HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 290/3/F625    most recent 00140.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (103) Citing Articles via Google Scholar Google Scholar Articles by Nakagawa, T. Articles by Johnson, R. J. Search for Related Content PubMed PubMed Citation Articles by Nakagawa, T. Articles by Johnson, R. J.

A causal role for uric acid in fructose-induced metabolic syndrome

Takahiko Nakagawa,¹ Hanbo Hu,¹ Sergey Zharikov,¹ Katherine R. Tuttle,² Robert A. Short,^2,3 Olena Glushakova,¹ Xiaosen Ouyang,¹ Daniel I. Feig,⁴ Edward R. Block,¹ Jaime Herrera-Acosta,^5, Jawaharlal M. Patel,¹ and Richard J. Johnson¹

¹Division of Nephrology, Hypertension, and Transplantation, University of Florida, Gainesville, Florida; ²Department of Research, The Heart Institute of Spokane, and ³Biostatistics, Washington State University, Spokane, Washington; ⁴Division of Nephrology-Medicine, Baylor College of Medicine, Houston, Texas; and ⁵Departamento de Nefrologia, Instituto Nacional de Cardiologia Ignacio Chavez, Tlalpan, Mexico

Submitted 6 April 2005 ; accepted in final form 26 September 2005

The worldwide epidemic of metabolic syndrome correlates with an elevation in serum uric acid as well as a marked increase in total fructose intake (in the form of table sugar and high-fructose corn syrup). Fructose raises uric acid, and the latter inhibits nitric oxide bioavailability. Because insulin requires nitric oxide to stimulate glucose uptake, we hypothesized that fructose-induced hyperuricemia may have a pathogenic role in metabolic syndrome. Four sets of experiments were performed. First, pair-feeding studies showed that fructose, and not dextrose, induced features (hyperinsulinemia, hypertriglyceridemia, and hyperuricemia) of metabolic syndrome. Second, in rats receiving a high-fructose diet, the lowering of uric acid with either allopurinol (a xanthine oxidase inhibitor) or benzbromarone (a uricosuric agent) was able to prevent or reverse features of metabolic syndrome. In particular, the administration of allopurinol prophylactically prevented fructose-induced hyperinsulinemia (272.3 vs.160.8 pmol/l, P < 0.05), systolic hypertension (142 vs. 133 mmHg, P < 0.05), hypertriglyceridemia (233.7 vs. 65.4 mg/dl, P < 0.01), and weight gain (455 vs. 425 g, P < 0.05) at 8 wk. Neither allopurinol nor benzbromarone affected dietary intake of control diet in rats. Finally, uric acid dose dependently inhibited endothelial function as manifested by a reduced vasodilatory response of aortic artery rings to acetylcholine. These data provide the first evidence that uric acid may be a cause of metabolic syndrome, possibly due to its ability to inhibit endothelial function. Fructose may have a major role in the epidemic of metabolic syndrome and obesity due to its ability to raise uric acid.

obesity; insulin resistance

This article has been cited by other articles:

				A. S Bomback, R. Katz, K. He, D. A Shoham, G. L Burke, and P. J Klemmer Sugar-sweetened beverage consumption and the progression of chronic kidney disease in the Multi-Ethnic Study of Atherosclerosis (MESA) Am. J. Clinical Nutrition, November 1, 2009; 90(5): 1172 - 1178. [Abstract] [Full Text] [PDF]

				P. L. Riches, A. F. Wright, and S. H. Ralston Recent insights into the pathogenesis of hyperuricaemia and gout Hum. Mol. Genet., October 15, 2009; 18(R2): R177 - R184. [Abstract] [Full Text] [PDF]

				M. Doblado and K. H. Moley Facilitative glucose transporter 9, a unique hexose and urate transporter Am J Physiol Endocrinol Metab, October 1, 2009; 297(4): E831 - E835. [Abstract] [Full Text] [PDF]

				Q.-H. Hu, C. Wang, J.-M. Li, D.-M. Zhang, and L.-D. Kong Allopurinol, rutin, and quercetin attenuate hyperuricemia and renal dysfunction in rats induced by fructose intake: renal organic ion transporter involvement Am J Physiol Renal Physiol, October 1, 2009; 297(4): F1080 - F1091. [Abstract] [Full Text] [PDF]

