The role of xanthine oxidoreductase and uric acid in metabolic syndrome

Abstract

Xanthine oxidoreductase (XOR) could contribute to the pathogenesis of metabolic syndrome through the oxidative stress and the inflammatory response induced by XOR-derived reactive oxygen species and uric acid. Hyperuricemia is strongly linked to hypertension, insulin resistance, obesity and hypertriglyceridemia. The serum level of XOR is correlated to triglyceride/high density lipoprotein cholesterol ratio, fasting glycemia, fasting insulinemia and insulin resistance index. Increased activity of endothelium-linked XOR may promote hypertension. In addition, XOR is implicated in pre-adipocyte differentiation and adipogenesis. XOR and uric acid play a role in cell transformation and proliferation as well as in the progression and metastatic process. Collected evidences confirm the contribution of XOR and uric acid in metabolic syndrome. However, in some circumstances XOR and uric acid may have anti-oxidant protective outcomes. The dual-face role of both XOR and uric acid explains the contradictory results obtained with XOR inhibitors and suggests caution in their therapeutic use.

Hepatocyte-Specific Ablation or Whole-Body Inhibition of Xanthine Oxidoreductase in Mice Corrects Obesity-Induced Systemic Hyperuricemia Without Improving Metabolic Abnormalities

“…Obesity is associated with substantial increases in blood UA and XOR activity (1,2). To address the effects of hepatocyte deletion of Xdh on this phenotype, HXO and FLX mice were exposed to an obesogenic diet for 26 weeks.…”

Effects of Phenolic Compounds Extracted From Salvia Frigida on Induced Hyperuricemia in Mice

“…Furthermore, the pro-inflammatory action of UA may induce cell transformation through reactive oxygen species (ROS) and reactive nitrogen species (RNS) generation. Besides, intracellular UA may contribute to decreasing the level of XOD expression [26]. Moreover, UA can actually inhibit XOD and thereby act as a feedback inhibitor of the enzyme; this effect is associated with increased ROS formation [21].…”

“…Hyperuricemia causes uncoupling of endothelial NO synthase which increases superoxide radical production [25]. UA-derived free radicals have been associated with several effects such as reduced availability of NO, cyclooxygenase-2 expression and up-regulation of the renin/ angiotensin pathway, platelet activation, migration and proliferation of vascular myocytes, and production of pro-inflammatory cytokines by macrophages [26].…”

“…XOD pathway is an important path in the oxidative damage to tissues. The UA conversion from hypoxanthine and xanthine by XOD is accompanied by the generation of superoxide anion and hydrogen peroxide and eventually give rise to hydroxyl radical through the Haber-Weiss and Fenton reactions in the presence of transition metals [4,26,[30][31][32]. These cytotoxic ROS are highly reactive and can directly oxidize macromolecules including DNA, protein, and lipids [30,31] which may result in cellular damage when produced in large amounts [32].…”

“…These cytotoxic ROS are highly reactive and can directly oxidize macromolecules including DNA, protein, and lipids [30,31] which may result in cellular damage when produced in large amounts [32]. Furthermore, XOD activities may produce RNS, although other enzymes are implicated in the generation of these [26] as with highly reactive peroxynitrite (OONO-) [33,34]. Accordingly, in this study, lipid peroxidation mediated by ROS and RNS has probably caused cell membrane damage leading to the release of XOD into the serum.…”