High uric acid directly inhibits insulin signalling and induces insulin resistance

被引：415

作者：

Zhu, Yuzhang ^{[1
]}

Hu, Yaqiu ^{[1
]}

Huang, Tianliang ^{[1
]}

Zhang, Yongneng ^{[1
]}

Li, Zhi ^{[1
]}

Luo, Chaohuan ^{[1
]}

Luo, Yinfeng ^{[1
]}

Yuan, Huier ^{[1
]}

Hisatome, Ichiro ^{[2
]}

Yamamoto, Tetsuya ^{[3
]}

Cheng, Jidong ^{[1
]}

机构：

[1] Shantou Univ, Coll Med, Affiliated Hosp 1, Dept Internal Med, Shantou 515031, Guangdong, Peoples R China

[2] Tottori Univ, Grad Sch Med Sci, Inst Regenerat Med & Biofunct, Div Regenerat Med & Therapeut, Yonago, Tottori, Japan

[3] Hyogo Coll Med, Dept Internal Med, Nishinomiya, Hyogo 6638501, Japan

来源：

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS | 2014年 / 447卷 / 04期

基金：

中国国家自然科学基金;

关键词：

Uric acid; Insulin resistance; Reactive oxygen species; Akt; IRS1; SUBSTRATE-1 TYROSINE PHOSPHORYLATION; CYTOKINE-INDUCED APOPTOSIS; ACTIVATED PROTEIN-KINASE; RECEPTOR SUBSTRATE-1; OXIDATIVE STRESS; EXPERIMENTAL HYPERURICEMIA; NADPH OXIDASE; RISK; INFLAMMATION; PREVALENCE;

D O I：

10.1016/j.bbrc.2014.04.080

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

Background and aim: Accumulating clinical evidence suggests that hyperuricemia is strongly associated with abnormal glucose metabolism and insulin resistance. However, how high uric acid (HUA) level causes insulin resistance remains unclear. We aimed to determine the direct role of HUA in insulin resistance in vitro and in vivo in mice. Methods: An acute hyperuricemia mouse model was created by potassium oxonate treatment, and the impact of HUA level on insulin resistance was investigated by glucose tolerance test, insulin tolerance test and insulin signalling, including phosphorylation of insulin receptor substrate 1 (IRS1) and Akt. HepG2 cells were exposed to HUA treatment and N-acetylcysteine (NAC), reactive oxygen species scavenger; IRSI and Akt phosphorylation was detected by Western blot analysis after insulin treatment. Results: Hyperuricemic mice showed impaired glucose tolerance with insulin resistance. Hyperuricemia inhibited phospho-Akt (Ser473) response to insulin and increased phosphor-IRS1 (Ser307) in liver, muscle and fat tissues. HUA induced oxidative stress, and the antioxidant NAC blocked HUA-induced IRSI activation and Akt inhibition in HepG2 cells. Conclusion: This study supplies the first evidence of HUA directly inducing insulin resistance in vivo and in vitro. Increased uric acid level may inhibit IRS1 and Akt insulin signalling and induce insulin resistance. The reactive oxygen species pathway plays a key role in HUA-induced insulin resistance. (c) 2014 Elsevier Inc. All rights reserved.

引用

页码：707 / 714

页数：8

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