Advertisement

High-Fructose Consumption and the Epigenetics of DNA Methylation

  • Hiroya YamadaEmail author
  • Eiji Munetsuna
  • Koji Ohashi
Reference work entry

Abstract

Epidemiological studies have been demonstrated that fructose, which are used for beverages, are associated with the incidence of metabolic disorders. However, the pathological mechanism of fructose effect remains unclear. Recently, there are accumulating evidences that nutrition status may induce epigenetic modification, which lead to cause several diseases such as diabetes. Interestingly, it is becoming clear that the adverse effect of fructose is mediated by epigenetic modifications. Here, this chapter describes the epigenetic effect of high-fructose consumption.

Keywords

Fructose metabolism High-fructose corn syrup Developmental origins of health and Disease (DOHaD) Pregnancy Programming Nonalcoholic fatty liver disease Metabolic syndrome DNA methylation Carnitine palmitoyltrasferase 1A Peroxisome proliferator-activated receptor-α Uncoupling proteins Mitochondrial DNA 

List of Abbreviations

ChREBP

Carbohydrate response element-binding protein

CPT1A

Carnitine palmitoyltransferase 1A

DHAP

Dihydroxyacetone phosphate

DOHaD

Developmental Origins of Health and Disease

F1P

Fructose 1-phosphate

GA

Glyceraldehyde

GA3P

Glyceraldehyde 3-phosphate

GK

Glucokinase

GLUT

Glucose transporter

HFCS

High-fructose corn syrup

LDLR

Low-density lipoprotein

MTTP

Microsomal triglyceride transfer protein large subunit

NAFLD

Nonalcoholic fatty liver disease

NASH

Nonalcoholic steatohepatitis

PFK

Phosphofructokinase

PKC

Protein kinase C

PPAR

Peroxisome proliferator-activated receptor

SREBP

Sterol regulatory element-binding protein

TG

Triglyceride

References

  1. Ba Y, Yu H, Liu F, Geng X, Zhu C, Zhu Q, Zheng T, Ma S, Wang G, Li Z, Zhang Y (2011) Relationship of folate, vitamin B12 and methylation of insulin-like growth factor-II in maternal and cord blood. Eur J Clin Nutr 65:480–485CrossRefGoogle Scholar
  2. Bonnard C, Durand A, Peyrol S, Chanseaume E, Chauvin MA, Morio B, Vidal H, Rieusset J (2008) Mitochondrial dysfunction results from oxidative stress in the skeletal muscle of diet-induced insulin-resistant mice. J Clin Invest 118:789–800PubMedPubMedCentralGoogle Scholar
  3. Bray GA (2013) Energy and fructose from beverages sweetened with sugar or high-fructose corn syrup pose a health risk for some people. Adv Nutr 4:220–225CrossRefGoogle Scholar
  4. Carabelli J, Burgueno AL, Rosselli MS, Gianotti TF, Lago NR, Pirola CJ, Sookoian S (2011) High fat diet-induced liver steatosis promotes an increase in liver mitochondrial biogenesis in response to hypoxia. J Cell Mol Med 15:1329–1338CrossRefGoogle Scholar
  5. Chang X, Yan H, Fei J, Jiang M, Zhu H, Lu D, Gao X (2010) Berberine reduces methylation of the MTTP promoter and alleviates fatty liver induced by a high-fat diet in rats. J Lipid Res 51:2504–2515CrossRefGoogle Scholar
  6. Crescenzo R, Bianco F, Falcone I, Coppola P, Liverini G, Iossa S (2013) Increased hepatic de novo lipogenesis and mitochondrial efficiency in a model of obesity induced by diets rich in fructose. Eur J Nutr 52:537–545CrossRefGoogle Scholar
  7. Crider KS, Yang TP, Berry RJ, Bailey LB (2012) Folate and DNA methylation: a review of molecular mechanisms and the evidence for folate's role. Adv Nutr 3:21–38CrossRefGoogle Scholar
  8. Dhingra R, Sullivan L, Jacques PF, Wang TJ, Fox CS, Meigs JB, D'agostino RB, Gaziano JM, Vasan RS (2007) Soft drink consumption and risk of developing cardiometabolic risk factors and the metabolic syndrome in middle-aged adults in the community. Circulation 116:480–488CrossRefGoogle Scholar
