Xanthine oxidase inhibition attenuates insulin resistance and diet-induced steatohepatitis in mice
Xanthine oxidase inhibition attenuates insulin resistance and diet-induced steatohepatitis in mice
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DOI：
10.1038/s41598-020-57784-3
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发表时间：
2020-01-21
影响因子：
4.6
通讯作者：
Ota, Tsuguhito
中科院分区：
文献类型：
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作者：
Nishikawa, Tomoki;Nagata, Naoto;Ota, Tsuguhito
高尿酸血症会导致非酒精性脂肪肝（NAFLD）的发展。黄嘌呤氧化酶 (XO) 是尿酸 (UA) 产生的限速酶，其药理抑制已被证明可以改善饮食诱导的肥胖小鼠的肝脏脂肪变性。然而，目前尚不清楚抑制 XO 是否可以改善非酒精性脂肪性肝炎 (NASH)（NAFLD 的一种更高级形式）的肝脏炎症和纤维化。在这里，我们研究了非布索坦和别嘌呤醇这两种临床上用于治疗痛风的 XO 抑制剂对 NASH 小鼠模型的影响。此外，我们针对患有高尿酸血症的 NAFLD 患者进行了一项单臂、开放标签的非布索坦干预研究。尽管 XO 抑制剂对血液 UA 水平具有类似的降尿酸作用，但非布索坦（而非别嘌呤醇）显着降低了 NASH 模型小鼠的肝脏 XO 活性和 UA 水平。肝脏 XO 活性和 UA 水平的降低伴随着胰岛素抵抗、脂质过氧化和肝脏中经典激活的 M1 样巨噬细胞积聚的减弱。此外，在伴有高尿酸血症的 NAFLD 患者中，非布索坦治疗 24 周可降低血清 UA 水平，同时降低血清肝酶、丙氨酸转氨酶和天冬氨酸转氨酶水平。 XO 可能是 NAFLD/NASH 的一个有前途的治疗靶点，特别是对于高尿酸血症患者。
Hyperuricemia drives the development of nonalcoholic fatty liver disease (NAFLD). Pharmacological inhibition of xanthine oxidase (XO), a rate-limiting enzyme for uric acid (UA) production, has been demonstrated to improve hepatic steatosis in diet-induced obese mice. However, it remains unclear whether inhibition of XO improves nonalcoholic steatohepatitis (NASH), a more advanced form of NAFLD, in terms of both liver inflammation and fibrosis. Here, we investigated the effects of febuxostat and allopurinol, two XO inhibitors clinically used for gout, on a mouse model of NASH. Furthermore, we conducted a single-arm, open-label intervention study with febuxostat for NAFLD patients with hyperuricemia. Despite a similar hypouricemic effect of the XO inhibitors on blood UA level, febuxostat, but not allopurinol, significantly decreased hepatic XO activity and UA levels in the NASH model mice. These reductions in hepatic XO activity and UA levels were accompanied by attenuation of insulin resistance, lipid peroxidation, and classically activated M1-like macrophage accumulation in the liver. Furthermore, in NAFLD patients with hyperuricemia, treatment with febuxostat for 24 weeks decreased the serum UA level, accompanied by reductions in the serum levels of liver enzymes, alanine aminotransferase and aspartate aminotransferase. XO may represent a promising therapeutic target in NAFLD/NASH, especially in patients with hyperuricemia.