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Digestive Diseases and Sciences

, Volume 61, Issue 5, pp 1282–1293 | Cite as

Role of Dietary Fructose and Hepatic De Novo Lipogenesis in Fatty Liver Disease

  • Samir Softic
  • David E. Cohen
  • C. Ronald KahnEmail author
Review

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a liver manifestation of metabolic syndrome. Overconsumption of high-fat diet (HFD) and increased intake of sugar-sweetened beverages are major risk factors for development of NAFLD. Today the most commonly consumed sugar is high fructose corn syrup. Hepatic lipids may be derived from dietary intake, esterification of plasma free fatty acids (FFA) or hepatic de novo lipogenesis (DNL). A central abnormality in NAFLD is enhanced DNL. Hepatic DNL is increased in individuals with NAFLD, while the contribution of dietary fat and plasma FFA to hepatic lipids is not significantly altered. The importance of DNL in NAFLD is further established in mouse studies with knockout of genes involved in this process. Dietary fructose increases levels of enzymes involved in DNL even more strongly than HFD. Several properties of fructose metabolism make it particularly lipogenic. Fructose is absorbed via portal vein and delivered to the liver in much higher concentrations as compared to other tissues. Fructose increases protein levels of all DNL enzymes during its conversion into triglycerides. Additionally, fructose supports lipogenesis in the setting of insulin resistance as fructose does not require insulin for its metabolism, and it directly stimulates SREBP1c, a major transcriptional regulator of DNL. Fructose also leads to ATP depletion and suppression of mitochondrial fatty acid oxidation, resulting in increased production of reactive oxygen species. Furthermore, fructose promotes ER stress and uric acid formation, additional insulin independent pathways leading to DNL. In summary, fructose metabolism supports DNL more strongly than HFD and hepatic DNL is a central abnormality in NAFLD. Disrupting fructose metabolism in the liver may provide a new therapeutic option for the treatment of NAFLD.

Keywords

NAFLD NASH Fructose HFD Metabolism De novo lipogenesis Liver 

Notes

Acknowledgments

This work was supported in part by NIH Grants R01 DK031036 and R01 DK033201 to C.R.K, R37 DK048873, R01 DK056626, and R01 DK103046 to D.E.C, and K12 HD000850 to S.S.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest to report.

References

  1. 1.
    Ford ES, Giles WH, Mokdad AH. Increasing prevalence of the metabolic syndrome among U.S. adults. Diabetes Care. 2004;27:2444–2449.PubMedCrossRefGoogle Scholar
  2. 2.
    Gotto AM Jr, Blackburn GL, Dailey GE III, et al. The metabolic syndrome: a call to action. Coron Artery Dis. 2006;17:77–80.PubMedCrossRefGoogle Scholar
  3. 3.
    Loomba R, Sanyal AJ. The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol. 2013;10:686–690.PubMedCrossRefGoogle Scholar
  4. 4.
    Chanmugam P, Guthrie JF, Cecilio S, Morton JF, Basiotis PP, Anand R. Did fat intake in the United States really decline between 1989–1991 and 1994–1996? J Am Diet Assoc. 2003;103:867–872.PubMedCrossRefGoogle Scholar
  5. 5.
    Lim JS, Mietus-Snyder M, Valente A, Schwarz JM, Lustig RH. The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome. Nat Rev Gastroenterol Hepatol. 2010;7:251–264.PubMedCrossRefGoogle Scholar
  6. 6.
    Yang Q, Zhang Z, Gregg EW, Flanders WD, Merritt R, Hu FB. Added sugar intake and cardiovascular diseases mortality among US adults. JAMA Intern Med. 2014;174:516–524.PubMedCrossRefGoogle Scholar
  7. 7.
    Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology. 2012;142:1592–1609.PubMedCrossRefGoogle Scholar
  8. 8.
    Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–1321.PubMedCrossRefGoogle Scholar
  9. 9.
    Zezos P, Renner EL. Liver transplantation and non-alcoholic fatty liver disease. World J Gastroenterol. 2014;20:15532–15538.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Soderberg C, Stal P, Askling J, et al. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology. 2010;51:595–602.PubMedCrossRefGoogle Scholar
  11. 11.
