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Comparison of free fructose and glucose to sucrose in the ability to cause fatty liver

Abstract

Background

There is evidence that disaccharide sucrose produce a greater increase in serum fructose and triglycerides (TGs) than the effect produced by their equivalent monosaccharides, suggesting that long-term exposure to sucrose or fructose + glucose could potentially result in different effects.

Aim of the study

We studied the chronic effects of a combination of free fructose and glucose relative to sucrose on rat liver.

Methods

Rats were fed either a combination of 30% fructose and 30% glucose (FG) or 60% sucrose (S). Control rats were fed normal rat chow (C). All rats were pair fed and were followed for 4 months. After killing, blood chemistries and liver tissue were examined.

Results

Both FG-fed- and S-fed rats developed early features of metabolic syndrome when compared with C. In addition, both diets induced hepatic alterations, including variable increases in hepatic TG accumulation and fatty liver, an increase in uric acid content in the liver, as well as an increase in hepatic levels of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-α) measured in liver homogenates.

Conclusions

Diets containing 30% of fructose either as free fructose and glucose, or as sucrose, induce metabolic syndrome, intrahepatic accumulation of uric acid and TGs, increased MCP-1 and TNF-α as well as fatty liver in rats. It will be relevant to determine clinically whether pharmacological reduction in uric acid levels might have a therapeutic advantage in the treatment of non-alcoholic fatty liver disease.

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References

  1. Abdelmalek MF, Suzuki A, Guy C, Johnson RJ (2007) Fructose induced hyperuricemia as a causal mechanism of nonalcoholic liver disease. Hepatology 46(Suppl 1):293A

    Google Scholar 

  2. Ackerman Z, Oron-Herman M, Grozovski M, Rosenthal T, Pappo O, Link G, Sela BA (2005) Fructose-induced fatty liver disease: hepatic effects of blood pressure and plasma triglyceride reduction. Hypertension 45:1012–1018

    Article  CAS  Google Scholar 

  3. Beck-Nielsen H, Pedersen O, Lindskov HO (1980) Impaired cellular insulin binding and insulin sensitivity induced by high-fructose feeding in normal subjects. Am J Clin Nutr 33:273–278

    CAS  Google Scholar 

  4. Blakely SR, Hallfrisch J, Reiser S, Prather ES (1981) Long-term effects of moderate fructose feeding on glucose tolerance parameters in rats. J Nutr 111:307–314

    CAS  Google Scholar 

  5. Brown CM, Dulloo AG, Yepuri G, Montani JP (2008) Fructose ingestion acutely elevates blood pressure in healthy young humans. Am J Physiol Regul Integr Comp Physiol 294:R730–R737

    CAS  Google Scholar 

  6. Brunt EM (2001) Nonalcoholic steatohepatitis: definition and pathology. Semin Liver Dis 21:3–16

    Article  CAS  Google Scholar 

  7. Cirillo P, Gersch MS, Mu W, Scherer PM, Kim KM, Gesualdo L, Henderson GN, Johnson RJ, Sautin YY (2009) Ketohexokinase-dependent metabolism of fructose induces proinflammatory mediators in proximal tubular cells. J Am Soc Nephrol 20:545–553

    Article  CAS  Google Scholar 

  8. Crespo J, Cayon A, Fernandez-Gil P, Hernandez-Guerra M, Mayorga M, Dominguez-Diez A, Fernandez-Escalante JC, Pons-Romero F (2001) Gene expression of tumor necrosis factor-alpha and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. Hepatology 34:1158–1163

    Article  CAS  Google Scholar 

  9. Ding WX, Yin XM (2004) Dissection of the multiple mechanisms of TNF-alpha-induced apoptosis in liver injury. J Cell Mol Med 8:445–454

    Article  CAS  Google Scholar 

  10. Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ (2005) Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest 115:1343–1351