  9. Dornas WC, de Lima WG, Pedrosa ML, Silva ME (2015) Health implications of high-fructose intake and current research. Adv Nutr 6:729–737CrossRefGoogle Scholar
  10. Douard V, Ferraris RP (2008) Regulation of the fructose transporter GLUT5 in health and disease. Am J Physiol Endocrinol Metab 295:E227–E237CrossRefGoogle Scholar
  11. Elliott SS, Keim NL, Stern JS, Teff K, Havel PJ (2002) Fructose, weight gain, and the insulin resistance syndrome. Am J Clin Nutr 76:911–922CrossRefGoogle Scholar
  12. Gluckman PD, Lillycrop KA, Vickers MH, Pleasants AB, Phillips ES, Beedle AS, Burdge GC, Hanson MA (2007) Metabolic plasticity during mammalian development is directionally dependent on early nutritional status. Proc Natl Acad Sci USA 104:12796–12800CrossRefGoogle Scholar
  13. Goran MI, Dumke K, Bouret SG, Kayser B, Walker RW, Blumberg B (2013) The obesogenic effect of high fructose exposure during early development. Nat Rev Endocrinol 9:494–500CrossRefGoogle Scholar
  14. Guerre-Millo M, Gervois P, Raspe E, Madsen L, Poulain P, Derudas B, Herbert JM, Winegar DA, Willson TM, Fruchart JC, Berge RK, Staels B (2000) Peroxisome proliferator-activated receptor alpha activators improve insulin sensitivity and reduce adiposity. J Biol Chem 275:16638–16642CrossRefGoogle Scholar
  15. Haas JT, Miao J, Chanda D, Wang Y, Zhao E, Haas ME, Hirschey M, Vaitheesvaran B, Farese RV Jr, Kurland IJ, Graham M, Crooke R, Foufelle F, Biddinger SB (2012) Hepatic insulin signaling is required for obesity-dependent expression of SREBP-1c mRNA but not for feeding-dependent expression. Cell Metab 15:873–884Google Scholar
  16. Herman MA, Samuel VT (2016) The sweet path to metabolic demise: fructose and lipid synthesis. Trends Endocrinol Metab 27:719–730CrossRefGoogle Scholar
  17. Huang CH, Su SL, Hsieh MC, Cheng WL, Chang CC, Wu HL, Kuo CL, Lin TT, Liu CS (2011) Depleted leukocyte mitochondrial DNA copy number in metabolic syndrome. J Atheroscler Thromb 18:867–873CrossRefGoogle Scholar
  18. Jen KL, Rochon C, Zhong SB, Whitcomb L (1991) Fructose and sucrose feeding during pregnancy and lactation in rats changes maternal and pup fuel metabolism. J Nutr 121:1999–2005CrossRefGoogle Scholar
  19. Kim AY, Park YJ, Pan X, Shin KC, Kwak SH, Bassas AF, Sallam RM, Park KS, Alfadda AA, Xu A, Kim JB (2015) Obesity-induced DNA hypermethylation of the adiponectin gene mediates insulin resistance. Nat Commun 6:7585CrossRefGoogle Scholar
  20. Kitagawa A, Ohta Y, Ohashi K (2012) Melatonin improves metabolic syndrome induced by high fructose intake in rats. J Pineal Res 52:403–413CrossRefGoogle Scholar
  21. Korkmaz A, Reiter RJ (2008) Epigenetic regulation: a new research area for melatonin? J Pineal Res 44:41–44PubMedGoogle Scholar
  22. Ledoux TA, Watson K, Barnett A, Nguyen NT, Baranowski JC, Baranowski T (2011) Components of the diet associated with child adiposity: a cross-sectional study. J Am Coll Nutr 30:536–546CrossRefGoogle Scholar
  23. Lillycrop KA, Phillips ES, Jackson AA, Hanson MA, Burdge GC (2005) Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring. J Nutr 135:1382–1386CrossRefGoogle Scholar
  24. Lindinger A, Peterli R, Peters T, Kern B, Von Flue M, Calame M, Hoch M, Eberle AN, Lindinger PW (2010) Mitochondrial DNA content in human omental adipose tissue. Obes Surg 20:84–92CrossRefGoogle Scholar
  25. Maersk M, Belza A, Stodkilde-Jorgensen H, Ringgaard S, Chabanova E, Thomsen H, Pedersen SB, Astrup A, Richelsen B (2012) Sucrose-sweetened beverages increase fat storage in the liver, muscle, and visceral fat depot: a 6-mo randomized intervention study. Am J Clin Nutr 95:283–289CrossRefGoogle Scholar