    Ong JP, Pitts A, Younossi ZM. Increased overall mortality and liver-related mortality in non-alcoholic fatty liver disease. J Hepatol. 2008;49:608–612.PubMedCrossRefGoogle Scholar
  12. 12.
    Kim D, Kim WR, Kim HJ, Therneau TM. Association between noninvasive fibrosis markers and mortality among adults with nonalcoholic fatty liver disease in the United States. Hepatology. 2013;57:1357–1365.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Targher G, Day CP, Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med. 2010;363:1341–1350.PubMedCrossRefGoogle Scholar
  14. 14.
    Cohen DE, Fisher EA. Lipoprotein metabolism, dyslipidemia, and nonalcoholic fatty liver disease. Semin Liver Dis. 2013;33:380–388.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Ebbeling CB, Feldman HA, Chomitz VR, et al. A randomized trial of sugar-sweetened beverages and adolescent body weight. N Engl J Med. 2012;367:1407–1416.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Malik VS, Willett WC, Hu FB. Sugar-sweetened beverages and BMI in children and adolescents: reanalyses of a meta-analysis. Am J Clin Nutr. 2009;89:438–439. (author reply 439-440).PubMedCrossRefGoogle Scholar
  17. 17.
    de Ruyter JC, Olthof MR, Seidell JC, Katan MB. A trial of sugar-free or sugar-sweetened beverages and body weight in children. N Engl J Med. 2012;367:1397–1406.PubMedCrossRefGoogle Scholar
  18. 18.
    Welsh JA, Sharma A, Cunningham SA, Vos MB. Consumption of added sugars and indicators of cardiovascular disease risk among US adolescents. Circulation. 2011;123:249–257.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    de Koning L, Malik VS, Kellogg MD, Rimm EB, Willett WC, Hu FB. Sweetened beverage consumption, incident coronary heart disease, and biomarkers of risk in men. Circulation. 2012;125:1735–1741.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Falcon A, Doege H, Fluitt A, et al. FATP2 is a hepatic fatty acid transporter and peroxisomal very long-chain acyl-CoA synthetase. Am J Physiol Endocrinol Metab. 2010;299:E384–E393.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Doege H, Grimm D, Falcon A, et al. Silencing of hepatic fatty acid transporter protein 5 in vivo reverses diet-induced non-alcoholic fatty liver disease and improves hyperglycemia. J Biol Chem. 2008;283:22186–22192.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Koonen DP, Jacobs RL, Febbraio M, et al. Increased hepatic CD36 expression contributes to dyslipidemia associated with diet-induced obesity. Diabetes. 2007;56:2863–2871.PubMedCrossRefGoogle Scholar
  23. 23.
    Nomura K, Yamanouchi T. The role of fructose-enriched diets in mechanisms of nonalcoholic fatty liver disease. J Nutr Biochem. 2012;23:203–208.PubMedCrossRefGoogle Scholar
  24. 24.
    Kaplan RS, Mayor JA, Johnston N, Oliveira DL. Purification and characterization of the reconstitutively active tricarboxylate transporter from rat liver mitochondria. J Biol Chem. 1990;265:13379–13385.PubMedGoogle Scholar
  25. 25.
    Brownsey RW, Boone AN, Elliott JE, Kulpa JE, Lee WM. Regulation of acetyl-CoA carboxylase. Biochem Soc Trans. 2006;34:223–227.PubMedCrossRefGoogle Scholar
  26. 26.
    Fullerton MD, Galic S, Marcinko K, et al. Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nat Med. 2013;19:1649–1654.PubMedCrossRefGoogle Scholar
  27. 27.
    Leavens KF, Birnbaum MJ. Insulin signaling to hepatic lipid metabolism in health and disease. Crit Rev Biochem Mol Biol. 2011;46:200–215.PubMedCrossRefGoogle Scholar
  28. 28.