    CAS  Google Scholar 

  11. Gersch MS, Mu W, Cirillo P, Reungjui S, Zhang L, Roncal C, Sautin YY, Johnson RJ, Nakagawa T (2007) Fructose, but not dextrose, accelerates the progression of chronic kidney disease. Am J Physiol Renal Physiol 293:F1256–F1261

    Article  CAS  Google Scholar 

  12. Glushakova O, Kosugi T, Roncal C, Mu W, Heinig M, Cirillo P, Sanchez-Lozada LG, Johnson RJ, Nakagawa T (2008) Fructose induces the inflammatory molecule ICAM-1 in endothelial cells. J Am Soc Nephrol 19:1712–1720

    Article  CAS  Google Scholar 

  13. Hallfrisch J (1990) Metabolic effects of dietary fructose. FASEB J 4:2652–2660

    CAS  Google Scholar 

  14. Hallfrisch J, Ellwood KC, Michaelis OE, Reiser S, O’Dorisio TM, Prather ES (1983) Effects of dietary fructose on plasma glucose and hormone responses in normal and hyperinsulinemic men. J Nutr 113:1819–1826

    CAS  Google Scholar 

  15. Havel PJ (2005) Dietary fructose: implications for dysregulation of energy homeostasis and lipid/carbohydrate metabolism. Nutr Rev 63:133–157

    Article  Google Scholar 

  16. Johnson RJ, Segal MS, Sautin Y, Nakagawa T, Feig DI, Kang DH, Gersch MS, Benner S, Sanchez-Lozada LG (2007) Potential role of sugar (fructose) in the epidemic of hypertension, obesity and the metabolic syndrome, diabetes, kidney disease, and cardiovascular disease. Am J Clin Nutr 86:899–906

    CAS  Google Scholar 

  17. Kanellis J, Watanabe S, Li JH, Kang DH, Li P, Nakagawa T, Wamsley A, Sheikh-Hamad D, Lan HY, Feng L, Johnson RJ (2003) Uric acid stimulates monocyte chemoattractant protein-1 production in vascular smooth muscle cells via mitogen-activated protein kinase and cyclooxygenase-2. Hypertension 41:1287–1293

    Article  CAS  Google Scholar 

  18. Kang DH, Park SK, Lee IK, Johnson RJ (2005) Uric acid-induced C-reactive protein expression: implication on cell proliferation and nitric oxide production of human vascular cells. J Am Soc Nephrol 16:3553–3562

    Article  CAS  Google Scholar 

  19. Kelley GL, Allan G, Azhar S (2004) High dietary fructose induces a hepatic stress response resulting in cholesterol and lipid dysregulation. Endocrinology 145:548–555

    Article  CAS  Google Scholar 

  20. Li Y, Xu C, Yu C, Xu L, Miao M (2009) Association of serum uric acid level with non-alcoholic fatty liver disease: a cross-sectional study. J Hepatol 50:1029–1034

    Article  CAS  Google Scholar 

  21. Lonardo A, Loria P, Leonardi F, Borsatti A, Neri P, Pulvirenti M, Verrone AM, Bagni A, Bertolotti M, Ganazzi D, Carulli N (2002) Fasting insulin and uric acid levels but not indices of iron metabolism are independent predictors of non-alcoholic fatty liver disease. A case–control study. Dig Liver Dis 34:204–211

    Article  CAS  Google Scholar 

  22. Macdonald I, Turner LJ (1968) Serum-fructose levels after sucrose or its constituent monosaccharides. Lancet 291:841–843

    Article  Google Scholar 

  23. Manco M, Marcellini M, Giannone G, Nobili V (2007) Correlation of serum TNF-alpha levels and histologic liver injury scores in pediatric nonalcoholic fatty liver disease. Am J Clin Pathol 127:954–960

    Article  CAS  Google Scholar 

  24. Marchesini G, Babini M (2006) Nonalcoholic fatty liver disease and the metabolic syndrome. Minerva Cardioangiol 54:229–239

