All Title Author
Keywords Abstract

PLOS ONE  2012 

Uric Acid Stimulates Fructokinase and Accelerates Fructose Metabolism in the Development of Fatty Liver

DOI: 10.1371/journal.pone.0047948

Full-Text   Cite this paper   Add to My Lib


Excessive dietary fructose intake may have an important role in the current epidemics of fatty liver, obesity and diabetes as its intake parallels the development of these syndromes and because it can induce features of metabolic syndrome. The effects of fructose to induce fatty liver, hypertriglyceridemia and insulin resistance, however, vary dramatically among individuals. The first step in fructose metabolism is mediated by fructokinase (KHK), which phosphorylates fructose to fructose-1-phosphate; intracellular uric acid is also generated as a consequence of the transient ATP depletion that occurs during this reaction. Here we show in human hepatocytes that uric acid up-regulates KHK expression thus leading to the amplification of the lipogenic effects of fructose. Inhibition of uric acid production markedly blocked fructose-induced triglyceride accumulation in hepatocytes in vitro and in vivo. The mechanism whereby uric acid stimulates KHK expression involves the activation of the transcription factor ChREBP, which, in turn, results in the transcriptional activation of KHK by binding to a specific sequence within its promoter. Since subjects sensitive to fructose often develop phenotypes associated with hyperuricemia, uric acid may be an underlying factor in sensitizing hepatocytes to fructose metabolism during the development of fatty liver.


