Role of Uric Acid Metabolism-Related Inflammation in the Pathogenesis of Metabolic Syndrome Components Such as Atherosclerosis and Nonalcoholic Steatohepatitis

Abstract

Uric acid (UA) is the end product of purine metabolism and can reportedly act as an antioxidant. However, recently, numerous clinical and basic research approaches have revealed close associations of hyperuricemia with several disorders, particularly those comprising the metabolic syndrome. In this review, we first outline the two molecular mechanisms underlying inflammation occurrence in relation to UA metabolism; one is inflammasome activation by UA crystallization and the other involves superoxide free radicals generated by xanthine oxidase (XO). Importantly, recent studies have demonstrated the therapeutic or preventive effects of XO inhibitors against atherosclerosis and nonalcoholic steatohepatitis, which were not previously considered to be related, at least not directly, to hyperuricemia. Such beneficial effects of XO inhibitors have been reported for other organs including the kidneys and the heart. Thus, a major portion of this review focuses on the relationships between UA metabolism and the development of atherosclerosis, nonalcoholic steatohepatitis, and related disorders. Although further studies are necessary, XO inhibitors are a potentially novel strategy for reducing the risk of many forms of organ failure characteristic of the metabolic syndrome.

New Perspectives in Rheumatology: Implications of the Cardiovascular Safety of Febuxostat and Allopurinol in Patients With Gout and Cardiovascular Morbidities Trial and the Associated Food and Drug Administration Public Safety Alert

“…Questions regarding the biologic plausibility of the CARES trial results. Xanthine oxidoreductase and excess soluble urate, the joint targets of XOI treatment, can exert noxious effects in the vasculature and other tissues (25)(26)(27)(28). Hence, the CARES trial leaves us with more questions than answers with respect to XOI effects on CV mortality.…”

“…Xanthine oxidoreductase has wide tissue expression, can be released into the circulation, and binds the surface of endothelial cells (25). XOI drugs directly reduce superoxide generation by the oxidized state of the enzyme, and limit oxidative stress and alter nitric oxide-redox balance, endothelial cell and mononuclear phagocyte activation, and inflammation in vitro and in vivo (25)(26)(27)(28). Furthermore, XOI treatment inhibits experimental atherogenesis in vivo in mice (27).…”

Influence of different concentrations of uric acid on oxidative stress in steatosis hepatocytes

“…With the duration of the stimulation of excess ROS, the OS would generate (22). The second is uric acid could access in cell to generate ROS through NOX (NADPH oxidase) (23), but this viewpoint mainly got from the studies on adipocytes, we did not clear whether this would happen in the hepatocytes.…”

<p>Uric Acid and Arterial Stiffness</p>

“…Inflammasomes are protein structures that may play a role in the onset and development of several diseases, including gout, nonalcoholic fatty liver disease and vascular disease. 44 Two main mechanisms explaining the relationship between hyperuricemia and arterial stiffness have been proposed: one independent of urate crystal and the other, urate crystal dependent. 45 In the former mechanism, soluble UA may pass into the vascular wall via urate transporter GLUT 9 (glucose transporter) or URATv1 (voltage-driven urate efflux transporter 1) and initiate intracellular inflammation and oxidative stress.…”

“…It has been shown that UA is related to insulin resistance 44 and represents an independent predictor for the development of type 2 diabetes mellitus. 103,104 Moreover, an independent predictive value of elevated UA for vascular complications and mortality of diabetic patients has been reported.…”