The Constitutive Activation of Egr-1/C/EBPa Mediates the Development of Type 2 Diabetes Mellitus by Enhancing Hepatic Gluconeogenesis

被引:21
作者
Shen, Ning
Jiang, Shan
Lu, Jia-Ming
Yu, Xiao
Lai, Shan-Shan
Zhang, Jing-Zi
Zhang, Jin-Long
Tao, Wei-Wei
Wang, Xiu-Xing
Xu, Na
Xue, Bin
Li, Chao-Jun
机构
[1] Minist Educ, Key Lab Model Anim Dis Study, Model Anim Res Ctr, Nanjing, Jiangsu, Peoples R China
[2] Nanjing Univ, Natl Resource Ctr Mutant Mice, Sch Med, Nanjing 210093, Jiangsu, Peoples R China
基金
中国国家自然科学基金;
关键词
INSULIN-RESISTANCE; GLUCOSE-PRODUCTION; POSTPRANDIAL HYPERGLYCEMIA; CELL PROLIFERATION; GENE-EXPRESSION; EGR-1; SUPPRESSION; GLUCAGON; GROWTH; TRANSCRIPTION;
D O I
10.1016/j.ajpath.2014.10.016
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
The sequential secretion of insulin and glucagon delicately maintains glucose homeostasis by inhibiting or enhancing hepatic gluconeogenesis during postprandial or fasting states, respectively. Increased glucagon/insulin ratio is believed to be a major cause of the hyperglycemia seen in type 2 diabetes. Herein, we reveal that the early growth response gene-1 (Egr-1) can be transiently activated by glucagon in hepatocytes, which mediates glucagon-regulated gluconeogenesis by increasing the expression of gluconeogenesis genes. Blockage of Egr-1 function in the liver of mice Led to Lower fasting blood glucose, better pyruvate tolerance, and higher hepatic glycogen content. The mechanism analysis demonstrated that Egr-1 can directly bind to the promoter of C/EBPa and regulate the expression of gluconeogenesis genes in the later phase of glucagon stimulation. The transient increase of Egr-1 by gLucagon kept the glucose homeostasis after fasting for longer periods of time, whereas constitutive Egr-1 elevation found in the liver of db/db mice and high serum glucagon Level overactivated the C/EBPa/gluconeogenesis pathway and resulted in hyperglycemia. Blockage of Egr-1 activation in prediabetic db/db mice was able to delay the progression of diabetes. Our results suggest that dysregulation of Egr-1/C/EBPa on glucagon stimulation may provide an alternative mechanistic explanation for type 2 diabetes.
引用
收藏
页码:513 / 523
页数:11
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