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Uric acid in metabolic syndrome: From an innocent bystander to a central player

Published:December 16, 2015DOI:https://doi.org/10.1016/j.ejim.2015.11.026

      Highlights

      • Uric acid is a novel risk factor for obesity, diabetes, and cardiorenal disease.
      • It is still premature to lower uric acid for reducing metabolic and cardiovascular disease.
      • Trials are needed to test if lowering uric acid can be beneficial in the prevention.

      Abstract

      Uric acid, once viewed as an inert metabolic end-product of purine metabolism, has been recently incriminated in a number of chronic disease states, including hypertension, metabolic syndrome, diabetes, non-alcoholic fatty liver disease, and chronic kidney disease. Several experimental and clinical studies support a role for uric acid as a contributory causal factor in these conditions. Here we discuss some of the major mechanisms linking uric acid to metabolic and cardiovascular diseases. At this time the key to understanding the importance of uric acid in these diseases will be the conduct of large clinical trials in which the effect of lowering uric acid on hard clinical outcomes is assessed. Elevated uric acid may turn out to be one of the more important remediable risk factors for metabolic and cardiovascular diseases.

      Keywords

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      References

        • Johnson R.J.
        • Stenvinkel P.
        • Martin S.L.
        • Jani A.
        • Sanchez-Lozada L.G.
        • Hill J.O.
        • et al.
        Redefining metabolic syndrome as a fat storage condition based on studies of comparative physiology.
        Obesity. 2013; 21: 659-664
        • Lanaspa M.A.
        • Cicerchi C.
        • Garcia G.
        • Li N.
        • Roncal-Jimenez C.A.
        • Rivard C.J.
        • et al.
        Counteracting roles of AMP deaminase and AMP kinase in the development of fatty liver.
        PLoS One. 2012; 7: e48801
        • Cicerchi C.
        • Li N.
        • Kratzer J.
        • Garcia G.
        • Roncal-Jimenez C.A.
        • Tanabe K.
        • et al.
        Uric acid-dependent inhibition of AMP kinase induces hepatic glucose production in diabetes and starvation: evolutionary implications of the uricase loss in hominids.
        FASEB J. 2014; 28: 3339-3350
        • Lanaspa M.A.
        • Epperson E.
        • Li N.
        • Cicerchi C.
        • Garcia G.
        • Roncal-Jimenez C.
        • et al.
        Opposing activity changes in AMP deaminase and AMP-activated protein kinase in the hibernating ground squirrel.
        PLoS One. 2015; 10e0123509
        • Lanaspa M.A.
        • Sanchez-Lozada L.G.
        • Choi Y.J.
        • Cicerchi C.
        • Kanbay M.
        • Roncal-Jimenez C.A.
        • 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
        • Choi Y.J.
        • Shin H.S.
        • Choi H.S.
        • Park J.W.
        • Jo I.
        • Oh E.S.
        • et al.
        Uric acid induces fat accumulation via generation of endoplasmic reticulum stress and SREBP-1c activation in hepatocytes.
        Lab Invest. 2014; 94: 1114-1125
        • Mahomed F.A.
        The etiology of Bright's disease and the prealbuminuric state.
        Med Chir Trans. 1874; 39: 197-228
        • Haig A.
        The connecting link between the high tension pulse and albuminuria.
        Br Med J. 1890; 1: 65-68
        • Davis N.C.
        The cardiovascular and renal relations and manifestations of gout.
        JAMA. 1897; 29: 261-262
        • Cannon P.J.
        • Stason W.B.
        • Demartini F.E.
        • Sommers S.C.
        • Laragh J.H.
        Hyperuricemia in primary and renal hypertension.
        N Engl J Med. 1966; 275: 457-464
        • Feig D.I.
        • Johnson R.J.
        Hyperuricemia in childhood primary hypertension.
        Hypertension. 2003; 42: 247-252
        • Johnson R.J.
        • Titte S.
        • Cade J.R.
        • Rideout B.A.
        • Oliver W.J.
        Uric acid, evolution and primitive cultures.
        Semin Nephrol. 2005; 25: 3-8
        • Mazzali M.
        • Hughes J.
        • Kim Y.G.
        • Jefferson J.A.
        • Kang D.H.
        • Gordon K.L.
        • et al.
        Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism.
        Hypertension. 2001; 38: 1101-1106
        • DeBosch B.J.
