Uric acid, despite being a major antioxidant in the human plasma, both correlates and predicts development of obesity, hypertension, and cardiovascular disease, conditions associated with oxidative stress. While one explanation for this paradox could be that a rise in uric acid represents an attempted protective response by the host, we review the evidence that uric acid may function either as an antioxidant (primarily in plasma) or pro-oxidant (primarily within the cell). We suggest that it is the pro-oxidative effects of uric acid that occur in cardiovascular disease and may have a contributory role in the pathogenesis of these conditions. KeywordsUric acid; redox homeostasis; metabolic syndrome; cardiovascular disease Uric acid is a final enzymatic product in the degradation of purine nucleosides and free bases in humans and Great Apes. The pathway of purine catabolism in humans is shortest among vertebrates because about 8-20 million years ago during primate evolution the activity of urate oxidase (uricase, an enzyme catalyzing conversion of uric acid to allantoin) was lost in a twostep mutation process. [1,2] In other mammals, the last enzymatic product of purine degradation chain is allantoin, which is excreted in the urine. Lower vertebrates (e.g., fish) have enzymes that further degrade allantoin to allantoic acid and glyoxylic acid and finally to urea. As a consequence, humans have to cope with relatively higher levels of uric acid in the blood (200-400 μM) and are prone to hyperuricemia and gout. [3] According to a hypothesis championed in the early eighties by Ames et al.,[4] the silencing of the uricase gene with an increase in the blood level of uric acid provided an evolutionary advantage for ancestors of Homo sapiens. This hypothesis was based on in vitro experiments which showed that uric acid is a powerful scavenger of singlet oxygen, peroxyl radicals (RO · 2 ) and hydroxyl radicals ( · OH). Urate circulating in elevated concentrations was proposed to be one of the major antioxidants of the plasma that protects cells from oxidative damage, thereby contributing to an increase in life span of our species and decreasing the risk for cancer.On the other hand, a vast literature on the epidemiology of cardiovascular disease, hypertension, and metabolic syndrome overwhelmingly shows that, at least among modern Homo sapiens, a high level of uric acid is strongly associated and in many cases predicts development of hypertension, [5][6][7] visceral obesity, [8][9][10] insulin resistance, [8,11,12] dyslipidemia, [8,[11][12][13] ANTIOXIDANT FUNCTION OF URIC ACID AND ITS LIMITATIONSThe ability of urate to scavenge oxygen radicals and protect the erythrocyte membrane from lipid oxidation was originally described by Kellogg and Fridovich,[21] and was characterized further by Ames et al.[4] Although these experiments defined a paradigm, they addressed effects of uric acid under specific conditions in which exogenously added uric acid protected cells from oxidants, which were also added exogenously to ...

Background: Uric acid is an independent risk factor in fructose-induced fatty liver, but whether it is a marker or a cause remains unknown. Results: Hepatocytes exposed to uric acid developed mitochondrial dysfunction and increased de novo lipogenesis, and its blockade prevented fructose-induced lipogenesis. Conclusion: Rather than a consequence, uric acid induces fatty liver Significance: Hyperuricemic people are more prone to develop fructose-induced fatty liver.

BACKGROUND/AIMS-While the rise in non-alcoholic fatty liver disease (NAFLD) parallels the increase in obesity and diabetes, a significant increase in dietary fructose consumption in industrialized countries has also occurred. The increased consumption of high fructose corn syrup, primarily in the form of soft-drinks, is linked with complications of the insulin resistance syndrome. Furthermore, the hepatic metabolism of fructose favors de novo lipogenesis and ATP depletion. We hypothesize that increased fructose consumption contributes to the development of NAFLD.

Uric acid is considered a major antioxidant in human blood that may protect against aging and oxidative stress. Despite its proposed protective properties, elevated levels of uric acid are commonly associated with increased risk for cardiovascular disease and mortality. Furthermore, recent experimental studies suggest that uric acid may have a causal role in hypertension and metabolic syndrome. All these conditions are thought to be mediated by oxidative stress. In this study we demonstrate that differentiation of cultured mouse adipocytes is associated with increased production of reactive oxygen species (ROS) and uptake of uric acid. Soluble uric acid stimulated an increase in NADPH oxidase activity and ROS production in mature adipocytes but not in preadipocytes. The stimulation of NADPH oxidase-dependent ROS by uric acid resulted in activation of MAP kinases p38 and ERK1/2, a decrease in nitric oxide bioavailability, and an increase in protein nitrosylation and lipid oxidation. Collectively, our results suggest that hyperuricemia induces redox-dependent signaling and oxidative stress in adipocytes. Since oxidative stress in the adipose tissue has recently been recognized as a major cause of insulin resistance and cardiovascular disease, hyperuricemia-induced alterations in oxidative homeostasis in the adipose tissue might play an important role in these derangements.

The intake of added sugars, such as from table sugar (sucrose) and high-fructose corn syrup has increased dramatically in the last hundred years and correlates closely with the rise in obesity, metabolic syndrome, and diabetes. Fructose is a major component of added sugars and is distinct from other sugars in its ability to cause intracellular ATP depletion, nucleotide turnover, and the generation of uric acid. In this article, we revisit the hypothesis that it is this unique aspect of fructose metabolism that accounts for why fructose intake increases the risk for metabolic syndrome. Recent studies show that fructose-induced uric acid generation causes mitochondrial oxidative stress that stimulates fat accumulation independent of excessive caloric intake. These studies challenge the long-standing dogma that “a calorie is just a calorie” and suggest that the metabolic effects of food may matter as much as its energy content. The discovery that fructose-mediated generation of uric acid may have a causal role in diabetes and obesity provides new insights into pathogenesis and therapies for this important disease.