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

Akifumi Kushiyama, Yusuke Nakatsu, Yasuka Matsunaga, Takeshi Yamamotoya, Keiichi Mori, Koji Ueda, Yuki Inoue, Hideyuki Sakoda, Midori Fujishiro, Hiraku Ono, Tomoichiro Asano, Akifumi Kushiyama, Yusuke Nakatsu, Yasuka Matsunaga, Takeshi Yamamotoya, Keiichi Mori, Koji Ueda, Yuki Inoue, Hideyuki Sakoda, Midori Fujishiro, Hiraku Ono, Tomoichiro Asano

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.

Conflict of interest statement

The authors have no competing interests regarding the publication of this report to declare.

Figures

Figure 1
Figure 1
Metabolic pathways involving UA.
Figure 2
Figure 2
MUC induces inflammasome activation. MUC activates the NF-κB pathway through TLR2/4, thereby increasing the expressions of pro-IL-1β or pro-IL-18. At the same time, MUC induces ROS release from mitochondria. The generated ROS detaches TXNIP from thioredoxin and enables TXNIP to interact with the NLRP3 complex. The binding of TXNIP to NLRP3 activates inflammasomes, leading to the production of mature IL-1β or IL-18. MUC: monosodium urate crystals, TLR: Toll-like receptor, TXNIP: thioredoxin-interacting protein, TXR: thioredoxin, and ROS: reactive oxygen species.
Figure 3
Figure 3
Involvement of XO in molecular pathologies related to inflammation; “causes and results.”
Figure 4
Figure 4
Increased catalyst activity of XO, originating from pathological and physiological events. Involvement of XO in pathophysiological processes suggests applications of XO inhibitors to the treatment of various disorders.

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