  26. Malik VS, Popkin BM, Bray GA, Despres JP, Willett WC, Hu FB (2010) Sugar-sweetened beverages and risk of metabolic syndrome and type 2 diabetes: a meta-analysis. Diabetes Care 33:2477–2483CrossRefGoogle Scholar
  27. Moller DE, Berger JP (2003) Role of PPARs in the regulation of obesity-related insulin sensitivity and inflammation. Int J Obes Relat Metab Disord 27(Suppl 3):S17–S21CrossRefGoogle Scholar
  28. Mortensen OH, Larsen LH, Orstrup LK, Hansen LH, Grunnet N, Quistorff B (2014) Developmental programming by high fructose decreases phosphorylation efficiency in aging offspring brain mitochondria, correlating with enhanced UCP5 expression. J Cereb Blood Flow Metab 34:1205–1211CrossRefGoogle Scholar
  29. Nagai Y, Nishio Y, Nakamura T, Maegawa H, Kikkawa R, Kashiwagi A (2002) Amelioration of high fructose-induced metabolic derangements by activation of PPARalpha. Am J Physiol Endocrinol Metab 282:E1180–E1190CrossRefGoogle Scholar
  30. Nelson MC, Neumark-Sztainer D, Hannan PJ, Story M (2009) Five-year longitudinal and secular shifts in adolescent beverage intake: findings from project EAT (eating among teens)-II. J Am Diet Assoc 109:308–312CrossRefGoogle Scholar
  31. Ohashi K, Ando Y, Munetsuna E, Yamada H, Yamazaki M, Nagura A, Taromaru N, Ishikawa H, Suzuki K, Teradaira R (2015a) Maternal fructose consumption alters messenger RNA expression of hippocampal StAR, PBR, P450(11beta), 11beta-HSD, and 17beta-HSD in rat offspring. Nutr Res 35:259–264CrossRefGoogle Scholar
  32. Ohashi K, Munetsuna E, Yamada H, Ando Y, Yamazaki M, Taromaru N, Nagura A, Ishikawa H, Suzuki K, Teradaira R, Hashimoto S (2015b) High fructose consumption induces DNA methylation at PPARalpha and CPT1A promoter regions in the rat liver. Biochem Biophys Res Commun 468:185–189CrossRefGoogle Scholar
  33. Perez-Pozo SE, Schold J, Nakagawa T, Sanchez-Lozada LG, Johnson RJ, Lillo JL (2010) Excessive fructose intake induces the features of metabolic syndrome in healthy adult men: role of uric acid in the hypertensive response. Int J Obes 34:454–461CrossRefGoogle Scholar
  34. Pirola CJ, Gianotti TF, Burgueno AL, Rey-Funes M, Loidl CF, Mallardi P, Martino JS, Castano GO, Sookoian S (2013) Epigenetic modification of liver mitochondrial DNA is associated with histological severity of nonalcoholic fatty liver disease. Gut 62:1356–1363CrossRefGoogle Scholar
  35. Pirola CJ, Scian R, Gianotti TF, Dopazo H, Rohr C, Martino JS, Castano GO, Sookoian S (2015) Epigenetic modifications in the biology of nonalcoholic fatty liver disease: the role of DNA hydroxymethylation and TET proteins. Medicine (Baltimore) 94:e1480CrossRefGoogle Scholar
  36. Popkin BM (2010) Patterns of beverage use across the lifecycle. Physiol Behav 100:4–9CrossRefGoogle Scholar
  37. Ramsden DB, Ho PW, Ho JW, Liu HF, So DH, Tse HM, Chan KH, Ho SL (2012) Human neuronal uncoupling proteins 4 and 5 (UCP4 and UCP5): structural properties, regulation, and physiological role in protection against oxidative stress and mitochondrial dysfunction. Brain Behav 2:468–478CrossRefGoogle Scholar
  38. Schulze MB, Manson JE, Ludwig DS, Colditz GA, Stampfer MJ, Willett WC, Hu FB (2004) Sugar-sweetened beverages, weight gain, and incidence of type 2 diabetes in young and middle-aged women. JAMA 292:927–934CrossRefGoogle Scholar
  39. Schwarz JM, Noworolski SM, Wen MJ, Dyachenko A, Prior JL, Weinberg ME, Herraiz LA, Tai VW, Bergeron N, Bersot TP, Rao MN, Schambelan M, Mulligan K (2015) Effect of a high-fructose weight-maintaining diet on lipogenesis and liver fat. J Clin Endocrinol Metab 100:2434–2442CrossRefGoogle Scholar
  40. Segovia SA, Vickers MH, Gray C, Reynolds CM (2014) Maternal obesity, inflammation, and developmental programming. Biomed Res Int 2014:418975CrossRefGoogle Scholar