        • Kluth O.
        • Fujiwara H.
        • Schurmann A.
        • Moley K.
        Early-onset metabolic syndrome in mice lacking the intestinal uric acid transporter SLC2A9.
        Nat Commun. 2014; 5: 4642
        • Sanchez-Lozada L.G.
        • Nakagawa T.
        • Kang D.H.
        • Feig D.I.
        • Franco M.
        • Johnson R.J.
        • et al.
        Hormonal and cytokine effects of uric acid.
        Curr Opin Nephrol Hypertens. 2006; 15: 30-33
        • Baldwin W.
        • McRae S.
        • Marek G.
        • Wymer D.
        • Pannu V.
        • Baylis C.
        • et al.
        Hyperuricemia as a mediator of the proinflammatory endocrine imbalance in the adipose tissue in a murine model of the metabolic syndrome.
        Diabetes. 2011; 60: 1258-1269
        • Watanabe S.
        • Kang D.H.
        • Feng L.
        • Nakagawa T.
        • Kanellis J.
        • Lan H.
        • et al.
        Uric acid, hominoid evolution, and the pathogenesis of salt-sensitivity.
        Hypertension. 2002; 40: 355-360
        • Soletsky B.
        • Feig D.I.
        Uric acid reduction rectifies prehypertension in obese adolescents.
        Hypertension. 2012; 60: 1148-1156
        • Feig D.I.
        • Soletsky B.
        • Johnson R.J.
        Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension: a randomized trial.
        JAMA. 2008; 300: 924-932
        • Assadi F.
        Allopurinol enhances the blood pressure lowering effect of enalapril in children with hyperuricemic essential hypertension.
        J Nephrol. 2014; 27: 51-56
        • Kanbay M.
        • Huddam B.
        • Azak A.
        • Solak Y.
        • Kadioglu G.K.
        • Kirbas I.
        • et al.
        A randomized study of allopurinol on endothelial function and estimated glomerular filtration rate in asymptomatic hyperuricemic subjects with normal renal function.
        Clin J Am Soc Nephrol. 2011; 6: 1887-1894
        • Kanbay M.
        • Ozkara A.
        • Selcoki Y.
        • Isik B.
        • Turgut F.
        • Bavbek N.
        • et al.
        Effect of treatment of hyperuricemia with allopurinol on blood pressure, creatinine clearance, and proteinuria in patients with normal renal functions.
        Int Urol Nephrol. 2007; 39: 1227-1233
        • Higgins P.
        • Walters M.R.
        • Murray H.M.
        • McArthur K.
        • McConnachie A.
        • Lees K.R.
        • et al.
        Allopurinol reduces brachial and central blood pressure, and carotid intima-media thickness progression after ischaemic stroke and transient ischaemic attack: a randomised controlled trial.
        Heart. 2014; 100: 1085-1092
        • Beattie C.J.
        • Fulton R.L.
        • Higgins P.
        • Padmanabhan S.
        • McCallum L.
        • Walters M.R.
        • et al.
        Allopurinol initiation and change in blood pressure in older adults with hypertension.
        Hypertension. 2014; 64: 1102-1107
        • Kim H.A.
        • Seo Y.I.
        • Song Y.W.
        Four-week effects of allopurinol and febuxostat treatments on blood pressure and serum creatinine level in gouty men.
        J Korean Med Sci. 2014; 29: 1077-1081
        • Madero M.
        • Rodriguez Castellanos F.E.
        • Jalal D.
        • Villalobos-Martin M.
        • Salazar J.
        • Vazquez-Rangel A.
        • et al.
        A pilot study on the impact of a low fructose diet and allopurinol on clinic blood pressure among overweight and prehypertensive subjects: a randomized placebo controlled trial.
        J Am Soc Hypertens. 2015; 9: 837-844
        • Pai B.H.
        • Swarnalatha G.
        • Ram R.
        • Dakshinamurty K.V.
        Allopurinol for prevention of progression of kidney disease with hyperuricemia.
        Indian J Nephrol. 2013; 23: 280-286
        • Jalalzadeh M.
        • Nurcheshmeh Z.
        • Mohammadi R.
        • Mousavinasab N.
        • Ghadiani M.H.
        The effect of allopurinol on lowering blood pressure in hemodialysis patients with hyperuricemia.