    Hillgartner FB, Salati LM, Goodridge AG. Physiological and molecular mechanisms involved in nutritional regulation of fatty acid synthesis. Physiol Rev. 1995;75:47–76.PubMedGoogle Scholar
  29. 29.
    Kawano Y, Cohen DE. Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease. J Gastroenterol. 2013;48:434–441.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Listenberger LL, Han X, Lewis SE, et al. Triglyceride accumulation protects against fatty acid-induced lipotoxicity. Proc Natl Acad Sci USA. 2003;100:3077–3082.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Shmueli E, Alberti KG, Record CO. Diacylglycerol/protein kinase C signalling: a mechanism for insulin resistance? J Intern Med. 1993;234:397–400.PubMedCrossRefGoogle Scholar
  32. 32.
    Kim JK, Fillmore JJ, Sunshine MJ, et al. PKC-theta knockout mice are protected from fat-induced insulin resistance. J Clin Invest. 2004;114:823–827.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Bezy O, Tran TT, Pihlajamaki J, et al. PKCdelta regulates hepatic insulin sensitivity and hepatosteatosis in mice and humans. J Clin Invest. 2011;121:2504–2517.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Taniguchi CM, Kondo T, Sajan M, et al. Divergent regulation of hepatic glucose and lipid metabolism by phosphoinositide 3-kinase via Akt and PKClambda/zeta. Cell Metab. 2006;3:343–353.PubMedCrossRefGoogle Scholar
  35. 35.
    Jornayvaz FR, Shulman GI. Diacylglycerol activation of protein kinase Cepsilon and hepatic insulin resistance. Cell Metab. 2012;15:574–584.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Takayama S, White MF, Kahn CR. Phorbol ester-induced serine phosphorylation of the insulin receptor decreases its tyrosine kinase activity. J Biol Chem. 1988;263:3440–3447.PubMedGoogle Scholar
  37. 37.
    Puri P, Baillie RA, Wiest MM, et al. A lipidomic analysis of nonalcoholic fatty liver disease. Hepatology. 2007;46:1081–1090.PubMedCrossRefGoogle Scholar
  38. 38.
    Monetti M, Levin MC, Watt MJ, et al. Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver. Cell Metab. 2007;6:69–78.PubMedCrossRefGoogle Scholar
  39. 39.
    Choi CS, Savage DB, Kulkarni A, et al. Suppression of diacylglycerol acyltransferase-2 (DGAT2), but not DGAT1, with antisense oligonucleotides reverses diet-induced hepatic steatosis and insulin resistance. J Biol Chem. 2007;282:22678–22688.PubMedCrossRefGoogle Scholar
  40. 40.
    Diraison F, Beylot M. Role of human liver lipogenesis and reesterification in triglycerides secretion and in FFA reesterification. Am J Physiol. 1998;274:E321–E327.PubMedGoogle Scholar
  41. 41.
    Parks EJ, Krauss RM, Christiansen MP, Neese RA, Hellerstein MK. Effects of a low-fat, high-carbohydrate diet on VLDL–triglyceride assembly, production, and clearance. J Clin Invest. 1999;104:1087–1096.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Hellerstein MK. De novo lipogenesis in humans: metabolic and regulatory aspects. Eur J Clin Nutr. 1999;53:S53–S65.PubMedCrossRefGoogle Scholar
  43. 43.
    Marques-Lopes I, Ansorena D, Astiasaran I, Forga L, Martinez JA. Postprandial de novo lipogenesis and metabolic changes induced by a high-carbohydrate, low-fat meal in lean and overweight men. Am J Clin Nutr. 2001;73:253–261.PubMedGoogle Scholar
  44. 44.
    Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. 2005;115:1343–1351.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Lambert JE, Ramos-Roman MA, Browning JD, Parks EJ. Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease. Gastroenterology. 2014;146:726–735.PubMedCrossRefGoogle Scholar
  46. 46.
    Diraison F, Moulin P, Beylot M. Contribution of hepatic de novo lipogenesis and reesterification of plasma non esterified fatty acids to plasma triglyceride synthesis during non-alcoholic fatty liver disease. Diabetes Metab. 2003;29:478–485.PubMedCrossRefGoogle Scholar
  47. 47.