    CAS  Google Scholar 

  25. Matikainen N, Manttari S, Westerbacka J, Vehkavaara S, Lundbom N, Yki-Jarvinen H, Taskinen MR (2007) Postprandial lipemia associates with liver fat content. J Clin Endocrinol Metab 92:3052–3059

    Article  CAS  Google Scholar 

  26. Melanson KJ, Zukley L, Lowndes J, Nguyen V, Angelopoulos TJ, Rippe JM (2007) Effects of high-fructose corn syrup and sucrose consumption on circulating glucose, insulin, leptin, and ghrelin and on appetite in normal-weight women. Nutrition 23:103–112

    Article  CAS  Google Scholar 

  27. Monsivais P, Perrigue MM, Drewnowski A (2007) Sugars and satiety: does the type of sweetener make a difference? Am J Clin Nutr 86:116–123

    CAS  Google Scholar 

  28. Nakagawa T, Hu H, Zharikov S, Tuttle KR, Short RA, Glushakova O, Ouyang X, Feig DI, Block ER, Herrera-Acosta J, Patel JM, Johnson RJ (2006) A causal role for uric acid in fructose-induced metabolic syndrome. Am J Physiol Renal Physiol 290:F625–F631

    Article  CAS  Google Scholar 

  29. Nakagawa T, Tuttle KR, Short RA, Johnson RJ (2005) Hypothesis: fructose-induced hyperuricemia as a causal mechanism for the epidemic of the metabolic syndrome. Nat Clin Pract Nephrol 1:80–86

    Article  CAS  Google Scholar 

  30. Nimitphong H, Phongkitkarun S, Rattarasarn C, Kongsooksai A, Chanprasertyothin S, Bunnag PA, Puavilai G (2008) Hepatic fat content is a determinant of postprandial triglyceride levels in type 2 diabetes mellitus patients with normal fasting triglyceride. Metabolism 57:644–649

    Article  CAS  Google Scholar 

  31. Oleszczuk A, Spannbauer M, Tannapfel A, Bluher M, Hengstler J, Pietsch UC, Schuhmacher A, Wittekind C, Hauss JP, Schon MR (2007) Regenerative capacity differs between micro- and macrovesicular hepatic steatosis. Exp Toxicol Pathol 59:205–213

    Article  Google Scholar 

  32. Ouyang X, Cirillo P, Sautin Y, McCall S, Bruchette JL, Diehl AM, Johnson RJ, Abdelmalek MF (2008) Fructose consumption as a risk factor for non-alcoholic fatty liver disease. J Hepatol 48:993–999

    Article  CAS  Google Scholar 

  33. Palmer JR, Boggs DA, Krishnan S, Hu FB, Singer M, Rosenberg L (2008) Sugar-sweetened beverages and incidence of type 2 diabetes mellitus in African American women. Arch Intern Med 168:1487–1492

    Article  Google Scholar 

  34. Porikos KP, Van Itallie TB (1983) Diet-induced changes in serum transaminase and triglyceride levels in healthy adult men. Role of sucrose and excess calories. Am J Med 75:624–630

    Article  CAS  Google Scholar 

  35. Rijkelijkhuizen JM, Doesburg T, Girman CJ, Mari A, Rhodes T, Gastaldelli A, Nijpels G, Dekker JM (2009) Hepatic fat is not associated with beta-cell function or postprandial free fatty acid response. Metabolism 58:196–203

    Article  CAS  Google Scholar 

  36. Sanchez-Lozada LG, Tapia E, Bautista-Garcia P, Soto V, Ávila-Casado C, Vega-Campos IP, Nakagawa T, Zhao L, Franco M, Johnson RJ (2008) Effects of febuxostat on metabolic and renal alterations in rats with fructose-induced metabolic syndrome. Am J Physiol Renal Physiol 294:F710–F718

    Article  CAS  Google Scholar 

  37. Sartorio A, Del CA, Agosti F, Mazzilli G, Bellentani S, Tiribelli C, Bedogni G (2007) Predictors of non-alcoholic fatty liver disease in obese children. Eur J Clin Nutr 61:877–883

