. DOI: 10.2337/db10-1011.

  • 2. Bruce KD Hanson MA. The developmental origins mechanisms and implications of metabolic syndrome. J Nutr. 2010;140(3):648-52. DOI: 10.3945/ jn.109.111179.

  • 3. Laker RC Wlodek ME Connelly JJ Yan Z. Epigenetic origins of metabolic disease: The impact of the maternal condition to the offspring epigenome and later health consequences. Food Science and Human Wellness. 2013;2(1):1-11. DOI: 10.1016/j.fshw.2013.03.002.

  • 4. Ginsberg HN Stalenhoef AFH. The metabolic syndrome: targeting dyslipidaemia to reduce coronary risk. J Cardiovasc Risk. 2003; 10(2):121-8. DOI: 10.1177/174182670301000207 DOI: 10.1097/00043798-200304000-00007.

  • 5. Brudaşcă I Cucuianu M. Pathogenic role of abnormal fatty acids and adipokines in the portal flow. Relevance for the metabolic syndrome hepatic steatosis and steatohepatitis. Rom J Int Med. 2007;45:149-57.

  • 6. Frazier-Wood AC Aslibekyan S Absher DM Hopkins PH Sha J Tsai MY et al. Methylation at CPT1A locus is associated with lipoprotein subfraction profiles. J Lipid Res. 2014;55(7):1324-30. DOI: 10.1194/jlr.M048504.

  • 7. Mendelson M Liang L Chen J Baccarelli A Hirschhorn JN S.K. Osganian SK de Ferranti SD. Epigenetic modifications associated with dyslipidemia among obese children and adolescents. CJC. 2014;30(10):S190-1.

  • 8. Mamtani M Kulkarni H Dyer T Göring HH Neary JL Cole SA et al. Genome- and epigenome-wide association study of hypertriglyceridemic waist in Mexican American families. Clin Epigenetics. 2016 Jan 20;8:6. DOI: 10.1186/s13148-016-0173-x.

  • 9. Lopez-Legarrea P Mansego ML Angeles Zulet M. SERPINE1 PAI-1 protein coding gene methylation levels and epigenetic relationships with adiposity changes in obese subjects with metabolic syndrome features under dietary restriction. J Clin Biochem Nutr. 2013;53(3):139-44. DOI: 10.3164/jcbn.13-54.

  • 10. Luttmer R Spijkerman AM Kok RM Jakobs C Blom HJ Serne EH Dekker JM. Metabolic syndrome components are associated with DNA hypomethylation. Obes Res Clin Pract. 2013 Mar-Apr;7(2):e106-e115. DOI: 10.1016/j.orcp.2012.06.001.

  • 11. Alkemade FE van Vliet P Henneman P van Dijk KW Hierck BP van Munsteren JC et al. Prenatal exposure to apoE deficiency and postnatal hypercholesterolemia are associated with altered cell-specific lysine methyltransferase and histone methylation patterns in the vasculature. Am J Pathol. 2010 Feb; 176(2): 542-8. DOI: 10.2353/ajpath.2010.090031.

  • 12. Fernandez AZ Siebel AL El-Osta A. Atherogenic factors and their epigenetic Relationships. Int J Vasc Med. 2010; 2010:437809. DOI: 10.1155/2010/437809.

  • 13. Yideng J Jianzhong Z Ying H Juan S Jinge Z Shenglan W et al. Homocysteine-mediated expression of SAHH DNMTs MBD2 and DNA hypomethylation potential pathogenic mechanism in VSMCs. DNA and Cell Biology 2007;26(8):603-11. DOI: 10.1089/ dna.2007.0584.

  • 14. Krishna SM Trollope AF Golledge J. The relevance of epigenetics to occlusive cerebral and peripheral arterial disease. Clin Sci. 2015;128(9)537-58. DOI: 10.1042/ CS20140491.

  • 15. Laker RC Wlodek ME Connelly JJ Yan Z. Epigenetic origins of metabolic disease: The impact of the maternal condition to the offspring epigenome and later health consequences. Food Science and Human Wellness. 2013;2(1):1-11. DOI: 10.1016/j.fshw.2013.03.002.

  • 16. Burdge GC Slater-Jefferies J Torrens C Phillips ES Hanson MA Lillycrop KA. Dietary protein restriction of pregnant rats in the F0 generation induces altered 1 methylation of hepatic gene promoters in the adult male offspring in the F1 and F2 generations. Br J Nutr. 2007;97:435-9. DOI: 10.1017/S0007114507352392.

  • 17. Hass BS Hart RW Lu MH Lyn-Cook BD. Effects of caloric restriction in animals on cellular function oncogene expression and DNA methylation in vitro. Mutat Res. 1993;295:281-9. DOI: 10.1016/0921-8734(93)90026-Y.

  • 18. Godfrey KM Sheppard A Gluckman PD Lillycrop KA Burdge GC McLean C et al. Epigenetic gene promoter methylation at birth is associated with child’s later adiposity. Diabetes. 2011;60:1528-34. DOI: 10.2337/db10-0979.

  • 19. Fu Q McKnight R A Yu X Wang L Callaway C W Lane R H. Uteroplacental insufficiency induces site specific changes in histone H3 covalent modifications and affects DNA-histone H3 positioning in day 0 IUGR rat liver. Physiol Genomics. 2004;20:108-16. DOI: 10.1152/physiolgenomics.00175.2004.