    Timlin MT, Parks EJ. Temporal pattern of de novo lipogenesis in the postprandial state in healthy men. Am J Clin Nutr. 2005;81:35–42.PubMedGoogle Scholar
  48. 48.
    Sevastianova K, Santos A, Kotronen A, et al. Effect of short-term carbohydrate overfeeding and long-term weight loss on liver fat in overweight humans. Am J Clin Nutr. 2012;96:727–734.PubMedCrossRefGoogle Scholar
  49. 49.
    Chong MF, Fielding BA, Frayn KN. Mechanisms for the acute effect of fructose on postprandial lipemia. Am J Clin Nutr. 2007;85:1511–1520.PubMedGoogle Scholar
  50. 50.
    Postic C, Girard J. Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. J Clin Invest. 2008;118:829–838.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Postic C, Girard J. The role of the lipogenic pathway in the development of hepatic steatosis. Diabetes Metab. 2008;34:643–648.PubMedCrossRefGoogle Scholar
  52. 52.
    Beigneux AP, Kosinski C, Gavino B, Horton JD, Skarnes WC, Young SG. ATP-citrate lyase deficiency in the mouse. J Biol Chem. 2004;279:9557–9564.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Pearce NJ, Yates JW, Berkhout TA, et al. The role of ATP citrate-lyase in the metabolic regulation of plasma lipids. Hypolipidemic effects of SB-204990, a lactone prodrug of the potent ATP citrate-lyase inhibitor SB-201076. Biochem J. 1998;334:113–119.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Preuss HG, Rao CV, Garis R, et al. An overview of the safety and efficacy of a novel, natural(-)-hydroxycitric acid extract (HCA-SX) for weight management. J Med. 2004;35:33–48.PubMedGoogle Scholar
  55. 55.
    Li JJ, Wang H, Tino JA, et al. 2-hydroxy-N-arylbenzenesulfonamides as ATP-citrate lyase inhibitors. Bioorg Med Chem Lett. 2007;17:3208–3211.PubMedCrossRefGoogle Scholar
  56. 56.
    Wang Q, Jiang L, Wang J, et al. Abrogation of hepatic ATP-citrate lyase protects against fatty liver and ameliorates hyperglycemia in leptin receptor-deficient mice. Hepatology. 2009;49:1166–1175.PubMedCrossRefGoogle Scholar
  57. 57.
    Wang Q, Li S, Jiang L, et al. Deficiency in hepatic ATP-citrate lyase affects VLDL–triglyceride mobilization and liver fatty acid composition in mice. J Lipid Res. 2010;51:2516–2526.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Kornacker MS, Lowenstein JM. Citrate and the conversion of carbohydrate into fat. The activities of citrate-cleavage enzyme and acetate thiokinase in livers of starved and re-fed rats. Biochem J. 1965;94:209–215.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Abu-Elheiga L, Matzuk MM, Kordari P, et al. Mutant mice lacking acetyl-CoA carboxylase 1 are embryonically lethal. Proc Natl Acad Sci USA. 2005;102:12011–12016.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Abu-Elheiga L, Matzuk MM, Abo-Hashema KA, Wakil SJ. Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2. Science. 2001;291:2613–2616.PubMedCrossRefGoogle Scholar
  61. 61.