    Article  CAS  Google Scholar 

  38. Segal MS, Gollub E, Johnson RJ (2007) Is the fructose index more relevant with regards to cardiovascular disease than the glycemic index? Eur J Nutr 46:406–417

    Article  CAS  Google Scholar 

  39. Stanhope KL, Griffen SC, Bair BR, Swarbrick MM, Keim NL, Havel PJ (2008) Twenty-four-hour endocrine and metabolic profiles following consumption of high-fructose corn syrup-, sucrose-, fructose-, and glucose-sweetened beverages with meals. Am J Clin Nutr 87:1194–1203

    CAS  Google Scholar 

  40. Stanhope KL, Havel PJ (2008) Fructose consumption: potential mechanisms for its effects to increase visceral adiposity and induce dyslipidemia and insulin resistance. Curr Opin Lipidol 19:16–24

    Article  CAS  Google Scholar 

  41. Stanhope KL, Schwarz JM, Keim NL, Griffen SC, Bremer AA, Graham JL, Hatcher B, Cox CL, Dyachenko A, Zhang W, McGahan JP, Seibert A, Krauss RM, Chiu S, Schaefer EJ, Ai M, Otokozawa S, Nakajima K, Nakano T, Beysen C, Hellerstein MK, Berglund L, Havel PJ (2009) Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. J Clin Invest 119:1322–1334

    Article  CAS  Google Scholar 

  42. Swarbrick MM, Stanhope KL, Elliott SS, Graham JL, Krauss RM, Christiansen MP, Griffen SC, Keim NL, Havel PJ (2008) Consumption of fructose-sweetened beverages for 10 weeks increases postprandial triacylglycerol and apolipoprotein-B concentrations in overweight and obese women. Br J Nutr 100:947–952

    Article  CAS  Google Scholar 

  43. Teff KL, Elliott SS, Tschop M, Kieffer TJ, Rader D, Heiman M, Townsend RR, Keim NL, D’Alessio D, Havel PJ (2004) Dietary fructose reduces circulating insulin and leptin, attenuates postprandial suppression of ghrelin, and increases triglycerides in women. J Clin Endocrinol Metab 89:2963–2972

    Article  CAS  Google Scholar 

  44. Thompson RG, Hayford JT, Hendrix JA (1979) Triglyceride concentrations: the disaccharide effect. Science 206:838–839

    Article  CAS  Google Scholar 

  45. Wexler BC (1982) Allantoxanamide-induced myocardial necrosis in Sprague-Dawley vs spontaneously hypertensive rats. Proc Soc Exp Biol Med 170:476–485

    CAS  Google Scholar 

  46. Wexler BC, Greenberg BP (1977) Effect of increased serum urate levels on virgin rats with no arteriosclerosis versus breeder rats with preexistent arteriosclerosis. Metabolism 26:1309–1320

    Article  CAS  Google Scholar 

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Acknowledgments

Supported by NIH grants HL-68607 and generous funds from Gatorade. Laura G. Sánchez-Lozada is supported by grant 081054 from CONACyT, Mexico.

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Correspondence to Laura G. Sánchez-Lozada.

Additional information

Laura G. Sánchez-Lozada and Wei Mu have contributed equally.

Dr R. J. Johnson and Dr T. Nakagawa have patent applications related to lowering uric acid in the treatment of metabolic syndrome. Dr Johnson also has a book, the Sugar Fix (Rodale, 2008; and Simon and Schuster, 2009) that discusses the potential role of fructose in the obesity epidemic.

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Sánchez-Lozada, L.G., Mu, W., Roncal, C. et al. Comparison of free fructose and glucose to sucrose in the ability to cause fatty liver. Eur J Nutr 49, 1–9 (2010). https://doi.org/10.1007/s00394-009-0042-x

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  • DOI: https://doi.org/10.1007/s00394-009-0042-x

Keywords

  • Non-alcoholic steatosis
  • Metabolic syndrome
  • Sucrose
  • Fructose