title: Xanthine oxidase in non-alcoholic fatty liver disease and hyperuricemia: One stone hits two birds.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Chengfu
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Xingyong
authors.initials: X
authors.lastname: Wan
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China; Department of Gastroenterology, Zhejiang University Ningbo Hospital, Ningbo, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Honglei
authors.initials: H
authors.lastname: Weng
authors.affiliation: Division of Intramural Research, National Institute on Minority Health and Health Disparities, National Institutes of Health, Bethesda, MD, USA; Laboratory of Biochemistry and Genetics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Yan
authors.affiliation: Department of Internal Medicine, Zhenhai Lianhua Hospital, Ningbo, China.
authors.forename: Min
authors.initials: M
authors.lastname: Miao
authors.affiliation: Division of Intramural Research, National Institute on Minority Health and Health Disparities, National Institutes of Health, Bethesda, MD, USA; Laboratory of Biochemistry and Genetics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Laboratory Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Genyun
authors.initials: G
authors.lastname: Xu
authors.affiliation: Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Steven
authors.initials: S
authors.lastname: Dooley
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. Electronic address: xiaofu@zju.edu.cn.
authors.forename: Youming
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. Electronic address: ych623@sina.com.
authors.forename: Chaohui
authors.initials: C
authors.lastname: Yu
mesh_terms: D000328:Adult; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D015331:Cohort Studies; D004195:Disease Models, Animal; D005260:Female; D055785:Gene Knockdown Techniques; D056945:Hep G2 Cells; D006801:Humans; D033461:Hyperuricemia / Q000201:enzymology* / Q000209:etiology*; D058847:Inflammasomes / Q000378:metabolism; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications* / Q000201:enzymology* / Q000517:prevention & control; D011446:Prospective Studies; D012307:Risk Factors; D014527:Uric Acid / Q000378:metabolism; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D014527:Uric Acid; D014969:Xanthine Oxidase
keywords: Fatty liver; Hyperuricemia; NLRP3 inflammasome; Uric acid; Xanthine oxidase