        J Res Med Sci. 2012; 17: 1039-1046
        • Goicoechea M.
        • de Vinuesa S.G.
        • Verdalles U.
        • Ruiz-Caro C.
        • Ampuero J.
        • Rincon A.
        • et al.
        Effect of allopurinol in chronic kidney disease progression and cardiovascular risk.
        Clin J Am Soc Nephrol. 2010; 5: 1388-1393
        • Khosla U.M.
        • Zharikov S.
        • Finch J.L.
        • Nakagawa T.
        • Roncal C.
        • Mu W.
        • et al.
        Hyperuricemia induces endothelial dysfunction.
        Kidney Int. 2005; 67: 1739-1742
        • Gersch C.
        • Palii S.P.
        • Kim K.M.
        • Angerhofer A.
        • Johnson R.J.
        • Henderson G.N.
        Inactivation of nitric oxide by uric acid.
        Nucleosides Nucleotides Nucleic Acids. 2008; 27: 967-978
        • Zharikov S.
        • Krotova K.
        • Hu H.
        • Baylis C.
        • Johnson R.J.
        • Block E.R.
        • et al.
        Uric acid decreases NO production and increases arginase activity in cultured pulmonary artery endothelial cells.
        Am J Physiol Cell Physiol. 2008; 295: C1183-C1190
        • Schwartz I.F.
        • Grupper A.
        • Chernichovski T.
        • Hillel O.
        • Engel A.
        • Schwartz D.
        Hyperuricemia attenuates aortic nitric oxide generation, through inhibition of arginine transport, in rats.
        J Vasc Res. 2011; 48: 252-260
        • Sanchez-Lozada L.G.
        • Lanaspa M.A.
        • Cristobal-Garcia M.
        • Garcia-Arroyo F.
        • Soto V.
        • Cruz-Robles D.
        • et al.
        Uric acid-induced endothelial dysfunction is associated with mitochondrial alterations and decreased intracellular ATP concentrations.
        Nephron Exp Nephrol. 2012; 121: e71-e78
        • Sanchez-Lozada L.G.
        • Tapia E.
        • Lopez-Molina R.
        • Nepomuceno T.
        • Soto V.
        • Avila-Casado C.
        • et al.
        Effects of acute and chronic L-arginine treatment in experimental hyperuricemia.
        Am J Physiol Renal Physiol. 2007; 292: F1238-F1244
        • Mazzali M.
        • Kanellis J.
        • Han L.
        • Feng L.
        • Xia Y.Y.
        • Chen Q.
        • et al.
        Hyperuricemia induces a primary renal arteriolopathy in rats by a blood pressure-independent mechanism.
        Am J Physiol Renal Physiol. 2002; 282: F991-F997
        • Chao H.H.
        • Liu J.C.
        • Lin J.W.
        • Chen C.H.
        • Wu C.H.
        • Cheng T.H.
        Uric acid stimulates endothelin-1 gene expression associated with NADPH oxidase in human aortic smooth muscle cells.
        Acta Pharmacol Sin. 2008; 29: 1301-1312
        • Cheng T.H.
        • Lin J.W.
        • Chao H.H.
        • Chen Y.L.
        • Chen C.H.
        • Chan P.
        • et al.
        Uric acid activates extracellular signal-regulated kinases and thereafter endothelin-1 expression in rat cardiac fibroblasts.
        Int J Cardiol. 2010; 139: 42-49
        • Kang D.H.
        • Park S.K.
        • Lee I.K.
        • Johnson R.J.
        Uric acid-induced C-reactive protein expression: implication on cell proliferation and nitric oxide production of human vascular cells.
        J Am Soc Nephrol. 2005; 16: 3553-3562
        • Yu M.A.
        • Sanchez-Lozada L.G.
        • Johnson R.J.
        • Kang D.H.
        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. 2010; 28: 1234-1242
        • Sautin Y.Y.
        • Nakagawa T.
        • Zharikov S.
        • Johnson R.J.
        Adverse effects of the classic antioxidant uric acid in adipocytes: NADPH oxidase-mediated oxidative/nitrosative stress.
        Am J Physiol Cell Physiol. 2007; 293: C584-C596
        • Corry D.B.
        • Eslami P.
        • Yamamoto K.
        • Nyby M.D.
        • Makino H.
        • Tuck M.L.
        Uric acid stimulates vascular smooth muscle cell proliferation and oxidative stress via the vascular renin–angiotensin system.
