Bao Ruixia, Chen Beibei, Wang Alexander, Wang Dan, Pan Jujie, Chen Qian, Wu Yuzheng, Zhu Zicheng, Yu Haiyang, Zhang Yi, Wang Tao
State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Jinghai District, Tianjin, 301617, China.
College of Education, University of Texas at Austin, 1912 Speedway Stop D5000, Austin, TX, 78712, USA.
Free Radic Biol Med. 2025 Jan;226:374-388. doi: 10.1016/j.freeradbiomed.2024.11.040. Epub 2024 Nov 22.
Overproduction of uric acid caused by increased expression and/or enhanced activity of xanthine oxidase (XO) is one of the major etiologies of hyperuricemia, which had a significant sex differences. As an important enzyme involved in production of reactive oxygen species and uric acid, activity of XO is highly correlated with hyperuricemia and its complications. However, the mechanisms underlying XO dysregulation remain unclear, and sex difference in the prevalence of hyperuricemia has been well known. To explore the potential role of intestinal farnesoid X receptor (FXR) on XO regulation and production, and the mechanisms of sex differences in this pathological process. Two hundred and sixty-one dyslipidemia participants and intestine-specific FXR-knockout mice were used to study the relationship between the intestinal FXR and the serum uric acid level. Western blotting, quantitative real-time PCR, and dual-luciferase reporter assay, were applied to clarify the regulatory role of FXR deficiency on XO. Special inhibitors, agonists, siRNA, sex hormones were used to investigate the mechanism of sex difference in FXR deficiency induced hyperuricemia in cell and animal model. Serum fibroblast growth factor 19 (FGF19) levels were lower in hyperuricemia patients in a sex difference manner. Increased local TNFα level driven by intestinal FXR deficiency/inhibition induced overexpression and hyperactivity of intestinal XO, leading to elevated intestinal uric acid synthesis, and subsequently resulting in hyperuricemia. We found that estrogens inhibited XO expression and activity, whereas androgens enhanced XO activity, leading to the sex difference in FXR deficiency induced hyperuricemia. Infliximab treatment eliminated the sex difference in uric acid levels in intestinal FXR-knockout mice. This study demonstrated the role of intestinal FXR in the pathogenesis of hyperuricemia, and partially elucidated the mechanisms underlying the sex differences of hyperuricemia.
黄嘌呤氧化酶（XO）表达增加和/或活性增强导致尿酸产生过多是高尿酸血症的主要病因之一，高尿酸血症存在显著的性别差异。作为参与活性氧和尿酸生成的重要酶，XO的活性与高尿酸血症及其并发症高度相关。然而，XO失调的潜在机制仍不清楚，高尿酸血症患病率的性别差异已为人所知。为了探讨肠道法尼酯X受体（FXR）在XO调节和产生中的潜在作用，以及这一病理过程中性别差异的机制。我们使用261名血脂异常参与者和肠道特异性FXR基因敲除小鼠来研究肠道FXR与血清尿酸水平之间的关系。采用蛋白质免疫印迹法、定量实时聚合酶链反应和双荧光素酶报告基因检测法，以阐明FXR缺乏对XO的调节作用。使用特异性抑制剂、激动剂、小干扰RNA、性激素来研究FXR缺乏诱导的高尿酸血症在细胞和动物模型中性别差异的机制。高尿酸血症患者血清成纤维细胞生长因子19（FGF19）水平以性别差异的方式降低。肠道FXR缺乏/抑制导致局部肿瘤坏死因子α（TNFα）水平升高，诱导肠道XO过表达和活性增强，导致肠道尿酸合成增加，进而导致高尿酸血症。我们发现雌激素抑制XO的表达和活性，而雄激素增强XO的活性，导致FXR缺乏诱导的高尿酸血症出现性别差异。英夫利昔单抗治疗消除了肠道FXR基因敲除小鼠尿酸水平的性别差异。本研究证明了肠道FXR在高尿酸血症发病机制中的作用，并部分阐明了高尿酸血症性别差异的潜在机制。
