Xanthine oxidase in non-alcoholic fatty liver disease and hyperuricemia: One stone hits two birds

J Hepatol. 2015 Jun;62(6):1412-9. doi: 10.1016/j.jhep.2015.01.019. Epub 2015 Jan 23.

Abstract

Background & aims: Hyperuricemia is a common feature of patients with non-alcoholic fatty liver disease (NAFLD). This study aimed to explore the causal relationship and underlying mechanisms between NAFLD and hyperuricemia.

Methods: We evaluated the impact of NAFLD on the development of hyperuricemia in a cohort of 5541 baseline hyperuricemia-free individuals. We further analyzed xanthine oxidase (XO), a rate-limiting enzyme that catalyzes uric acid production, as a candidate to link NAFLD and hyperuricemia.

Results: In the first study, a 7-year prospective analysis found that NAFLD was strongly associated with subsequent development of hyperuricemia. Cox proportional hazards regression analyses showed that age, gender, and body mass index adjusted hazard ratio (95% confidence interval) for incident hyperuricemia was 1.609 (1.129-2.294) in individuals with NAFLD, as compared with those without NAFLD at baseline. In the second study, we observed that expression and activity of XO were significantly increased in cellular and mouse models of NAFLD. Knocking down XO expression or inhibiting XO activity significantly decreases uric acid production and attenuates free fatty acids-induced fat accumulation in HepG2 cells. Inhibiting XO activity also significantly prevents the development of and ameliorates established hepatic steatosis induced by a high-fat diet in mice. Further experiments indicated that XO regulates activation of the NLRP3 inflammasome, which may be essential for the regulatory effect of XO on NAFLD.

Conclusions: NAFLD significantly increases the risk of incident hyperuricemia. XO is a mediator of the relationship between NAFLD and hyperuricemia, and may serve as a novel therapeutic target for the two linked diseases.

Keywords: Fatty liver; Hyperuricemia; NLRP3 inflammasome; Uric acid; Xanthine oxidase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Carrier Proteins / metabolism
  • Cohort Studies
  • Disease Models, Animal
  • Female
  • Gene Knockdown Techniques
  • Hep G2 Cells
  • Humans
  • Hyperuricemia / enzymology*
  • Hyperuricemia / etiology*
  • Inflammasomes / metabolism
  • Lipid Metabolism
  • Male
  • Mice
  • Middle Aged
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Non-alcoholic Fatty Liver Disease / complications*
  • Non-alcoholic Fatty Liver Disease / enzymology*
  • Non-alcoholic Fatty Liver Disease / prevention & control
  • Prospective Studies
  • Risk Factors
  • Uric Acid / metabolism
  • Xanthine Oxidase / antagonists & inhibitors
  • Xanthine Oxidase / genetics
  • Xanthine Oxidase / metabolism*

Substances

  • Carrier Proteins
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Uric Acid
  • Xanthine Oxidase