    Abu-Elheiga L, Wu H, Gu Z, Bressler R, Wakil SJ. Acetyl-CoA carboxylase 2-/- mutant mice are protected against fatty liver under high-fat, high-carbohydrate dietary and de novo lipogenic conditions. J Biol Chem. 2012;287:12578–12588.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Olson DP, Pulinilkunnil T, Cline GW, Shulman GI, Lowell BB. Gene knockout of Acc2 has little effect on body weight, fat mass, or food intake. Proc Natl Acad Sci USA. 2010;107:7598–7603.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Mao J, DeMayo FJ, Li H, et al. Liver-specific deletion of acetyl-CoA carboxylase 1 reduces hepatic triglyceride accumulation without affecting glucose homeostasis. Proc Natl Acad Sci USA. 2006;103:8552–8557.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Harada N, Oda Z, Hara Y, et al. Hepatic de novo lipogenesis is present in liver-specific ACC1-deficient mice. Mol Cell Biol. 2007;27:1881–1888.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Savage DB, Choi CS, Samuel VT, et al. Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2. J Clin Invest. 2006;116:817–824.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Wakil SJ, Abu-Elheiga LA. Fatty acid metabolism: target for metabolic syndrome. J Lipid Res. 2009;50:S138–S143.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Chirala SS, Chang H, Matzuk M, et al. Fatty acid synthesis is essential in embryonic development: fatty acid synthase null mutants and most of the heterozygotes die in utero. Proc Natl Acad Sci USA. 2003;100:6358–6363.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Chakravarthy MV, Pan Z, Zhu Y, et al. “New” hepatic fat activates PPARalpha to maintain glucose, lipid, and cholesterol homeostasis. Cell Metab. 2005;1:309–322.PubMedCrossRefGoogle Scholar
  69. 69.
    Chakravarthy MV, Lodhi IJ, Yin L, et al. Identification of a physiologically relevant endogenous ligand for PPARalpha in liver. Cell. 2009;138:476–488.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Cohen P, Miyazaki M, Socci ND, et al. Role for stearoyl-CoA desaturase-1 in leptin-mediated weight loss. Science. 2002;297:240–243.PubMedCrossRefGoogle Scholar
  71. 71.
    Ntambi JM, Miyazaki M, Stoehr JP, et al. Loss of stearoyl-CoA desaturase-1 function protects mice against adiposity. Proc Natl Acad Sci USA. 2002;99:11482–11486.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Jiang G, Li Z, Liu F, et al. Prevention of obesity in mice by antisense oligonucleotide inhibitors of stearoyl-CoA desaturase-1. J Clin Invest. 2005;115:1030–1038.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Gutierrez-Juarez R, Pocai A, Mulas C, et al. Critical role of stearoyl-CoA desaturase-1 (SCD1) in the onset of diet-induced hepatic insulin resistance. J Clin Invest. 2006;116:1686–1695.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Miyazaki M, Flowers MT, Sampath H, et al. Hepatic stearoyl-CoA desaturase-1 deficiency protects mice from carbohydrate-induced adiposity and hepatic steatosis. Cell Metab. 2007;6:484–496.PubMedCrossRefGoogle Scholar
  75. 75.
    Mauvoisin D, Mounier C. Hormonal and nutritional regulation of SCD1 gene expression. Biochimie. 2011;93:78–86.PubMedCrossRefGoogle Scholar
  76. 76.
    Mordier S, Iynedjian PB. Activation of mammalian target of rapamycin complex 1 and insulin resistance induced by palmitate in hepatocytes. Biochem Biophys Res Commun. 2007;362:206–211.PubMedCrossRefGoogle Scholar
  77. 77.
    Matsuzaka T, Atsumi A, Matsumori R, et al. Elovl6 promotes nonalcoholic steatohepatitis. Hepatology. 2012;56:2199–2208.PubMedCrossRefGoogle Scholar
  78. 78.
    Moon YA, Ochoa CR, Mitsche MA, Hammer RE, Horton JD. Deletion of ELOVL6 blocks the synthesis of oleic acid but does not prevent the development of fatty liver or insulin resistance. J Lipid Res. 2014;55:2597–2605.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Tandra S, Yeh MM, Brunt EM, et al. Presence and significance of microvesicular steatosis in nonalcoholic fatty liver disease. J Hepatol. 2011;55:654–659.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Vilar L, Oliveira CP, Faintuch J, et al. High-fat diet: a trigger of non-alcoholic steatohepatitis? Preliminary findings in obese subjects. Nutrition. 2008;24:1097–1102.PubMedCrossRefGoogle Scholar
  81. 81.
    Machado RM, Stefano JT, Oliveira CP, et al. Intake of trans fatty acids causes nonalcoholic steatohepatitis and reduces adipose tissue fat content. J Nutr. 2010;140:1127–1132.PubMedCrossRefGoogle Scholar
  82. 82.
