20-HETE attenuates the response of glucose-stimulated insulin secretion through the AKT/GSK-3β/Glut2 pathway

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• 作者：Bijun Zhang ; Guangrui Lai ; Jingjing Wu ; Ru Sun ; Runhong Xu ; Xianghong Yang…
• 关键词：20 ; hydroxyeicosatetraenoic acid ; Glucose ; stimulated insulin secretion ; Glucose transporter 2 ; Glycogen synthase kinase ; 3β
• 刊名：Endocrine
• 出版年：2016
• 出版时间：November 2016
• 年：2016
• 卷：54
• 期：2
• 页码：371-382
• 全文大小：2,003 KB
• 刊物主题：Endocrinology; Diabetes; Internal Medicine; Science, general;
• 出版者：Springer US
• ISSN：1559-0100
• 卷排序：54

文摘

We previously generated cytochrome P450 4F2 (CYP4F2) transgenic mice that have high levels of 20-hydroxyeicosatetraenoic acid (20-HETE) production; these mice exhibit both hypertension and hyperglycemia without insulin resistance. Currently, it is unclear whether and how 20-HETE affects insulin secretion, thus resulting in hyperglycemia. In this study, we found that 20-HETE attenuated glucose-stimulated insulin secretion (GSIS) in CYP4F2 transgenic mice as well as in rat insulinoma INS-1E cells treated with 0.5 μM 20-HETE. HET0016, a selective inhibitor of 20-HETE synthesis, reversed the reduction in GSIS leading to a decrease in blood glucose in the transgenic mice. Furthermore, the expression of glucose transporter 2 (Glut2), Ser473 phosphorylation of protein kinase B (AKT), and Ser9 phosphorylation of glycogen synthase kinase-3β (GSK-3β) were decreased in CYP4F2 transgenic mice compared with wild-type mice. In vitro experiments in INS-1E cells revealed that 20-HETE activated the AKT/GSK-3β pathway and thereby decreased Glut2 expression by inhibiting activator protein 1 (AP-1). TWS119, a GSK-3β selective inhibitor, blocked the 20-HETE-mediated reduction in Glut2 expression. Therefore, we concluded that 20-HETE inhibition of Glut2 contributes to the reduction in GSIS, at least in part, through the AKT/GSK-3β/AP-1/Glut2 pathway.