        J Hypertens. 2008; 26: 269-275
        • Sanchez-Lozada L.G.
        • Rivard C.
        • Lanaspa M.
        • Roncal C.
        • Franco M.
        • Sautin Y.
        • et al.
        Uric acid alters mitochondrial biogenesis in cultured human endothelial cells.
        Am Soc Nephrol Annual Meeting. 2009 (abstract)
        • Sanchez-Lozada L.G.
        • Soto V.
        • Tapia E.
        • Avila-Casado C.
        • Sautin Y.Y.
        • Nakagawa T.
        • et al.
        Role of oxidative stress in the renal abnormalities induced by experimental hyperuricemia.
        Am J Physiol Renal Physiol. 2008; 295: F1134-F1141
        • Rao G.N.
        • Corson M.A.
        • Berk B.C.
        Uric acid stimulates vascular smooth muscle cell proliferation by increasing platelet-derived growth factor A-chain expression.
        J Biol Chem. 1991; 266: 8604-8608
        • Kanellis J.
        • Watanabe S.
        • Li J.H.
        • Kang D.H.
        • Li P.
        • Nakagawa T.
        • et al.
        Uric acid stimulates monocyte chemoattractant protein-1 production in vascular smooth muscle cells via mitogen-activated protein kinase and cyclooxygenase-2.
        Hypertension. 2003; 41: 1287-1293
        • Duckworth D.
        A treatise on gout.
        C Griffin & Co, London1889 (476 pp.)
        • Kylin E.
        Studien uber das hypertonie–hyperglykamie–hyperurikamiesyndrome.
        Zbl inn Med. 1923; 44: 105-127
        • Johnson R.J.
        • Nakagawa T.
        • Sanchez-Lozada L.G.
        • Shafiu M.
        • Sundaram S.
        • Le M.
        • et al.
        Sugar, uric acid, and the etiology of diabetes and obesity.
        Diabetes. 2013; 62: 3307-3315
        • Facchini F.
        • Chen Y.D.
        • Hollenbeck C.B.
        • Reaven G.M.
        Relationship between resistance to insulin-mediated glucose uptake, urinary uric acid clearance, and plasma uric acid concentration.
        JAMA. 1991; 266: 3008-3011
        • Krishnan E.
        • Pandya B.J.
        • Chung L.
        • Hariri A.
        • Dabbous O.
        Hyperuricemia in young adults and risk of insulin resistance, prediabetes, and diabetes: a 15-year follow-up study.
        Am J Epidemiol. 2012; 176: 108-116
        • Cook S.
        • Hugli O.
        • Egli M.
        • Vollenweider P.
        • Burcelin R.
        • Nicod P.
        • et al.
        Clustering of cardiovascular risk factors mimicking the human metabolic syndrome X in eNOS null mice.
        Swiss Med Wkly. 2003; 133: 360-363
        • Roncal-Jimenez C.A.
        • Lanaspa M.A.
        • Rivard C.J.
        • Nakagawa T.
        • Sanchez-Lozada L.G.
        • Jalal D.
        • et al.
        Sucrose induces fatty liver and pancreatic inflammation in male breeder rats independent of excess energy intake.
        Metab Clin Exp. 2011; 60: 1259-1270
        • Scott F.W.
        • Trick K.D.
        • Stavric B.
        • Braaten J.T.
        • Siddiqui Y.
        Uric acid-induced decrease in rat insulin secretion.
        Proc Soc Exp Biol Med. 1981; 166: 123-128
        • Ogino K.
        • Kato M.
        • Furuse Y.
        • Kinugasa Y.
        • Ishida K.
        • Osaki S.
        • et al.
        Uric acid-lowering treatment with benzbromarone in patients with heart failure: a double-blind placebo-controlled crossover preliminary study.
        Circ Heart Fail. 2010; 3: 73-81
        • Facchini C.
        • Malfatto G.
        • Giglio A.
        • Facchini M.
        • Parati G.
        • Branzi G.
        Lung ultrasound and transthoracic impedance for noninvasive evaluation of pulmonary congestion in heart failure.
        J Cardiovasc Med. 2015; (in press)
        • Dogan A.
        • Yarlioglues M.
        • Kaya M.G.
        • Karadag Z.
        • Dogan S.
        • Ardic I.
        • et al.
