The roles of ATF3 in liver dysfunction and the regulation of phosphoenolpyruvate carboxykinase gene expression
The roles of ATF3 in liver dysfunction and the regulation of phosphoenolpyruvate carboxykinase gene expression
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DOI：
10.1074/jbc.m200727200
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发表时间：
2002-05-31
影响因子：
4.8
通讯作者：
Hai, TW
中科院分区：
文献类型：
--
作者：
Allen-Jennings, AE;Hartman, MG;Hai, TW
激活转录因子3(ATF3)是转录因子ATF/cAMP反应元件结合蛋白家族中的一员，是一种转录抑制因子，其相应基因ATF3的表达受多种胁迫信号的诱导。在这篇报道中，我们证明了在肝脏中表达ATF3的转基因小鼠出现了肝功能障碍的症状，如血清胆红素、碱性磷酸酶、丙氨酸转氨酶、天冬氨酸转氨酶和胆汁酸水平升高。此外，这些小鼠有与低血糖相一致的生理反应，包括血清中胰岛素和胰升糖素的比率较低，脂肪组织质量减少。凝胶迁移率改变分析表明，ATF3结合于编码葡萄糖异生酶磷酸烯醇式丙酮酸羧酸激酶(PEPCK)基因启动子的ATF/cAMP反应元件位置。瞬时转染实验表明，ATF3抑制了PEPCK启动子的活性。综上所述，我们的结果与ATF3在肝脏中的表达通过抑制糖异生而导致葡萄糖稳态障碍的模型是一致的。由于ATF3是一个应激诱导基因，这些小鼠可能为研究一些应激相关肝病的分子机制提供了一个模型。
Activating transcription factor 3 (ATF3), a member of the ATF/cAMP-responsive element-binding protein family of transcription factors, is a transcriptional repressor, and the expression of its corresponding gene, ATF3, is induced by many stress signals. In this report, we demonstrate that transgenic mice expressing ATF3 in the liver had symptoms of liver dysfunction such as high levels of serum bilirubin, alkaline phosphatase, alanine transaminase, aspartate transaminase, and bile acids. In addition, these mice had physiological responses consistent with hypoglycemia including a low insulin:glucagon ratio in the serum and reduced adipose tissue mass. Electrophoretic mobility shift assays indicated that ATF3 bound to the ATF/cAMP-responsvie element site derived from the promoter of the gene encoding the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK). Furthermore, transient transfection assays indicated that ATF3 repressed the activity of the PEPCK promoter. Taken together, our results are consistent with the model that the expression of ATF3 in the liver results in defects in glucose homeostasis by repressing gluconeogenesis. Because ATF3 is a stress-inducible gene, these mice may provide a model to investigate the molecular mechanisms of some stress-associated liver diseases.