20-HETE Induces Hyperglycemia through the cAMP/PKA-PhK-GP Pathway
20-HETE Induces Hyperglycemia through the cAMP/PKA-PhK-GP Pathway
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20-HETE 通过 cAMP/PKA-PhK-GP 途径诱导高血糖
DOI：
10.1210/me.2012-1139
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发表时间：
2012-11-01
影响因子：
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通讯作者：
Zhao, Yanyan
中科院分区：
文献类型：
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作者：
Lai, Guangrui;Wu, Jingjing;Zhao, Yanyan
我们先前产生的细胞色素P450 4F 2（CYP 4F 2）转基因小鼠，并显示高20-羟基二十碳四烯酸（20-HETE）的生产，这导致血压升高。然而，尚不清楚20-HETE是否影响葡萄糖代谢。我们测定了转基因小鼠的空腹血糖、胰岛素、肝脏CYP 4F 2表达、肝微粒体产生的20-HETE以及肝脏20-HETE水平。我们还评估了糖原磷酸化酶（GP）活性和cAMP/蛋白激酶A（PKA）-磷酸化酶激酶（PhK）-GP途径，以及胰岛素受体底物1和葡萄糖转运蛋白在体内和体外的表达。转基因小鼠肝脏CYP 4F 2过表达，肝脏20-HETE和空腹血糖水平升高，但胰岛素水平正常。与野生型小鼠相比，转基因小鼠GP活性增加，cAMP/PKA-PhK-GP通路被激活。此外，这些改变通过添加N-羟基-N '-（4-丁基-2甲基苯基）甲脒（其是选择性20-HETE抑制剂）而消除。在Bel 7402细胞中进一步验证了结果。此外，转基因小鼠具有功能性胰岛素信号传导，并且20-HETE对Bel 7402细胞中的胰岛素信号传导没有影响，排除了在CYP 4F 2转基因小鼠中观察到的高血糖是由胰岛素功能障碍引起的，因为靶组织对胰岛素敏感。我们的研究表明，20-HETE可以诱导高血糖症，至少部分，通过cAMP/PKA-PhK-GP途径，而不是通过胰岛素信号通路。（分子内分泌学26：1907-1916，2012）
We previously generated cytochrome P450 4F2 (CYP4F2) transgenic mice and showed high 20-hydroxyeicosatetraenoic acid (20-HETE) production, which resulted in an elevation of blood pressure. However, it was unclear whether 20-HETE affected glucose metabolism. We measured fasting plasma glucose, insulin, hepatic CYP4F2 expression, and 20-HETE production by hepatic microsomes, and hepatic 20-HETE levels in transgenic mice. We also assessed glycogen phosphorylase (GP) activity and the cAMP/protein kinase A (PKA)-phosphorylase kinase (PhK)-GP pathway, as well as expressions of insulin receptor substrate 1 and glucose transporters in vivo and in vitro. The transgenic mice had overexpressed hepatic CYP4F2, high hepatic 20-HETE and fasting plasma glucose levels but normal insulin level. The GP activity was increased and the cAMP/PKA-PhK-GP pathway was activated in the transgenic mice compared with wild-type mice. Moreover, these alterations were eliminated with the addition of N-hydroxy-N'-(4-butyl-2 methylphenyl) formamidine, which is a selective 20-HETE inhibitor. The results were further validated in Bel7402 cells. In addition, the transgenic mice had functional insulin signaling, and 20-HETE had no effect on insulin signaling in Bel7402 cells, excluding that the observed hyperglycemia in CYP4F2 transgenic mice resulted from insulin dysfunction, because the target tissues were sensitive to insulin. Our study suggested that 20-HETE can induce hyperglycemia, at least in part, through the cAMP/PKA-PhK-GP pathway but not through the insulin-signaling pathway. (Molecular Endocrinology 26: 1907-1916, 2012)