  41. Serradas P, Giroix MH, Saulnier C, Gangnerau MN, Borg LA, Welsh M, Portha B, Welsh N (1995) Mitochondrial deoxyribonucleic acid content is specifically decreased in adult, but not fetal, pancreatic islets of the Goto-Kakizaki rat, a genetic model of noninsulin-dependent diabetes. Endocrinology 136:5623–5631CrossRefGoogle Scholar
  42. Shi L, Shi L, Zhang H, Hu Z, Wang C, Zhang D, Song G (2013) Oxymatrine ameliorates non-alcoholic fatty liver disease in rats through peroxisome proliferator-activated receptor-alpha activation. Mol Med Rep 8:439–445CrossRefGoogle Scholar
  43. Sloboda DM, Li M, Patel R, Clayton ZE, Yap C, Vickers MH (2014) Early life exposure to fructose and offspring phenotype: implications for long term metabolic homeostasis. J Obes 2014:203474CrossRefGoogle Scholar
  44. Stanhope KL, Havel PJ (2009) Fructose consumption: considerations for future research on its effects on adipose distribution, lipid metabolism, and insulin sensitivity in humans. J Nutr 139:1236S–1241SCrossRefGoogle Scholar
  45. Tappy L, Le KA (2010) Metabolic effects of fructose and the worldwide increase in obesity. Physiol Rev 90:23–46CrossRefGoogle Scholar
  46. Teff KL, Grudziak J, Townsend RR, Dunn TN, Grant RW, Adams SH, Keim NL, Cummings BP, Stanhope KL, Havel PJ (2009) Endocrine and metabolic effects of consuming fructose- and glucose-sweetened beverages with meals in obese men and women: influence of insulin resistance on plasma triglyceride responses. J Clin Endocrinol Metab 94:1562–1569CrossRefGoogle Scholar
  47. Turner N, Bruce CR, Beale SM, Hoehn KL, So T, Rolph MS, Cooney GJ (2007) Excess lipid availability increases mitochondrial fatty acid oxidative capacity in muscle: evidence against a role for reduced fatty acid oxidation in lipid-induced insulin resistance in rodents. Diabetes 56:2085–2092CrossRefGoogle Scholar
  48. Ventura EE, Davis JN, Goran MI (2011) Sugar content of popular sweetened beverages based on objective laboratory analysis: focus on fructose content. Obesity (Silver Spring) 19:868–874CrossRefGoogle Scholar
  49. Xu X, So JS, Park JG, Lee AH (2013) Transcriptional control of hepatic lipid metabolism by SREBP and ChREBP. Semin Liver Dis 33:301–311CrossRefGoogle Scholar
  50. Yamazaki M, Munetsuna E, Yamada H, Ando Y, Mizuno G, Murase Y, Kondo K, Ishikawa H, Teradaira R, Suzuki K, Ohashi K (2016) Fructose consumption induces hypomethylation of hepatic mitochondrial DNA in rats. Life Sci 149:146–152CrossRefGoogle Scholar
  51. Ye JM, Doyle PJ, Iglesias MA, Watson DG, Cooney GJ, Kraegen EW (2001) Peroxisome proliferator-activated receptor (PPAR)-alpha activation lowers muscle lipids and improves insulin sensitivity in high fat-fed rats: comparison with PPAR-gamma activation. Diabetes 50:411–417CrossRefGoogle Scholar
  52. Zhang J, Zhang F, Didelot X, Bruce KD, Cagampang FR, Vatish M, Hanson M, Lehnert H, Ceriello A, Byrne CD (2009) Maternal high fat diet during pregnancy and lactation alters hepatic expression of insulin like growth factor-2 and key microRNAs in the adult offspring. BMC Genomics 10:478CrossRefGoogle Scholar
  53. Zou M, Arentson EJ, Teegarden D, Koser SL, Onyskow L, Donkin SS (2012) Fructose consumption during pregnancy and lactation induces fatty liver and glucose intolerance in rats. Nutr Res 32:588–598CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of HygieneFujita health University School of MedicineToyoakeJapan
  2. 2.Department of BiochemistryFujita Health University School of MedicineToyoakeJapan
  3. 3.Department of Clinical BiochemistryFujita Health University School of Health SciencesToyoakeJapan

Personalised recommendations