Deletion of Nck1 attenuates hepatic ER stress signaling and improves glucose tolerance and insulin signaling in liver of obese mice
Deletion of Nck1 attenuates hepatic ER stress signaling and improves glucose tolerance and insulin signaling in liver of obese mice
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DOI：
10.1152/ajpendo.00088.2010
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发表时间：
2011-03-01
影响因子：
5.1
通讯作者：
Larose, Louise
中科院分区：
文献类型：
--
作者：
Latreille, Mathieu;Laberge, Marie-Kristine;Larose, Louise
Latreille M，Laberge M，Bourret G，Yamani L，Larose L.缺失Nock1可减弱肝脏ER应激信号，改善肥胖小鼠肝脏的糖耐量和胰岛素信号。Am J生理学内分泌代谢300：E423-E434,2011。2010年6月29日首次出版；DOI：10.1152/ajpendo.00088.2010。-肥胖已被证明会在内质网(ER)产生压力，并启动未折叠蛋白反应(UPR)的激活。据报道，这是通过激活肌醇需要酶1α(IRE1α)-c-jun氨基末端激酶(JNK)途径，导致胰岛素受体底物-1(IRS-1)在抑制部位的磷酸化，阻断胰岛素受体信号转导，在选择性组织中导致胰岛素抵抗。在这项研究中，我们报告了包含Src同源结构域的适配器蛋白Nck 1，先前被证明调节UPR，在肥胖诱导的ER应激信号和胰岛素作用的抑制中具有重要的功能。我们检测了肥胖的NKK1(-/-)和NKK1(-/-)小鼠的葡萄糖耐量、胰岛素敏感性和信号，以及ER应激标志物和Ser(307)处的IRS-1磷酸化。我们的发现表明，肥胖的Nock1基因缺陷小鼠表现出葡萄糖代谢的改善，并伴随着肝脏中胰岛素信号的增强。与肥胖野生型小鼠相比，这与IRE1α和JNK活性减弱以及Ser(307)处的IRS-1磷酸化有关。与我们在体内的数据一致，我们报告了在HepG2细胞中使用siRNA下调Nck 1导致thapsigargin诱导的IRE1α激活和信号转导以及IRS-1在Ser307处的磷酸化减少，而它显著增强了胰岛素信号转导。总体而言，在肝脏和培养细胞中，我们发现Nck 1的缺失减弱了UPR信号及其对胰岛素信号的抑制作用。综上所述，我们的发现表明，Nock1参与了UPR的调节，肥胖继发于UPR，损害了葡萄糖稳态和胰岛素的作用。
Latreille M, Laberge M, Bourret G, Yamani L, Larose L. Deletion of Nck1 attenuates hepatic ER stress signaling and improves glucose tolerance and insulin signaling in liver of obese mice. Am J Physiol Endocrinol Metab 300: E423-E434, 2011. First published June 29, 2010; doi:10.1152/ajpendo.00088.2010.-Obesity has been shown to create stress in the endoplasmic reticulum ( ER), and that initiates the activation of the unfolded protein response (UPR). This has been reported to cause insulin resistance in selective tissues through activation of the inositol-requiring enzyme 1 alpha (IRE1 alpha)-c-Jun NH2-terminal kinase (JNK) pathway, which results in the phosphorylation of the insulin receptor substrate-1 (IRS-1) at an inhibitory site and blocks insulin receptor signaling. In this study, we report that the Src homology domain-containing adaptor protein Nck1, previously shown to modulate the UPR, is of functional importance in obesity-induced ER stress signaling and inhibition of insulin actions. We have examined obese Nck1(-/-) and Nck1(-/-) mice for glucose tolerance, insulin sensitivity, and signaling as well as for ER stress markers and IRS-1 phosphorylation at Ser(307). Our findings show that obese Nck1-deficient mice display improved glucose disposal accompanied by enhanced insulin signaling in liver. This correlates with attenuated IRE1 alpha and JNK activation and IRS-1 phosphorylation at Ser(307) compared with obese wild-type mice. Consistent with our in vivo data, we report that downregulation of Nck1 using siRNA in HepG2 cells results in decreased thapsigargin-induced IRE1 alpha activation and signaling and IRS-1 phosphorylation at Ser(307), whereas it markedly enhances insulin signaling. Overall, in liver and in cultured cells, we show that depletion of Nck1 attenuates the UPR signal and its inhibitory action on insulin signaling. Taken all together, our findings implicate Nck1 in regulating the UPR, which secondary to obesity impairs glucose homeostasis and insulin actions.