[1]  Yusuf S, Reddy S, Ounpuu S, Anand S (2001) Global burden of cardiovascular diseases: part I: general considerations, the epidemiologic transition, risk factors, and impact of urbanization. Circulation 104: 2746–2753.
[2]  Wanless IR, Lentz JS (1990) Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatology 12: 1106–1110.
[3]  Stanhope KL, Schwarz JM, Keim NL, Griffen SC, Bremer AA, et al. (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.
[4]  Johnson RJ, Perez-Pozo SE, Sautin YY, Manitius J, Sanchez-Lozada LG, et al. (2009) Hypothesis: could excessive fructose intake and uric acid cause type 2 diabetes? Endocr Rev 30: 96–116.
[5]  Nakagawa T, Hu H, Zharikov S, Tuttle KR, Short RA, et al. (2006) A causal role for uric acid in fructose-induced metabolic syndrome. Am J Physiol Renal Physiol 290: F625–631.
[6]  Tappy L, Le KA (2010) Metabolic effects of fructose and the worldwide increase in obesity. Physiol Rev 90: 23–46.
[7]  Havel PJ (2005) Dietary fructose: implications for dysregulation of energy homeostasis and lipid/carbohydrate metabolism. Nutr Rev 63: 133–157.
[8]  Hallfrisch J (1990) Metabolic effects of dietary fructose. FASEB J 4: 2652–2660.
[9]  Van den Berghe G (1986) Fructose: metabolism and short-term effects on carbohydrate and purine metabolic pathways. Prog Biochem Pharmacol 21: 1–32.
[10]  Bode JC, Zelder O, Rumpelt HJ, Wittkamp U (1973) Depletion of liver adenosine phosphates and metabolic effects of intravenous infusion of fructose or sorbitol in man and in the rat. Eur J Clin Invest 3: 436–441.
[11]  Cortez-Pinto H, Chatham J, Chacko VP, Arnold C, Rashid A, et al. (1999) Alterations in liver ATP homeostasis in human nonalcoholic steatohepatitis: a pilot study. Jama 282: 1659–1664.
[12]  Masuo K, Kawaguchi H, Mikami H, Ogihara T, Tuck ML (2003) Serum uric acid and plasma norepinephrine concentrations predict subsequent weight gain and blood pressure elevation. Hypertension 42: 474–480.
[13]  Kodama S, Saito K, Yachi Y, Asumi M, Sugawara A, et al. (2009) Association between serum uric acid and development of type 2 diabetes. Diabetes Care 32: 1737–1742.
[14]  Lee K (2009) Relationship between uric acid and hepatic steatosis among Koreans. Diabetes and Metabolism 35: 447–451.
[15]  Burant CF, Saxena M (1994) Rapid reversible substrate regulation of fructose transporter expression in rat small intestine and kidney. Am J Physiol 267: G71–79.
[16]  Korieh A, Crouzoulon G (1991) Dietary regulation of fructose metabolism in the intestine and in the liver of the rat. Duration of the effects of a high fructose diet after the return to the standard diet. Arch Int Physiol Biochim Biophys 99: 455–460.
[17]  Ouyang X, Cirillo P, Sautin Y, McCall S, Bruchette JL, et al. (2008) Fructose consumption as a risk factor for non-alcoholic fatty liver disease. J Hepatol 48: 993–999.
[18]  Bricambert J, Miranda J, Benhamed F, Girard J, Postic C, et al. (2010) Salt-inducible kinase 2 links transcriptional coactivator p300 phosphorylation to the prevention of ChREBP-dependent hepatic steatosis in mice. J Clin Invest 120: 4316–4331.
[19]  Lanaspa MA, Andres-Hernando A, Li N, Rivard CJ, Cicerchi C, et al. (2010) The expression of aquaporin-1 in the medulla of the kidney is dependent on the transcription factor associated with hypertonicity, TonEBP. J Biol Chem 285: 31694–31703.
[20]  Ma L, Robinson LN, Towle HC (2006) ChREBP*Mlx is the principal mediator of glucose-induced gene expression in the liver. J Biol Chem 281: 28721–28730.
[21]  Koo HY, Wallig MA, Chung BH, Nara TY, Cho BH, et al. (2008) Dietary fructose induces a wide range of genes with distinct shift in carbohydrate and lipid metabolism in fed and fasted rat liver. Biochim Biophys Acta 1782: 341–348.
[22]  Koo HY, Miyashita M, Cho BH, Nakamura MT (2009) Replacing dietary glucose with fructose increases ChREBP activity and SREBP-1 protein in rat liver nucleus. Biochem Biophys Res Commun 390: 285–289.
[23]  Xu C, Yu C, Xu L, Miao M, Li Y (2010) High serum uric acid increases the risk for nonalcoholic Fatty liver disease: a prospective observational study. PLoS ONE 5: e11578.
[24]  Kuo CF, Yu KH, Luo SF, Chiu CT, Ko YS, et al. (2010) Gout and risk of non-alcoholic fatty liver disease. Scand J Rheumatol 39: 466–471.
[25]  Yamada T, Suzuki S, Fukatsu M, Wada T, Yoshida T, et al. (2010) Elevated serum uric acid is an independent risk factor for nonalcoholic fatty liver disease in Japanese undergoing a health checkup. Acta Gastroenterol Belg 73: 12–17.
[26]  Ferreira VS, Pernambuco RB, Lopes EP, Morais CN, Rodrigues MC, et al. (2010) Frequency and risk factors associated with non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus. Arq Bras Endocrinol Metabol 54: 362–368.
[27]  Petta S, Camma C, Cabibi D, Di Marco V, Craxi A (2011) Hyperuricemia is associated with histological liver damage in patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther 34: 757–766.
[28]  Abdelmalek MF, Lazo M, Horska A, Bonekamp S, Lipkin EW, et al. (2012) Higher dietary fructose is associated with impaired hepatic adenosine triphosphate homeostasis in obese individuals with type 2 diabetes. Hepatology 56: 952–960.
[29]  Xu CF, Yu CH, Xu L, Sa XY, Li YM (2010) Hypouricemic therapy: a novel potential therapeutic option for nonalcoholic fatty liver disease. Hepatology 52: 1865–1866.
[30]  Hallfrisch J, Ellwood K, Michaelis OE, Reiser S, Prather ES (1986) Plasma fructose, uric acid, and inorganic phosphorus responses of hyperinsulinemic men fed fructose. J Am Coll Nutr 5: 61–68.
[31]  Hallfrisch J, Ellwood KC, Michaelis OE, Reiser S, O’Dorisio TM, et al. (1983) Effects of dietary fructose on plasma glucose and hormone responses in normal and hyperinsulinemic men. J Nutr 113: 1819–1826.
[32]  Hallfrisch J, Reiser S, Prather ES (1983) Blood lipid distribution of hyperinsulinemic men consuming three levels of fructose. Am J Clin Nutr 37: 740–748.
[33]  Le KA, Ith M, Kreis R, Faeh D, Bortolotti M, et al. (2009) Fructose overconsumption causes dyslipidemia and ectopic lipid deposition in healthy subjects with and without a family history of type 2 diabetes. Am J Clin Nutr 89: 1760–1765.
[34]  Facchini F, Chen YD, Hollenbeck CB, Reaven GM (1991) Relationship between resistance to insulin-mediated glucose uptake, urinary uric acid clearance, and plasma uric acid concentration. Jama 266: 3008–3011.
[35]  Couchepin C, Le KA, Bortolotti M, da Encarnacao JA, Oboni JB, et al. (2008) Markedly blunted metabolic effects of fructose in healthy young female subjects compared with male subjects. Diabetes Care 31: 1254–1256.
[36]  Chung SS, Ho EC, Lam KS, Chung SK (2003) Contribution of polyol pathway to diabetes-induced oxidative stress. J Am Soc Nephrol 14: S233–236.
[37]  Kawaguchi T, Osatomi K, Yamashita H, Kabashima T, Uyeda K (2002) Mechanism for fatty acid “sparing” effect on glucose-induced transcription: regulation of carbohydrate-responsive element-binding protein by AMP-activated protein kinase. J Biol Chem 277: 3829–3835.
[38]  Foretz M, Ancellin N, Andreelli F, Saintillan Y, Grondin P, et al. (2005) Short-term overexpression of a constitutively active form of AMP-activated protein kinase in the liver leads to mild hypoglycemia and fatty liver. Diabetes 54: 1331–1339.
[39]  Feig DI, Kang DH, Johnson RJ (2008) Uric acid and cardiovascular risk. N Engl J Med 359: 1811–1821.
[40]  Johnson RJ, Kang DH, Feig D, Kivlighn S, Kanellis J, et al. (2003) Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease? Hypertension 41: 1183–1190.
[41]  Kanellis J, Watanabe S, Li JH, Kang DH, Li P, et al. (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.
[42]  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.
[43]  Yu MA, Sanchez-Lozada LG, Johnson RJ, Kang DH (2010) Oxidative stress with an activation of the renin-angiotensin system in human vascular endothelial cells as a novel mechanism of uric acid-induced endothelial dysfunction. J Hypertens 28: 1234–1242.
[44]  Johnson RJ, Andrews P, Benner SA, Oliver W (2010) Theodore E. Woodward award. The evolution of obesity: insights from the mid-Miocene. Trans Am Clin Climatol Assoc 121: 295–305; discussion 305–298.


comments powered by Disqus