        Effect of long-term and high-dose allopurinol therapy on endothelial function in normotensive diabetic patients.
        Blood Press. 2011; 20: 182-187
        • Pfister R.
        • Barnes D.
        • Luben R.
        • Forouhi N.G.
        • Bochud M.
        • Khaw K.T.
        • et al.
        No evidence for a causal link between uric acid and type 2 diabetes: a Mendelian randomisation approach.
        Diabetologia. 2011; 54: 2561-2569
        • Yang Q.
        • Kottgen A.
        • Dehghan A.
        • Smith A.V.
        • Glazer N.L.
        • Chen M.H.
        • et al.
        Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors.
        Circ Cardiovasc Genet. 2010; 3: 523-530
        • Johnson R.J.
        • Merriman T.
        • Lanaspa M.A.
        Causal or noncausal relationship of uric acid with diabetes.
        Diabetes. 2015; 64: 2720-2722
        • Masuo K.
        • Kawaguchi H.
        • Mikami H.
        • Ogihara T.
        • Tuck M.L.
        Serum uric acid and plasma norepinephrine concentrations predict subsequent weight gain and blood pressure elevation.
        Hypertension. 2003; 42: 474-480
        • Sirota J.C.
        • McFann K.
        • Targher G.
        • Johnson R.J.
        • Chonchol M.
        • Jalal D.I.
        Elevated serum uric acid levels are associated with non-alcoholic fatty liver disease independently of metabolic syndrome features in the United States: liver ultrasound data from the National Health and Nutrition Examination Survey.
        Metab Clin Exp. 2013; 62: 392-399
        • Lee J.W.
        • Cho Y.K.
        • Ryan M.
        • Kim H.
        • Lee S.W.
        • Chang E.
        • et al.
        Serum uric acid as a predictor for the development of nonalcoholic fatty liver disease in apparently healthy subjects: a 5-year retrospective cohort study.
        Gut Liver. 2010; 4: 378-383
        • Lonardo A.
        • Loria P.
        • Leonardi F.
        • Borsatti A.
        • Neri P.
        • Pulvirenti M.
        • et al.
        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. 2002; 34: 204-211
        • Petta S.
        • Camma C.
        • Cabibi D.
        • Di Marco V.
        • Craxi A.
        Hyperuricemia is associated with histological liver damage in patients with non-alcoholic fatty liver disease.
        Aliment Pharmacol Ther. 2011; 34: 757-766
        • Ryu S.
        • Chang Y.
        • Kim S.G.
        • Cho J.
        • Guallar E.
        Serum uric acid levels predict incident nonalcoholic fatty liver disease in healthy Korean men.
        Metab Clin Exp. 2011; 60: 860-866
        • Xu C.
        • Yu C.
        • Xu L.
        • Miao M.
        • Li Y.
        High serum uric acid increases the risk for nonalcoholic fatty liver disease: a prospective observational study.
        PLoS One. 2010; 5: e11578
        • Tapia E.
        • Cristobal M.
        • Garcia-Arroyo F.E.
        • Soto V.
        • Monroy-Sanchez F.
        • Pacheco U.
        • et al.
        Synergistic effect of uricase blockade plus physiological amounts of fructose–glucose on glomerular hypertension and oxidative stress in rats.
        Am J Physiol Renal Physiol. 2013; 304: F727-F736
        • Choi Y.J.
        • Shin H.S.
        • Choi H.S.
        • Park J.W.
        • Jo I.
        • Oh E.S.
        • et al.
        Uric acid induces fat accumulation via generation of endoplasmic reticulum stress and SREBP-1c activation in hepatocytes.
        Lab Investig. 2014; 94: 1114-1125
        • Lanaspa M.A.
        • Sanchez-Lozada L.G.
        • Cicerchi C.
        • Li N.
        • Roncal-Jimenez C.A.
        • Ishimoto T.
        • et al.
        Uric acid stimulates fructokinase and accelerates fructose metabolism in the development of fatty liver.
        PLoS One. 2012; 7: e47948
        • Kono H.
        • Rusyn I.
        • Bradford B.U.
        • Connor H.D.
        • Mason R.P.
        • Thurman R.G.
        Allopurinol prevents early alcohol-induced liver injury in rats.
        J Pharmacol Exp Ther. 2000; 293: 296-303
        • Choi H.K.
        • Atkinson K.
        • Karlson E.W.
