Uric acid regulates hepatic steatosis and insulin resistance through the NLRP3 inflammasome-dependent mechanism
Uric acid regulates hepatic steatosis and insulin resistance through the NLRP3 inflammasome-dependent mechanism
复制标题
尿酸通过NLRP3炎症小体依赖性机制调节肝脂肪变性和胰岛素抵抗
DOI：
10.1016/j.jhep.2015.11.022
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发表时间：
2016-04-01
影响因子：
25.7
通讯作者：
Yu, Chaohui
中科院分区：
文献类型：
--
作者：
Wan, Xingyong;Xu, Chengfu;Yu, Chaohui
背景与目的：高尿酸血症显著增加非酒精性脂肪性肝病（NAFLD）和胰岛素抵抗的风险。然而，造成这种关联的机制尚不清楚。本研究旨在探讨尿酸在NAFLD和胰岛素抵抗发展中的作用及其潜在机制。方法：我们初步分析了尿酸对小鼠和HepG2和L02两种细胞模型肝脂肪变性和胰岛素抵抗的影响。随后，我们研究了含有3 （NLRP3）炎症小体的nod样受体家族pyrin结构域在尿酸诱导的脂肪堆积和胰岛素信号损伤中的作用。结果：我们发现尿酸在体内和体外均可直接诱导肝细胞脂肪堆积、胰岛素抵抗和胰岛素信号损伤。我们还发现尿酸可诱导NLRP3炎性体激活，而在高脂饮食小鼠NAFLD模型中，别嘌呤醇降低尿酸可抑制NLRP3炎性体激活。此外，在HepG2细胞和L02细胞中，敲低NLRP3的表达可显著减弱尿酸诱导的脂肪堆积。抑制NLRP3的表达也能在两种细胞类型中挽救尿酸诱导的胰岛素信号损伤。结论：尿酸通过NLRP3炎性体调节肝脏脂肪变性和胰岛素抵抗。尿酸可能是治疗NAFLD和胰岛素抵抗的新靶点。(C) 2015欧洲肝脏研究协会。Elsevier B.V.版权所有。
Background & Aims: Hyperuricemia significantly increases risk of non-alcoholic fatty liver disease (NAFLD) and insulin resistance. However, the mechanisms responsible for this association are as yet unclear. This study aimed to investigate the effects and underlying mechanisms of uric acid on development of NAFLD and insulin resistance.Methods: We initially analyzed the impact of uric acid on the development of hepatic steatosis and insulin resistance in mice and in two cell models, HepG2 and L02. Subsequently, we studied the role of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in uric acid-induced fat accumulation and insulin signaling impairment.Results: We found that uric acid directly induces hepatocyte fat accumulation, insulin resistance, and insulin signaling impairment both in vivo and in vitro. We also found that uric acid induced NLRP3 inflammasome activation, whereas lowering uric acid by allopurinol inhibited NLRP3 inflammasome activation in a high fat diet mouse model of NAFLD. Moreover, knocking down NLRP3 expression significantly attenuated uric acid-induced fat accumulation both in HepG2 cells and L02 cells. Knocking down NLRP3 expression also rescued uric acid-induced insulin signaling impairment in both cell types.Conclusions: Uric acid regulates hepatic steatosis and insulin resistance through the NLRP3 inflammasome. Uric acid may be a new therapeutic target for NAFLD and insulin resistance. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.