Decreased expression of endoplasmic reticulum chaperone GRP78 in liver of diabetic mice
Decreased expression of endoplasmic reticulum chaperone GRP78 in liver of diabetic mice
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DOI：
10.1016/j.bbrc.2011.11.118
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发表时间：
2012-01-06
影响因子：
3.1
通讯作者：
Hatayama, Takumi
中科院分区：
文献类型：
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作者：
Yamagishi, Nobuyuki;Ueda, Takashi;Hatayama, Takumi
为了确定与糖尿病发展相关的分子靶点，我们使用高分辨率二维凝胶电泳结合基质辅助激光解吸/电离飞行时间质谱仪分析了肥胖糖尿病db/db小鼠的肝脏蛋白质组。通过比较非糖尿病db/+和糖尿病db/db小鼠，糖尿病小鼠的6个蛋白质和1个蛋白质分别显著减少和增加。在这些蛋白质中，GRP78和蛋白质二硫键异构酶A3是参与内质网应激相关的未折叠蛋白反应的两个蛋白质，并表明GRP78在糖尿病db/db小鼠肝脏中的表达降低是由于GRP78蛋白质合成的减少而不是RNA转录的减少。此外，我们还发现油酸处理的人肝细胞系HepG2细胞中GRP78的表达减少，并且减弱了胰岛素刺激对AKT的激活。这些结果提示，GRP78表达降低可能通过抑制AKT的激活而诱导胰岛素抵抗，并在2型糖尿病的发生发展中起重要作用。(C)2011 Elsevier Inc.保留所有权利。
To identify molecular targets associated with the development of diabetes, we analyzed the hepatic proteome of obese diabetic db/db mice using electrophoresis on a high-resolution two-dimensional gel combined with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. By comparison between non-diabetic db/+ and diabetic db/db mice, six proteins and one protein were significantly decreased and increased in the diabetic mice, respectively. Among these proteins, two of the decreased proteins are involved in endoplasmic reticulum (ER) stress-related unfolded protein response, GRP78 and protein disulfide isomerase A3, and it was revealed that the decreased GRP78 expression in the liver of diabetic db/db mice is due to the reduction of GRP78 protein synthesis rather than RNA transcription. In addition, we found that the treatment of human hepatocyte HepG2 cells with oleic acid decreased the expression of GRP78, and attenuated the activation of AKT by insulin stimulation. These results suggest that decreased GRP78 expression may induce resistance to insulin by inhibiting the AKT activation, and plays an important role in the development of type 2 diabetes. (C) 2011 Elsevier Inc. All rights reserved.