				L.-C. SEE, C.-F. KUO, F.-H. CHUANG, H.-Y. LI, Y.-M. CHEN, H.-W. CHEN, and K.-H. YU Serum Uric Acid Is Independently Associated with Metabolic Syndrome in Subjects with and without a Low Estimated Glomerular Filtration Rate J Rheumatol, August 1, 2009; 36(8): 1691 - 1698. [Abstract] [Full Text] [PDF]

				T. Kosugi, T. Nakayama, M. Heinig, L. Zhang, Y. Yuzawa, L. G. Sanchez-Lozada, C. Roncal, R. J. Johnson, and T. Nakagawa Effect of lowering uric acid on renal disease in the type 2 diabetic db/db mice Am J Physiol Renal Physiol, August 1, 2009; 297(2): F481 - F488. [Abstract] [Full Text] [PDF]

				T. J. Angelopoulos, J. Lowndes, L. Zukley, K. J. Melanson, V. Nguyen, A. Huffman, and J. M. Rippe The Effect of High-Fructose Corn Syrup Consumption on Triglycerides and Uric Acid J. Nutr., June 1, 2009; 139(6): 1242S - 1245S. [Abstract] [Full Text] [PDF]

				L. Jiao, A. Flood, A. F. Subar, A. R. Hollenbeck, A. Schatzkin, and R. Stolzenberg-Solomon Glycemic Index, Carbohydrates, Glycemic Load, and the Risk of Pancreatic Cancer in a Prospective Cohort Study Cancer Epidemiol. Biomarkers Prev., April 1, 2009; 18(4): 1144 - 1151. [Abstract] [Full Text] [PDF]

				J. P. Forman, H. Choi, and G. C. Curhan Fructose and Vitamin C Intake Do Not Influence Risk for Developing Hypertension J. Am. Soc. Nephrol., April 1, 2009; 20(4): 863 - 871. [Abstract] [Full Text] [PDF]

				P. Cirillo, M. S. Gersch, W. Mu, P. M. Scherer, K. M. Kim, L. Gesualdo, G. N. Henderson, R. J. Johnson, and Y. Y. Sautin Ketohexokinase-Dependent Metabolism of Fructose Induces Proinflammatory Mediators in Proximal Tubular Cells J. Am. Soc. Nephrol., March 1, 2009; 20(3): 545 - 553. [Abstract] [Full Text] [PDF]

				M. E. Choi The Not-so-Sweet Side of Fructose J. Am. Soc. Nephrol., March 1, 2009; 20(3): 457 - 459. [Full Text] [PDF]

				D. I. Feig and R. J. Johnson Allopurinol and the Role of Uric Acid in Hypertension--Reply JAMA, January 21, 2009; 301(3): 270 - 271. [Full Text] [PDF]

				L. Pacifico, V. Cantisani, C. Anania, E. Bonaiuto, F. Martino, R. Pascone, and C. Chiesa Serum uric acid and its association with metabolic syndrome and carotid atherosclerosis in obese children Eur. J. Endocrinol., January 1, 2009; 160(1): 45 - 52. [Abstract] [Full Text] [PDF]

				A. M. Bataille, J. Goldmeyer, and J. L. Renfro Avian renal proximal tubule epithelium urate secretion is mediated by Mrp4 Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2008; 295(6): R2024 - R2033. [Abstract] [Full Text] [PDF]

				A. Shapiro, W. Mu, C. Roncal, K.-Y. Cheng, R. J. Johnson, and P. J. Scarpace Fructose-induced leptin resistance exacerbates weight gain in response to subsequent high-fat feeding Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2008; 295(5): R1370 - R1375. [Abstract] [Full Text] [PDF]

				J. R. Vasselli Fructose-induced leptin resistance: discovery of an unsuspected form of the phenomenon and its significance. Focus on "Fructose-induced leptin resistance exacerbates weight gain in response to subsequent high-fat feeding," by Shapiro et al. Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2008; 295(5): R1365 - R1369. [Full Text] [PDF]

				S. Zharikov, K. Krotova, H. Hu, C. Baylis, R. J. Johnson, E. R. Block, and J. Patel Uric acid decreases NO production and increases arginase activity in cultured pulmonary artery endothelial cells Am J Physiol Cell Physiol, November 1, 2008; 295(5): C1183 - C1190. [Abstract] [Full Text] [PDF]