    Goran MI, Ulijaszek SJ, Ventura EE. High fructose corn syrup and diabetes prevalence: a global perspective. Glob Public Health. 2013;8:55–64.PubMedCrossRefGoogle Scholar
  83. 83.
    Collino M. High dietary fructose intake: sweet or bitter life? World J Diabetes. 2011;2:77–81.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Stanhope KL, Schwarz JM, Keim NL, et al. Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. J Clin Invest. 2009;119:1322–1334.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Silbernagel G, Machann J, Unmuth S, et al. Effects of 4-week very-high-fructose/glucose diets on insulin sensitivity, visceral fat and intrahepatic lipids: an exploratory trial. Br J Nutr. 2011;106:79–86.PubMedCrossRefGoogle Scholar
  86. 86.
    Cox CL, Stanhope KL, Schwarz JM, et al. Consumption of fructose- but not glucose-sweetened beverages for 10 weeks increases circulating concentrations of uric acid, retinol binding protein-4, and gamma-glutamyl transferase activity in overweight/obese humans. Nutr Metab (Lond). 2012;9:68.CrossRefGoogle Scholar
  87. 87.
    Solga S, Alkhuraishe AR, Clark JM, et al. Dietary composition and nonalcoholic fatty liver disease. Dig Dis Sci. 2004;49:1578–1583.PubMedCrossRefGoogle Scholar
  88. 88.
    Abdelmalek MF, Suzuki A, Guy C, et al. Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease. Hepatology. 2010;51:1961–1971.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Jin R, Welsh JA, Le NA, et al. Dietary fructose reduction improves markers of cardiovascular disease risk in Hispanic-American adolescents with NAFLD. Nutrients. 2014;6:3187–3201.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Mager DR, Iniguez IR, Gilmour S, Yap J. The effect of a low fructose and low glycemic index/load (FRAGILE) dietary intervention on indices of liver function, cardiometabolic risk factors, and body composition in children and adolescents with nonalcoholic fatty liver disease (NAFLD). J Parenter Enteral Nutr. 2015;39:73–84.CrossRefGoogle Scholar
  91. 91.
    Lustig RH, Mulligan K, Noworolski SM, et al. Isocaloric fructose restriction and metabolic improvement in children with obesity and metabolic syndrome. Obesity (Silver Spring). 2016;24:453–460.CrossRefGoogle Scholar
  92. 92.
    Ouyang X, Cirillo P, Sautin Y, et al. Fructose consumption as a risk factor for non-alcoholic fatty liver disease. J Hepatol. 2008;48:993–999.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Zelber-Sagi S, Nitzan-Kaluski D, Goldsmith R, et al. Long term nutritional intake and the risk for non-alcoholic fatty liver disease (NAFLD): a population based study. J Hepatol. 2007;47:711–717.PubMedCrossRefGoogle Scholar
  94. 94.
    Thuy S, Ladurner R, Volynets V, et al. Nonalcoholic fatty liver disease in humans is associated with increased plasma endotoxin and plasminogen activator inhibitor 1 concentrations and with fructose intake. J Nutr. 2008;138:1452–1455.PubMedGoogle Scholar
  95. 95.
    Papandreou D, Karabouta Z, Pantoleon A, Rousso I. Investigation of anthropometric, biochemical and dietary parameters of obese children with and without non-alcoholic fatty liver disease. Appetite. 2012;59:939–944.PubMedCrossRefGoogle Scholar
  96. 96.