  • 20. Bruce KD Cagampang FR. Epigenetic priming of the metabolic syndrome. Toxicol Mech Method. 2011;21(4):353-61. DOI: 10.3109/15376516.2011.559370.

  • 21. Buckley AJ Keserü B Briody J. Thompson M Ozanne SE Thompson CH. Altered body composition and metabolism in the male offspring of high fat-fed rats. Metabolism. 2005;54:500-7. DOI: 10.1016/j.metabol.2004.11.003.

  • 22. Plagemann A Harder T Brunn M Harder A Roepke K Wittrock-Staar M et al. Hypothalamic proopiomelanocortin promoter methylation becomes altered by early overfeeding: an epigenetic model of obesity and the metabolic syndrome. J Physiol 2009; 587(Pt 20):4963-76. DOI: 10.1113/jphysiol.2009.176156.

  • 23. Clausen TD Mathiesen ER Hansen T Pedersen O Jensen DM Lauenborg J et al. Overweight and the metabolic syndrome in adult offspring of women with diet-treated gestational diabetes mellitus or type 1 diabetes. J Clin Endocrinol Metab. 2009;94:2464-70. DOI: 10.1210/jc.2009-0305.

  • 24. Reik W. Stability and flexibility of epigenetic gene regulation in mammalian development. Nature. 2007;447:425-32. DOI: 10.1038/nature05918.

  • 25. Bhutani N Burns DM Blau HM. DNA demethylation dynamics. Cell. 2011;146:866-72. DOI: 10.1016/j. cell.2011.08.042.

  • 26. van Abeelen AF Elias SG Bossuyt PM Grobbee DE van der Schouw YT Roseboom TJ et al. Famine exposure in the young and the risk of type 2 diabetes in adulthood. Diabetes. 2012; 61:2255-60. DOI: 10.2337/ db11-1559.

  • 27. Barrès R Osler ME Yan J Runne A Fritz T Caidahl K. Non-CpG methylation of the PGC- 1 alpha promoter through DNMT3B controls mitochondrial density. Cell Metab. 2009;10:189-98. DOI: 10.1016/j. cmet.2009.07.011.

  • 28. Sookoian S Rosselli MS Gemma C Burgue-o AL Fernández Gianotti T Casta-o GO Pirola CJ. Epigenetic regulation of insulin resistance in nonalcoholic fatty liver disease: impact of liver methylation of the peroxisome proliferator-activated receptor γ coactivator 1α promoter. Hepatology. 2010; 52: 1992-2000. DOI: 10.1002/hep.23927.

  • 29. 29. Nitert MD Dayeh T Volkov P Elgzyri T Hall E Nilsson E et al. Impact of an exercise intervention on DNA methylation in skeletal muscle from first-degree relatives of patients with type 2 diabetes. Diabetes. 2012;61: 3322-32. DOI: 10.2337/db11-1653.

  • 30. Rönn T Volkov P Davegårdh C Dayeh T Hall E Olsson AH et al. A six months exercise intervention influences the genome-wide DNA methylation pattern in human adipose tissue. PLoS Genet. 2013;9(6):e1003572. DOI: 10.1371/journal.pgen.1003572.

  • 31. van Otterdijk SD Mathers JC Strathdee G. Do age-related changes in DNA methylation play a role in the development of age-related diseases? Biochem Soc Trans. 2013;41:803-7. DOI: 10.1042/BST20120358.

  • 32. Zhang Y Cerjak D Ali O. Finding Epigenetic determinants of the metabolic syndrome. Austin J Endocrinol Diabetes. 2014;1(6):1029.

  • 33. Wan YZ Gao P Zhou S Zhang ZQ Hao DL Lian LS et al. SIRT1-mediated epigenetic downregulation of plasminogen activator inhibitor-1 prevents vascular endothelial replicative senescence. Aging Cell. 2014;13(5):890-9. DOI: 10.1111/acel.12247.

  • 34. Painter RC Osmond C Gluckman P Hanson M Phillips DI Roseboom TJ. Transgenerational effects of prenatal exposure to the Dutch famine on neonatal adiposity and health in later life. BJOG. 2008;115:1243-9. DOI: 10.1111/j.1471-0528.2008.01822.x.

  • 35. Anway MD Cupp AS Uzumcu M Skinner MK. Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science. 2005;308:1466-9. DOI: 10.1126/science.1108190.

  • 36. Waterland RA Travisano M Tahiliani KG Rached MT Mirza S. Methyl donor supplementation prevents transgenerational amplification of obesity. Int J Obes. 2008;32:1373-9. DOI: 10.1038/ijo.2008.100.

  • 37. Soubry A Hoyo C Jirtle RL Murphy SK. A paternal environmental legacy: evidence for epigenetic inheritance through the male germ line. Bioessays. 2014; 36:359-71. DOI: 10.1002/bies.201300113.

  • 38. Ng SF Lin RC Laybutt DR Barres R Owens JA Morris MJ. Chronic high-fat diet in fathers programs β-cell dysfunction in female rat offspring. Nature. 2010 Oct 21;467(7318):963-6. DOI: 10.1038/nature09491.

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