				D. I. Feig, D.-H. Kang, and R. J. Johnson Uric Acid and Cardiovascular Risk N. Engl. J. Med., October 23, 2008; 359(17): 1811 - 1821. [Full Text] [PDF]

				M. T. Le, M. Shafiu, W. Mu, and R. J. Johnson SLC2A9--a fructose transporter identified as a novel uric acid transporter Nephrol. Dial. Transplant., September 1, 2008; 23(9): 2746 - 2749. [Full Text] [PDF]

				O. Glushakova, T. Kosugi, C. Roncal, W. Mu, M. Heinig, P. Cirillo, L. G. Sanchez-Lozada, R. J. Johnson, and T. Nakagawa Fructose Induces the Inflammatory Molecule ICAM-1 in Endothelial Cells J. Am. Soc. Nephrol., September 1, 2008; 19(9): 1712 - 1720. [Abstract] [Full Text] [PDF]

				A. Brandstatter, S. Kiechl, B. Kollerits, S. C. Hunt, I. M. Heid, S. Coassin, J. Willeit, T. D. Adams, T. Illig, P. N. Hopkins, et al. Sex-Specific Association of the Putative Fructose Transporter SLC2A9 Variants With Uric Acid Levels Is Modified by BMI Diabetes Care, August 1, 2008; 31(8): 1662 - 1667. [Abstract] [Full Text] [PDF]

				V. Douard and R. P. Ferraris Regulation of the fructose transporter GLUT5 in health and disease Am J Physiol Endocrinol Metab, August 1, 2008; 295(2): E227 - E237. [Abstract] [Full Text] [PDF]

				M. S Segal, L. G Sanchez-Lozada, and R. J Johnson Reply to RJ Hine and JS White Am. J. Clinical Nutrition, April 1, 2008; 87(4): 1063 - 1064. [Full Text] [PDF]

				L. G. Sanchez-Lozada, E. Tapia, V. Soto, C. Avila-Casado, M. Franco, L. Zhao, and R. J. Johnson Treatment with the xanthine oxidase inhibitor febuxostat lowers uric acid and alleviates systemic and glomerular hypertension in experimental hyperuricaemia Nephrol. Dial. Transplant., April 1, 2008; 23(4): 1179 - 1185. [Abstract] [Full Text] [PDF]

				L. G. Sanchez-Lozada, E. Tapia, P. Bautista-Garcia, V. Soto, C. Avila-Casado, I. P. Vega-Campos, T. Nakagawa, L. Zhao, M. Franco, and R. J. Johnson Effects of febuxostat on metabolic and renal alterations in rats with fructose-induced metabolic syndrome Am J Physiol Renal Physiol, April 1, 2008; 294(4): F710 - F718. [Abstract] [Full Text] [PDF]

				M. Underwood Sugary drinks, fruit, and increased risk of gout BMJ, February 9, 2008; 336(7639): 285 - 286. [Full Text] [PDF]

				A. Dehghan, M. van Hoek, E. J.G. Sijbrands, A. Hofman, and J. C.M. Witteman High Serum Uric Acid as a Novel Risk Factor for Type 2 Diabetes Diabetes Care, February 1, 2008; 31(2): 361 - 362. [Abstract] [Full Text] [PDF]

				G. A Bray How bad is fructose? Am. J. Clinical Nutrition, October 1, 2007; 86(4): 895 - 896. [Full Text] [PDF]

				R. J Johnson, M. S Segal, Y. Sautin, T. Nakagawa, D. I Feig, D.-H. Kang, M. S Gersch, S. Benner, and L. G Sanchez-Lozada Potential role of sugar (fructose) in the epidemic of hypertension, obesity and the metabolic syndrome, diabetes, kidney disease, and cardiovascular disease Am. J. Clinical Nutrition, October 1, 2007; 86(4): 899 - 906. [Abstract] [Full Text] [PDF]

				S. Reungjui, C. A. Roncal, W. Mu, T. R. Srinivas, D. Sirivongs, R. J. Johnson, and T. Nakagawa Thiazide Diuretics Exacerbate Fructose-Induced Metabolic Syndrome J. Am. Soc. Nephrol., October 1, 2007; 18(10): 2724 - 2731. [Abstract] [Full Text] [PDF]

				M. S. Gersch, W. Mu, P. Cirillo, S. Reungjui, L. Zhang, C. Roncal, Y. Y. Sautin, R. J. Johnson, and T. Nakagawa Fructose, but not dextrose, accelerates the progression of chronic kidney disease Am J Physiol Renal Physiol, October 1, 2007; 293(4): F1256 - F1261. [Abstract] [Full Text] [PDF]