    Welsh JA, Sharma AJ, Grellinger L, Vos MB. Consumption of added sugars is decreasing in the United States. Am J Clin Nutr. 2011;94:726–734.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Jin R, Le NA, Liu S, et al. Children with NAFLD are more sensitive to the adverse metabolic effects of fructose beverages than children without NAFLD. J Clin Endocrinol Metab. 2012;97:E1088–E1098.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Ishimoto T, Lanaspa MA, Rivard CJ, et al. High-fat and high-sucrose (western) diet induces steatohepatitis that is dependent on fructokinase. Hepatology. 2013;58:1632–1643.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Kohli R, Kirby M, Xanthakos SA, et al. High-fructose, medium chain trans fat diet induces liver fibrosis and elevates plasma coenzyme Q9 in a novel murine model of obesity and nonalcoholic steatohepatitis. Hepatology. 2010;52:934–944.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Charlton M, Krishnan A, Viker K, et al. Fast food diet mouse: novel small animal model of NASH with ballooning, progressive fibrosis, and high physiological fidelity to the human condition. Am J Physiol Gastrointest Liver Physiol. 2011;301:G825–G834.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Tsuchiya H, Ebata Y, Sakabe T, Hama S, Kogure K, Shiota G. High-fat, high-fructose diet induces hepatic iron overload via a hepcidin-independent mechanism prior to the onset of liver steatosis and insulin resistance in mice. Metabolism. 2013;62:62–69.PubMedCrossRefGoogle Scholar
  102. 102.
    Kennedy AR, Pissios P, Otu H, et al. A high-fat, ketogenic diet induces a unique metabolic state in mice. Am J Physiol Endocrinol Metab. 2007;292:E1724–E1739.PubMedCrossRefGoogle Scholar
  103. 103.
    Garbow JR, Doherty JM, Schugar RC, et al. Hepatic steatosis, inflammation, and ER stress in mice maintained long term on a very low-carbohydrate ketogenic diet. Am J Physiol Gastrointest Liver Physiol. 2011;300:G956–G967.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Schugar RC, Crawford PA. Low-carbohydrate ketogenic diets, glucose homeostasis, and nonalcoholic fatty liver disease. Curr Opin Clin Nutr Metab Care. 2012;15:374–380.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Hellerstein MK, Schwarz JM, Neese RA. Regulation of hepatic de novo lipogenesis in humans. Annu Rev Nutr. 1996;16:523–557.PubMedCrossRefGoogle Scholar
  106. 106.
    Meier JJ, Veldhuis JD, Butler PC. Pulsatile insulin secretion dictates systemic insulin delivery by regulating hepatic insulin extraction in humans. Diabetes. 2005;54:1649–1656.PubMedCrossRefGoogle Scholar
  107. 107.
    Nestel PJ, Havel RJ, Bezman A. Sites of initial removal of chylomicron triglyceride fatty acids from the blood. J Clin Invest. 1962;41:1915–1921.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Nakagawa T, Hu H, Zharikov S, et al. A causal role for uric acid in fructose-induced metabolic syndrome. Am J Physiol Renal Physiol. 2006;290:F625–F631.PubMedCrossRefGoogle Scholar
  109. 109.
    Asipu A, Hayward BE, O’Reilly J, Bonthron DT. Properties of normal and mutant recombinant human ketohexokinases and implications for the pathogenesis of essential fructosuria. Diabetes. 2003;52:2426–2432.PubMedCrossRefGoogle Scholar
  110. 110.
    Gaby AR. Adverse effects of dietary fructose. Altern Med Rev. 2005;10:294–306.PubMedGoogle Scholar
  111. 111.
    Boesiger P, Buchli R, Meier D, Steinmann B, Gitzelmann R. Changes of liver metabolite concentrations in adults with disorders of fructose metabolism after intravenous fructose by 31P magnetic resonance spectroscopy. Pediatr Res. 1994;36:436–440.PubMedCrossRefGoogle Scholar
  112. 112.
    Abdelmalek MF, Lazo M, Horska A, et al. Higher dietary fructose is associated with impaired hepatic adenosine triphosphate homeostasis in obese individuals with type 2 diabetes. Hepatology. 2012;56:952–960.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Cha SH, Wolfgang M, Tokutake Y, Chohnan S, Lane MD. Differential effects of central fructose and glucose on hypothalamic malonyl-CoA and food intake. Proc Natl Acad Sci USA. 2008;105:16871–16875.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Schmid AI, Szendroedi J, Chmelik M, Krssak M, Moser E, Roden M. Liver ATP synthesis is lower and relates to insulin sensitivity in patients with type 2 diabetes. Diabetes Care. 2011;34:448–453.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Cortez-Pinto H, Chatham J, Chacko VP, Arnold C, Rashid A, Diehl AM. Alterations in liver ATP homeostasis in human nonalcoholic steatohepatitis: a pilot study. JAMA. 1999;282:1659–1664.PubMedCrossRefGoogle Scholar
  116. 116.
