title: 20-HETE attenuates the response of glucose-stimulated insulin secretion through the AKT/GSK-3β/Glut2 pathway.
abstract: 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), Ser473phosphorylation of protein kinase B (AKT), and Ser9phosphorylation 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.
authors: Department of Clinical Genetics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.|Department of Medical Genetics, China Medical University, Shenyang, Liaoning, China.
authors: Bijun
authors: B
authors: Zhang
authors: Department of Clinical Genetics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.
authors: Guangrui
authors: G
authors: Lai
authors: Department of Medical Genetics, China Medical University, Shenyang, Liaoning, China.
authors: Jingjing
authors: J
authors: Wu
authors: Department of Medical Genetics, China Medical University, Shenyang, Liaoning, China.
authors: Ru
authors: R
authors: Sun
authors: Department of Clinical Genetics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.|Department of Medical Genetics, China Medical University, Shenyang, Liaoning, China.
authors: Runhong
authors: R
authors: Xu
authors: Department of Pathology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.
authors: Xianghong
authors: X
authors: Yang
authors: Department of Pathology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.
authors: Yafei
authors: Y
authors: Qi
authors: Department of Clinical Genetics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China. yyzhao@sj-hospital.org.|Department of Medical Genetics, China Medical University, Shenyang, Liaoning, China. yyzhao@sj-hospital.org.
authors: Yanyan
authors: Y
authors: Zhao
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D045744:Cell Line, Tumor; D000072470:Cytochrome P450 Family 4 / Q000235:genetics; D005947:Glucose / Q000494:pharmacology*; D051273:Glucose Transporter Type 2 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D001786:Blood Glucose; D051273:Glucose Transporter Type 2; D006893:Hydroxyeicosatetraenoic Acids; D007328:Insulin; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; C465348:Cyp4f1 protein, rat; D000072470:Cytochrome P450 Family 4; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose
keywords: 20-hydroxyeicosatetraenoic acid; Glucose transporter 2; Glucose-stimulated insulin secretion; Glycogen synthase kinase-3β