				Y. Y. Sautin, T. Nakagawa, S. Zharikov, and R. J. Johnson Adverse effects of the classic antioxidant uric acid in adipocytes: NADPH oxidase-mediated oxidative/nitrosative stress Am J Physiol Cell Physiol, August 1, 2007; 293(2): C584 - C596. [Abstract] [Full Text] [PDF]

				X. Gao, L. Qi, N. Qiao, H. K. Choi, G. Curhan, K. L. Tucker, and A. Ascherio Intake of Added Sugar and Sugar-Sweetened Drink and Serum Uric Acid Concentration in US Men and Women Hypertension, August 1, 2007; 50(2): 306 - 312. [Abstract] [Full Text] [PDF]

				L. G. Sanchez-Lozada, E. Tapia, R. Lopez-Molina, T. Nepomuceno, V. Soto, C. Avila-Casado, T. Nakagawa, R. J. Johnson, J. Herrera-Acosta, and M. Franco Effects of acute and chronic L-arginine treatment in experimental hyperuricemia Am J Physiol Renal Physiol, April 1, 2007; 292(4): F1238 - F1244. [Abstract] [Full Text] [PDF]

				A. A. Ejaz, W. Mu, D.-H. Kang, C. Roncal, Y. Y. Sautin, G. Henderson, I. Tabah-Fisch, B. Keller, T. M. Beaver, T. Nakagawa, et al. Could Uric Acid Have a Role in Acute Renal Failure? Clin. J. Am. Soc. Nephrol., January 1, 2007; 2(1): 16 - 21. [Abstract] [Full Text] [PDF]

				C. A. Roncal, W. Mu, B. Croker, S. Reungjui, X. Ouyang, I. Tabah-Fisch, R. J. Johnson, and A. Ahsan Ejaz Effect of elevated serum uric acid on cisplatin-induced acute renal failure Am J Physiol Renal Physiol, January 1, 2007; 292(1): F116 - F122. [Abstract] [Full Text] [PDF]

				J. P. Forman, H. Choi, and G. C. Curhan Plasma Uric Acid Level and Risk for Incident Hypertension Among Men J. Am. Soc. Nephrol., January 1, 2007; 18(1): 287 - 292. [Abstract] [Full Text] [PDF]

				L. G. Sanchez-Lozada, E. Tapia, A. Jimenez, P. Bautista, M. Cristobal, T. Nepomuceno, V. Soto, C. Avila-Casado, T. Nakagawa, R. J. Johnson, et al. Fructose-induced metabolic syndrome is associated with glomerular hypertension and renal microvascular damage in rats Am J Physiol Renal Physiol, January 1, 2007; 292(1): F423 - F429. [Abstract] [Full Text] [PDF]

				P. Cirillo, W. Sato, S. Reungjui, M. Heinig, M. Gersch, Y. Sautin, T. Nakagawa, and R. J. Johnson Uric Acid, the Metabolic Syndrome, and Renal Disease J. Am. Soc. Nephrol., December 1, 2006; 17(12_suppl_3): S165 - S168. [Abstract] [Full Text] [PDF]

				T. S. Perlstein, O. Gumieniak, G. H. Williams, D. Sparrow, P. S. Vokonas, M. Gaziano, S. T. Weiss, and A. A. Litonjua Uric Acid and the Development of Hypertension: The Normative Aging Study Hypertension, December 1, 2006; 48(6): 1031 - 1036. [Abstract] [Full Text] [PDF]

				P. B. Mellen, A. J. Bleyer, T. P. Erlinger, G. W. Evans, F. J. Nieto, L. E. Wagenknecht, M. R. Wofford, and D. M. Herrington Serum Uric Acid Predicts Incident Hypertension in a Biethnic Cohort: The Atherosclerosis Risk in Communities Study Hypertension, December 1, 2006; 48(6): 1037 - 1042. [Abstract] [Full Text] [PDF]

				D. I. Feig, B. Rodriguez-Iturbe, T. Nakagawa, and R. J. Johnson Nephron Number, Uric Acid, and Renal Microvascular Disease in the Pathogenesis of Essential Hypertension Hypertension, July 1, 2006; 48(1): 25 - 26. [Full Text] [PDF]