Gender effect of hyperuricemia on the development of nonalcoholic fatty liver disease (NAFLD): A clinical analysis and mechanistic study

• Published in: Biomedicine & pharmacotherapy 2019-09, Vol.117, p.109158-109158, Article 109158
• Main Authors: Xu, Keyang, Zhao, Xu, Fu, Xiaoqing, Xu, Kechen, Li, Zhaoyi, Miao, Liangbin, Li, Yan, Cai, Zhaobin, Qiao, Liang, Bao, Jianfeng
• Format: Article
• Language: English
• Subjects: Adult; Androgen receptor (AR); Animals; Female; Humans; Hyperuricemia; Hyperuricemia - blood; Hyperuricemia - complications; Liver - metabolism; Male; Middle Aged; Non-alcoholic Fatty Liver Disease - blood; Non-alcoholic Fatty Liver Disease - etiology; Nonalcoholic fatty liver disease (NAFLD); Rats, Sprague-Dawley; Sex Characteristics; Silent information regulator 1 (SIRT1); Uric Acid - blood; Xanthine oxidase (XO)
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2019.109158

•Male NAFLD patients with hyperuricemia displayed more frequent and extensive liver injury than their female counterparts.•This may potentially explain the male predominance of hepatocellular carcinoma pending confirmation in more studies.•Serum uric acids (SUA) was positively correlated with key clinical parameters in NALFD patients.•A NAFLD rat model with hyperuricemia was successfully established.•UA may promote hepatic injury in NAFLD through suppressing SIRT1 signaling. Hyperuricemia is a risk factor for nonalcoholic fatty liver disease (NAFLD), however, the effect of gender on the hyperuricemia-related NAFLD development remains unclear. Here, we evaluated the clinical characteristics of NAFLD patients with hyperuricemia, and experimentally recapitulated this condition in male rats in order to gain insights on the possible impact of gender on the development of NAFLD in patients with hyperuricemia. The clinical characteristics of 238 NAFLD patients, together with the impacts of hyperuricemia on the major parameters related to the development of NALFD were analysed. In animal studies, NAFLD with hyperuricemia was induced in male SD rats using high-yeast high-fat diet containing potassium oxonate. The impact of uric acids on liver pathology, and the expression patterns of key molecules involved in the development of NAFLD, including silent information regulator 1 (SIRT1), nuclear factor kappa B subunit p65 (NF-κB p65), fork-head box class O-3a (FOXO3a), androgen receptor (AR), and xanthine oxidase (XO) were analysed. Male NAFLD patients with hyperuricemia displayed more frequent and extensive liver injury than those in female patients. In male rats, hyperuricemia was associated with increased levels of insulin, alanine aminotransferase (ALT) and triglyceride (TG). At the molecular level, hyperuricemia was associated with decreased expression of SIRT1 and its phosphorylation, phosphorylation of FOXO3a, increased expression of AR and XO, and deacetylation of NF-κB P65. Hyperuricemia is a compounding factor for NAFLD, particularly in males. The severer hepatic injury observed in male NAFLD patients may be attributed to the suppression of SIRT1 signalling induced by hyperuricemia.