        • Willett W.
        • Curhan G.
        Purine-rich foods, dairy and protein intake, and the risk of gout in men.
        N Engl J Med. 2004; 350: 1093-1103
        • Johnson R.J.
        • Nakagawa T.
        • Sanchez-Lozada L.G.
        • Lanaspa M.A.
        • Tamura Y.
        • Tanabe K.
        • et al.
        Umami: the taste that drives purine intake.
        J Rheumatol. 2013; 40: 1794-1796
        • Ogryzlo M.A.
        Hyperuricemia induced by high fat diets and starvation.
        Arthritis Rheum. 1965; 8: 799-822
        • Johnson R.J.
        • Segal M.S.
        • Sautin Y.
        • Nakagawa T.
        • Feig D.I.
        • Kang D.H.
        • et al.
        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. 2007; 86: 899-906
        • Malik V.S.
        • Pan A.
        • Willett W.C.
        • Hu F.B.
        Sugar-sweetened beverages and weight gain in children and adults: a systematic review and meta-analysis.
        Am J Clin Nutr. 2013; 98 (1084–102)
        • Malik V.S.
        • Popkin B.M.
        • Bray G.A.
        • Despres J.P.
        • Willett W.C.
        • Hu F.B.
        Sugar-sweetened beverages and risk of metabolic syndrome and type 2 diabetes: a meta-analysis.
        Diabetes Care. 2010; 33: 2477-2483
        • Basu S.
        • Yoffe P.
        • Hills N.
        • Lustig R.H.
        The relationship of sugar to population-level diabetes prevalence: an econometric analysis of repeated cross-sectional data.
        PLoS One. 2013; 8: e57873
        • Ishimoto T.
        • Lanaspa M.A.
        • Le M.T.
        • Garcia G.E.
        • Diggle C.P.
        • Maclean P.S.
        • et al.
        Opposing effects of fructokinase C and A isoforms on fructose-induced metabolic syndrome in mice.
        Proc Natl Acad Sci U S A. 2012; 109: 4320-4325
        • Ishimoto T.
        • Lanaspa M.A.
        • Rivard C.J.
        • Roncal-Jimenez C.A.
        • Orlicky D.J.
        • Cicerchi C.
        • et al.
        High-fat and high-sucrose (western) diet induces steatohepatitis that is dependent on fructokinase.
        Hepatology. 2013; 58: 1632-1643
        • Lanaspa M.A.
        • Ishimoto T.
        • Li N.
        • Cicerchi C.
        • Orlicky D.J.
        • Ruzicky P.
        • et al.
        Endogenous fructose production and metabolism in the liver contributes to the development of metabolic syndrome.
        Nat Commun. 2013; 4: 2434
        • Sanchez-Lozada L.G.
        • Tapia E.
        • Bautista-Garcia P.
        • Soto V.
        • Avila-Casado C.
        • Vega-Campos I.P.
        • et al.
        Effects of febuxostat on metabolic and renal alterations in rats with fructose-induced metabolic syndrome.
        Am J Physiol Renal Physiol. 2008; 294: F710-F718
        • Cox C.L.
        • Stanhope K.L.
        • Schwarz J.M.
        • Graham J.L.
        • Hatcher B.
        • Griffen S.C.
        • et al.
        Consumption of fructose-sweetened beverages for 10 weeks reduces net fat oxidation and energy expenditure in overweight/obese men and women.
        Eur J Clin Nutr. 2012; 66: 201-208
        • Cox C.L.
        • Stanhope K.L.
        • Schwarz J.M.
        • Graham J.L.
        • Hatcher B.
        • Griffen S.C.
        • 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
        • Stanhope K.L.
        • Bremer A.A.
        • Medici V.
        • Nakajima K.
        • Ito Y.
        • Nakano T.
        • et al.
        Consumption of fructose and high fructose corn syrup increase postprandial triglycerides, LDL-cholesterol, and apolipoprotein-B in young men and women.
        J Clin Endocrinol Metab. 2011; 96: E1596-E1605
        • Stanhope K.L.
        • Griffen S.C.
        • Keim N.L.
        • Ai M.
        • Otokozawa S.
        • Nakajima K.
        • et al.
        Consumption of fructose-, but not glucose-sweetened beverages produces an atherogenic lipid profile in overweight/obese men and women.
        Diabetes. 2007; 56 (abstr): A16
        • Stanhope K.L.
