Obesity-induced over expression of miRNA-143 inhibits insulin-stimulated AKT activation and impairs glucose metabolism
Obesity-induced over expression of miRNA-143 inhibits insulin-stimulated AKT activation and impairs glucose metabolism
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DOI：
10.1038/ncb2211
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发表时间：
2011-04-01
影响因子：
21.3
通讯作者：
Bruening, Jens C.
中科院分区：
文献类型：
--
作者：
Jordan, Sabine D.;Krueger, Markus;Bruening, Jens C.
迄今为止，改变的转录后基因沉默对胰岛素抵抗和2型糖尿病的发展的贡献仍然难以捉摸。在这里，我们证明了microRNA（miR）-143和145的表达在肥胖遗传和饮食小鼠模型的肝脏中上调。诱导的miR-143而非miR-145的转基因过表达损害胰岛素刺激的AKT活化和葡萄糖稳态。相反，miR-143-145簇缺陷的小鼠被保护免于发展肥胖相关的胰岛素抵抗。对miR-143过表达小鼠肝脏蛋白表达的基于定量质谱的分析显示，氧化固醇结合蛋白相关蛋白（ORP）8的miR-143依赖性下调。在培养的肝细胞中ORP 8表达的减少损害了胰岛素诱导AKT活化的能力，揭示了AKT调节的ORP 8依赖性机制。我们的实验提供了直接的证据表明，失调的转录后基因沉默有助于肥胖诱导的胰岛素抵抗的发展，并表征了miR-143-ORP 8通路作为治疗肥胖相关糖尿病的潜在靶点。
The contribution of altered post-transcriptional gene silencing to the development of insulin resistance and type2 diabetes mellitus so far remains elusive. Here, we demonstrate that expression of microRNA (miR)-143 and 145 is upregulated in the liver of genetic and dietary mouse models of obesity. Induced transgenic overexpression of miR-143, but not miR-145, impairs insulin-stimulated AKT activation and glucose homeostasis. Conversely, mice deficient for the miR-143-145 cluster are protected from the development of obesity-associated insulin resistance. Quantitative-mass-spectrometry-based analysis of hepatic protein expression in miR-143-overexpressing mice revealed miR-143-dependent downregulation of oxysterol-binding-protein-related protein (ORP) 8. Reduced ORP8 expression in cultured liver cells impairs the ability of insulin to induce AKT activation, revealing an ORP8-dependent mechanism of AKT regulation. Our experiments provide direct evidence that dysregulated post-transcriptional gene silencing contributes to the development of obesity-induced insulin resistance, and characterize the miR-143-ORP8 pathway as a potential target for the treatment of obesity-associated diabetes.