Fructose Intake, Serum Uric Acid, and Cardiometabolic Disorders: A Critical Review

Abstract

There is a direct relationship between fructose intake and serum levels of uric acid (UA), which is the final product of purine metabolism. Recent preclinical and clinical evidence suggests that chronic hyperuricemia is an independent risk factor for hypertension, metabolic syndrome, and cardiovascular disease. It is probably also an independent risk factor for chronic kidney disease, Type 2 diabetes, and cognitive decline. These relationships have been observed for high serum UA levels (>5.5 mg/dL in women and >6 mg/dL in men), but also for normal to high serum UA levels (5-6 mg/dL). In this regard, blood UA levels are much higher in industrialized countries than in the rest of the world. Xanthine-oxidase inhibitors can reduce UA and seem to minimize its negative effects on vascular health. Other dietary and pathophysiological factors are also related to UA production. However, the role of fructose-derived UA in the pathogenesis of cardiometabolic disorders has not yet been fully clarified. Here, we critically review recent research on the biochemistry of UA production, the relationship between fructose intake and UA production, and how this relationship is linked to cardiometabolic disorders.

Keywords: cardiometabolic disorders; epidemiology; fructose; pathophysiology; uric acid; xanthine oxidase.

Figure 1

Uric acid formation through xanthine oxidase activity. (A) Under ischemic or inflammatory conditions, xanthine dehydrogenase (XDH) is converted to xanthine oxidase (XO) via the oxidation of sulfhydryl residues or proteolysis of XDH. In the presence of oxygen, XO catalyses the oxidation of hypoxanthine to xanthine and then to uric acid (UA), with consequent production of the superoxide anion (O₂⁻) and hydrogen peroxide (H₂O₂). The competitive antagonist allopurinol is converted in the active form, oxypurinol, via XO activity, acting as an XO inhibitor; (B) During hypoxanthine conversion to xanthine and then UA, high levels of H₂O₂ and O₂⁻ are produced and converted to O₂ and H₂O₂, spontaneously or in a reaction catalyzed by the enzyme superoxide dismutase (SOD).

Figure 2

Fructose-induced uric acid formation: risk factor biomarkers. In hepatocytes, fructokinase catalyzes the rapid phosphorylation of fructose to fructose-1-phosphate, using ATP as a phosphate donor. Intracellular phosphate (Pi) levels decrease, stimulating the activity of AMP deaminase (AMPD). AMPD converts AMP to inosine monophosphate (IMP). IMP is metabolized to inosine, which is further degraded to xanthine and hypoxanthine by xanthine oxidase (XO), ultimately generating uric acid (UA). UA can react with nitric oxide (NO), reducing NO bioavailability and inducing dinucleotide phosphate oxidase (NOX) activation and mitochondrial dysfunction. In turn, this promotes oxidative stress and endothelial dysfunction. Fructose per se can also induce oxidative stress.