Endoplasmic reticulum stress increases glucose-6-phosphatase and glucose cycling in liver cells
Endoplasmic reticulum stress increases glucose-6-phosphatase and glucose cycling in liver cells
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DOI：
10.1210/en.2005-1014
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发表时间：
2006-01-01
期刊：
影响因子：
4.8
通讯作者：
Pagliassotti, MJ
中科院分区：
文献类型：
--
作者：
Wang, D;Wei, YR;Pagliassotti, MJ
肝脏葡萄糖生成调节受损是代谢综合征的特征，代谢综合征是一组疾病，包括肥胖、胰岛素抵抗、2型糖尿病和心血管疾病。有人提出，持续的内质网应激，这似乎发生在肥胖症和糖尿病，调节胰岛素在肝脏中的作用。在这项研究中，我们表明，实验诱导内质网应激增加表达和活性的葡萄糖-6-磷酸酶和葡萄糖释放和葡萄糖循环的能力，在原代大鼠肝细胞和H4 IIE肝细胞。葡萄糖-6-磷酸酶催化亚基的表达增加主要是由于转录增加。葡萄糖-6-磷酸酶启动子的缺失分析确定了位于转录起始位点-233和-187之间的内质网应激反应区。实验诱导内质网应激增加了c-jun N-末端激酶的活性。预防内质网应激介导的c-jun N-末端激酶的活化降低了葡萄糖-6-磷酸酶催化亚基的表达、葡萄糖-6-磷酸酶活性、葡萄糖释放和葡萄糖循环。这些数据表明，肝细胞中持续的内质网应激引起适应，部分通过激活c-jun N-末端激酶介导，其作用是增加肝细胞葡萄糖释放和葡萄糖循环的能力。
Impaired regulation of hepatic glucose production is a characteristic feature of the metabolic syndrome, a cluster of diseases that includes obesity, insulin resistance, type 2 diabetes, and cardiovascular disease. It has been proposed that sustained endoplasmic reticulum stress, which appears to occur in obesity and diabetes, modulates insulin action in the liver. In this study, we show that experimental induction of endoplasmic reticulum stress increases expression and activity of glucose-6-phosphatase and the capacity for glucose release and glucose cycling in primary rat hepatocytes and H4IIE liver cells. Increased expression of the catalytic subunit of glucose-6-phosphatase was largely a result of increased transcription. Deletion analysis of the glucose-6-phosphatase promoter identified an endoplasmic reticulum stress-responsive region located between -233 and -187 with respect to the transcriptional start site. Experimental induction of endoplasmic reticulum stress increased the activity of c-jun N-terminal kinase. Prevention of endoplasmic reticulum stress-mediated activation of c-jun N-terminal kinase reduced the expression of the catalytic subunit of glucose-6-phosphatase, glucose-6-phosphatase activity, glucose release, and glucose cycling. These data demonstrate that sustained endoplasmic reticulum stress in the hepatocyte provokes adaptations, mediated in part via activation of c-jun N-terminal kinase, that act to increase hepatocellular capacity for glucose release and glucose cycling.