Slide Session : OS-GAS-03 ; Gastroenterology : Xanthine Oxidase Promotes Hyperuricemia and Nonal-coholic Fatty Liver Disease in Patients and Mice = Slide Session : OS-GAS-03 ; Gastroenterology : Xanthine Oxidase Promotes Hyperuricemia and Nonal-coholic Fatty Liver Disease in Patients and Mice

다국어 초록 (Multilingual Abstract)

Background: Hyperuricemia has been commonly found in patients with nonalcoholic fatty liver disease (NAFLD). This study aimed to clarify the causal relationship between NAFLD and hyperuricemia and to explore their underlying mechanisms. Methods: First, we evaluated the impact of NAFLD on development of hyperuricemia in a cohort of 5541 hyperuricemia-free individuals. Second, we analyzed the involvement of xanthine oxidase (XO), a rate-limiting enzyme catalyzes uric acid production, in the relationship between NAFLD and hyperuricemia in cultured HepG2 cells and a murine model of NAFLD. Results: In the first study, 7-year prospective analysis found that NAFLD was strongly associated with subsequent development of hyperuricemia. Cox proportional hazards regression analyses showed that the age, gender, and body mass index adjusted hazard ratio (95% CI) for incident hyperuricemia was 1.609 (1.129 - 2.294) in individuals with NAFLD compared with those without NAFLD. In the second study, we observed that the expression and activity of XO were significantly increased in cellular and mouse models of NAFLD. Knocking down XO expression or inhibiting XO activity significantly inhibited uric acid production and attenuated free fatty acids (FFA)-induced fat accumulation in HepG2 cells. Inhibition of XO activity also significantly decreased serum uric acid levels and ameliorated high fat diet-induced hepatic steatosis in mice. Further experiments indicated that XO regulates the activation of NLRP3 inflammasome, which may be essential for the regulatory effect of XO on NAFLD. Conclusions: XO promotes hyperuricemia and the development of NAFLD, which may serve as a novel therapeutic target for NAFLD.