        • Schwarz J.M.
        • Keim N.L.
        • Griffen S.C.
        • Bremer A.A.
        • Graham J.L.
        • 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
        • Swarbrick M.M.
        • Stanhope K.L.
        • Elliott S.S.
        • Graham J.L.
        • Krauss R.M.
        • Christiansen M.P.
        • et al.
        Consumption of fructose-sweetened beverages for 10 weeks increases postprandial triacylglycerol and apolipoprotein-B concentrations in overweight and obese women.
        Br J Nutr. 2008; : 1-6
        • Perez-Pozo S.E.
        • Schold J.
        • Nakagawa T.
        • Sanchez-Lozada L.G.
        • Johnson R.J.
        • Lillo J.L.
        Excessive fructose intake induces the features of metabolic syndrome in healthy adult men: role of uric acid in the hypertensive response.
        Int J Obes (Lond). 2010; 34: 454-461
        • Kahn K.
        • Serfozo P.
        • Tipton P.A.
        Identification of the true product of the urate oxidase reaction.
        J Am Chem Soc. 1997; 119: 5435-5442
        • Kratzer J.T.
        • Lanaspa M.A.
        • Murphy M.N.
        • Cicerchi C.
        • Graves C.L.
        • Tipton P.A.
        • et al.
        Evolutionary history and metabolic insights of ancient mammalian uricases.
        Proc Natl Acad Sci U S A. 2014; 111: 3763-3768
        • Johnson R.J.
        • Andrews P.
        Fructose, uricase, and the back-to-Africa hypothesis.
        Evol Anthropol. 2010; 19: 250-257
        • Johnson R.J.
        • Andrews P.
        The fat gene: a genetic mutation in prehistoric apes may underlie today's pandemic of obesity and diabetes.
        Sci Am. 2015; 313: 64-69
        • Ames B.N.
        • Cathcart R.
        • Schwiers E.
        • Hochstein P.
        Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis.
        Proc Natl Acad Sci U S A. 1981; 78: 6858-6862
        • Sutin A.R.
        • Cutler R.G.
        • Camandola S.
        • Uda M.
        • Feldman N.H.
        • Cucca F.
        • et al.
        Impulsivity is associated with uric acid: evidence from humans and mice.
        Biol Psychiatry. 2014; 75: 31-37
        • Gosling A.L.
        • Matisoo-Smith E.
        • Merriman T.R.
        Gout in Maori.
        Rheumatology (Oxford). 2014; 53: 773-774
        • Johnson R.J.
        • Lanaspa M.A.
        • Sanchez-Lozada L.G.
        • Rivard C.J.
        • Rodriguez-Iturbe B.
        • Merriman T.R.
        • et al.
        Fat storage syndrome in Pacific peoples: a combination of environment and genetics?.
        Public Health Dialog. 2014; 20: 11-16
        • Gertler M.M.
        • Garn S.M.
        • Levine S.A.
        Serum uric acid in relation to age and physique in health and in coronary heart disease.
        Ann Intern Med. 1951; 34: 1421-1431
        • Culleton B.F.
        • Larson M.G.
        • Kannel W.B.
        • Levy D.
        Serum uric acid and risk for cardiovascular disease and death: the Framingham Heart Study.
        Ann Intern Med. 1999; 131: 7-13
        • Vaccarino V.
        • Krumholz H.M.
        Risk factors for cardiovascular disease: one down, many more to evaluate.
        Ann Intern Med. 1999; 131: 62-63
        • Johnson R.J.
        • Kivlighn S.D.
        • Kim Y.G.
        • Suga S.
        • Fogo A.B.
        Reappraisal of the pathogenesis and consequences of hyperuricemia in hypertension, cardiovascular disease, and renal disease.
        Am J Kidney Dis. 1999; 33: 225-234
        • Johnson R.J.
        • Tuttle K.R.
        Much ado about nothing, or much to do about something? The continuing controversy over the role of uric acid in cardiovascular disease.
        Hypertension. 2000; 35: E10
        • Noman A.
        • Ang D.S.
        • Ogston S.
        • Lang C.C.
        • Struthers A.D.
        Effect of high-dose allopurinol on exercise in patients with chronic stable angina: a randomised, placebo controlled crossover trial.
        Lancet. 2010; 375: 2161-2167
        • Kao M.P.
        • Ang D.S.