    Horton JD, Bashmakov Y, Shimomura I, Shimano H. Regulation of sterol regulatory element binding proteins in livers of fasted and refed mice. Proc Natl Acad Sci USA. 1998;95:5987–5992.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Shimomura I, Bashmakov Y, Ikemoto S, Horton JD, Brown MS, Goldstein JL. Insulin selectively increases SREBP-1c mRNA in the livers of rats with streptozotocin-induced diabetes. Proc Natl Acad Sci USA. 1999;96:13656–13661.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Softic S, Kirby M, Berger NG, Shroyer NF, Woods SC, Kohli R. Insulin concentration modulates hepatic lipid accumulation in mice in part via transcriptional regulation of fatty acid transport proteins. PLoS ONE. 2012;7:e38952.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Biddinger SB, Hernandez-Ono A, Rask-Madsen C, et al. Hepatic insulin resistance is sufficient to produce dyslipidemia and susceptibility to atherosclerosis. Cell Metab. 2008;7:125–134.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Emanuelli B, Vienberg SG, Smyth G, et al. Interplay between FGF21 and insulin action in the liver regulates metabolism. J Clin Invest. 2014;124:515–527.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Michael MD, Kulkarni RN, Postic C, et al. Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. Mol Cell. 2000;6:87–97.PubMedCrossRefGoogle Scholar
  122. 122.
    Taniguchi CM, Emanuelli B, Kahn CR. Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol. 2006;7:85–96.PubMedCrossRefGoogle Scholar
  123. 123.
    Boucher J, Kleinridders A, Kahn CR. Insulin receptor signaling in normal and insulin-resistant states. Cold Spring Harb Perspect Biol. 2014;6:a009191.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Haas JT, Miao J, Chanda D, et al. Hepatic insulin signaling is required for obesity-dependent expression of SREBP-1c mRNA but not for feeding-dependent expression. Cell Metab. 2012;15:873–884.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Lee AH, Scapa EF, Cohen DE, Glimcher LH. Regulation of hepatic lipogenesis by the transcription factor XBP1. Science. 2008;320:1492–1496.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Jurczak MJ, Lee AH, Jornayvaz FR, et al. Dissociation of inositol-requiring enzyme (IRE1alpha)-mediated c-Jun N-terminal kinase activation from hepatic insulin resistance in conditional X-box-binding protein-1 (XBP1) knock-out mice. J Biol Chem. 2012;287:2558–2567.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Gregor MF, Yang L, Fabbrini E, et al. Endoplasmic reticulum stress is reduced in tissues of obese subjects after weight loss. Diabetes. 2009;58:693–700.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Lanaspa MA, Sanchez-Lozada LG, Choi YJ, et al. Uric acid induces hepatic steatosis by generation of mitochondrial oxidative stress: potential role in fructose-dependent and -independent fatty liver. J Biol Chem. 2012;287:40732–40744.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Johnson RJ, Nakagawa T, Sanchez-Lozada LG, et al. Sugar, uric acid, and the etiology of diabetes and obesity. Diabetes. 2013;62:3307–3315.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Kohli R, Pan X, Malladi P, Wainwright MS, Whitington PF. Mitochondrial reactive oxygen species signal hepatocyte steatosis by regulating the phosphatidylinositol 3-kinase cell survival pathway. J Biol Chem. 2007;282:21327–21336.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Samir Softic
    • 1
    • 2
  • David E. Cohen
    • 3
  • C. Ronald Kahn
    • 1
    Email author
  1. 1.Section on Integrative Physiology and MetabolismJoslin Diabetes CenterBostonUSA
  2. 2.Department of Gastroenterology, Hepatology and NutritionBoston Children’s HospitalBostonUSA
  3. 3.Division of Gastroenterology, Department of MedicineBrigham and Women’s Hospital, Harvard Medical SchoolBostonUSA

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