        • Gandy S.J.
        • Nadir M.A.
        • Houston J.G.
        • Lang C.C.
        • et al.
        Allopurinol benefits left ventricular mass and endothelial dysfunction in chronic kidney disease.
        J Am Soc Nephrol. 2011; 22: 1382-1389
        • Grimaldi-Bensouda L.
        • Alperovitch A.
        • Aubrun E.
        • Danchin N.
        • Rossignol M.
        • Abenhaim L.
        • et al.
        Impact of allopurinol on risk of myocardial infarction.
        Ann Rheum Dis. 2015; 74: 836-842
        • Goicoechea M.
        • Garcia de Vinuesa S.
        • Verdalles U.
        • Verde E.
        • Macias N.
        • Santos A.
        • et al.
        Allopurinol and progression of CKD and cardiovascular events: long-term Follow-up of a randomized clinical trial.
        Am J Kidney Dis. 2015; 65: 543-549
        • Hoieggen A.
        • Alderman M.H.
        • Kjeldsen S.E.
        • Julius S.
        • Devereux R.B.
        • De Faire U.
        • et al.
        The impact of serum uric acid on cardiovascular outcomes in the LIFE study.
        Kidney Int. 2004; 65: 1041-1049
        • Terawaki H.
        • Nakayama M.
        • Miyazawa E.
        • Murata Y.
        • Nakayama K.
        • Matsushima M.
        • et al.
        Effect of allopurinol on cardiovascular incidence among hypertensive nephropathy patients: the Gonryo study.
        Clin Exp Nephrol. 2013; 17: 549-553
        • Waring W.S.
        • Convery A.
        • Mishra V.
        • Shenkin A.
        • Webb D.J.
        • Maxwell S.R.
        Uric acid reduces exercise-induced oxidative stress in healthy adults.
        Clin Sci. 2003; 105: 425-430
        • Gersch C.
        • Palii S.P.
        • Imaram W.
        • Kim K.M.
        • Karumanchi S.A.
        • Angerhofer A.
        • et al.
        Reactions of peroxynitrite with uric acid: formation of reactive intermediates, alkylated products and triuret, and in vivo production of triuret under conditions of oxidative stress.
        Nucleosides Nucleotides Nucleic Acids. 2009; 28: 118-149
        • Imaram W.
        • Gersch C.
        • Kim K.M.
        • Johnson R.J.
        • Henderson G.N.
        • Angerhofer A.
        Radicals in the reaction between peroxynitrite and uric acid identified by electron spin resonance spectroscopy and liquid chromatography mass spectrometry.
        Free Radic Biol Med. 2010; 49: 275-281
        • Reyes A.J.
        • Leary W.P.
        The ALLHAT and the cardioprotection conferred by diuretics in hypertensive patients: a connection with uric acid?.
        Cardiovasc Drugs Ther. 2002; 16: 485-487
        • Reungjui S.
        • Roncal C.A.
        • Mu W.
        • Srinivas T.R.
        • Sirivongs D.
        • Johnson R.J.
        • et al.
        Thiazide diuretics exacerbate fructose-induced metabolic syndrome.
        J Am Soc Nephrol. 2007; 18: 2724-2731
        • George J.
        • Carr E.
        • Davies J.
        • Belch J.J.
        • Struthers A.
        High-dose allopurinol improves endothelial function by profoundly reducing vascular oxidative stress and not by lowering uric acid.
        Circulation. 2006; 114: 2508-2516
        • Parsa A.
        • Brown E.
        • Weir M.R.
        • Fink J.C.
        • Shuldiner A.R.
        • Mitchell B.D.
        • et al.
        Genotype-based changes in serum uric acid affect blood pressure.
        Kidney Int. 2012; 81: 502-507
        • Mallamaci F.
        • Testa A.
        • Leonardis D.
        • Tripepi R.
        • Pisano A.
        • Spoto B.
        • et al.
        A polymorphism in the major gene regulating serum uric acid associates with clinic SBP and the white-coat effect in a family-based study.
        J Hypertens. 2014; 32: 1621-1628
        • Preitner F.
        • Pimentel A.
        • Metref S.
        • Berthonneche C.
        • Sarre A.
        • Moret C.
        • et al.
        No development of hypertension in the hyperuricemic liver-Glut9 knockout mouse.
        Kidney Int. 2015; 87: 940-947