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), 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.
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C. Tan, U. Voss, S. Svensson, D. Erlinge, B. Olde, High glucose and free fatty acids induce beta cell apoptosis via autocrine effects of ADP acting on the P2Y(13) receptor. Purinergic Signal. 9, 67–79 (2013)
M.V. Jensen, J.W. Joseph, S.M. Ronnebaum, S.C. Burgess, A.D. Sherry, C.B. Newgard, Metabolic cycling in control of glucose-stimulated insulin secretion. Am. J. Physiol. Endocrinol. Metab. 295, E1287–E1297 (2008)
A. Leturque, E. Brot-Laroche, M. Le Gall, GLUT2 mutations, translocation, and receptor function in diet sugar managing. Am. J. Physiol. Endocrinol. Metab. 296, E985–E992 (2009)
M.T. Guillam, E. Hümmler, E. Schaerer, J.I. Yeh, M.J. Birnbaum, F. Beermann et al., Early diabetes and abnormal postnatal pancreatic islet development in mice lacking Glut-2. Nat. Genet. 17, 327–330 (1997)
M.T. Guillam, P. Dupraz, B. Thorens, Glucose uptake, utilization, and signaling in GLUT2-null islets. Diabetes 49, 1485–1491 (2000)
K. Ohtsubo, M.Z. Chen, J.M. Olefsky, J.D. Marth, Pathway to diabetes through attenuation of pancreatic beta cell glycosylation and glucose transport. Nat. Med. 17, 1067–1075 (2011)
A. Jörns, M. Tiedge, E. Sickel, S. Lenzen, Loss of GLUT2 glucose transporter expression in pancreatic beta cells from diabetic Chinese hamsters. Virchows Arch. 428, 177–185 (1996)
D.A. Babu, T.G. Deering, R.G. Mirmira, A feat of metabolic proportions: Pdx1 orchestrates islet development and function in the maintenance of glucose homeostasis. Mol. Genet. Metab. 92, 43–55 (2007)
J.W. Kim, Y.H. Ahn, C/EBP binding activity to site F of the rat GLUT2 glucose transporter gene promoter is attenuated by c-Jun in vitro. Exp. Mol. Med. 34, 379–384 (2002)
S. Schnell, M. Schaefer, C. Schöfl, Free fatty acids increase cytosolic free calcium and stimulate insulin secretion from beta-cells through activation of GPR40. Mol. Cell Endocrinol. 263, 173–180 (2007)
S. Kashyap, R. Belfort, A. Gastaldelli, T. Pratipanawatr, R. Berria, W. Pratipanawatr et al., A sustained increase in plasma free fatty acids impairs insulin secretion in nondiabetic subjects genetically predisposed to develop type 2 diabetes. Diabetes 52, 2461–2474 (2003)
D.K. Hagman, M.G. Latour, S.K. Chakrabarti, G. Fontes, J. Amyot, C. Tremblay et al., Cyclical and alternating infusions of glucose and intralipid in rats inhibit insulin gene expression and Pdx-1 binding in islets. Diabetes 57, 424–431 (2008)
K.S. Gwiazda, T.L. Yang, Y. Lin, J.D. Johnson, Effects of palmitate on ER and cytosolic Ca2+ homeostasis in β-cells. Am. J. Physiol. Endocrinol. Metab. 296, E690–E701 (2009)
R.N. Bone, Y. Gai, V. Magrioti, M.G. Kokotou, T. Ali, X. Lei et al., Inhibition of Ca2+-independent phospholipase A2β (iPLA2β) ameliorates islet infiltration and incidence of diabetes in NOD mice. Diabetes 64, 541–554 (2015)
G. Dixon, J. Nolan, N.H. McClenaghan, P.R. Flatt, P. Newsholme, Arachidonic acid, palmitic acid and glucose are important for the modulation of clonal pancreatic beta-cell insulin secretion, growth and functional integrity. Clin. Sci. (Lond.) 106, 191–199 (2004)
R.J. Roman, P-450 metabolites of arachidonic acid in the control of cardiovascular function. Physiol. Rev. 82, 131–185 (2002)
J.R. Falck, S. Manna, J. Moltz, N. Chacos, J. Capdevila, Epoxyeicosatrienoic acids stimulate glucagon and insulin release from isolated rat pancreatic islets. Biochem. Biophys. Res. Commun. 114, 743–749 (1983)
P. Luo, H.H. Chang, Y. Zhou, S. Zhang, S.H. Hwang, C. Morisseau et al., Inhibition or deletion of soluble epoxide hydrolase prevents hyperglycemia, promotes insulin secretion, and reduces islet apoptosis. J. Pharmacol. Exp. Ther. 334, 430–438 (2010)
A.A. Eid, Y. Gorin, B.M. Fagg, R. Maalouf, J.L. Barnes, K. Block et al., Mechanisms of podocyte injury in diabetes: role of cytochrome P450 and NADPH oxidases. Diabetes 58, 1201–1211 (2009)
M.H. Yousif, I.F. Benter, K.M. Dunn, A.J. Dahly-Vernon, S. Akhtar, R.J. Roman, Role of 20-hydroxyeicosatetraenoic acid in altering vascular ireactivity in diabetes. Auton. Autacoid Pharmacol. 29, 1–12 (2009)
X. Liu, Y. Zhao, L. Wang, X. Yang, Z. Zheng, Y. Zhang et al., Overexpression of cytochrome P450 4F2 in mice increases 20-hydroxyeicosatetraenoic acid production and arterial blood pressure. Kidney Int. 75, 1288–1296 (2009)
J. Wu, X. Liu, G. Lai, X. Yang, L. Wang, Y. Zhao, Synergistical effect of 20-HETE and high salt on NKCC2 protein and blood pressure via ubiquitin-proteasome pathway. Hum. Genet. 132, 179–187 (2013)
G. Lai, J. Wu, X. Liu, Y. Zhao, 20-HETE induces hyperglycemia through the cAMP/PKA-PhK-GP pathway. Mol. Endocrinol. 26, 1907–1916 (2012)
F. Park, W.E. Sweeney, G. Jia, R.J. Roman, E.D. Avner, 20-HETE mediates proliferation of renal epithelial cells in polycystic kidney disease. J. Am. Soc. Nephrol. 19, 1929–1939 (2008)
J. Cheng, J.S. Ou, H. Singh, J.R. Falck, D. Narsimhaswamy, K.A. Pritchard Jr., M.L. Schwartzman, 20-hydroxyeicosatetraenoic acid causes endothelial dysfunction via eNOS uncoupling. Am. J. Physiol. Heart Circ. Physiol. 294, H1018–H1026 (2008)
W. Liu, J. Hao, L. Zhu, F. Li, Q. Liu, S. Liu, S. Zhao, H. Li, H. Duan, Phospho-GSK-3β is involved in the high-glucose-mediated lipid deposition in renal tubular cells in diabetes. Int. J. Biochem. Cell Biol. 45, 2066–2075 (2013)
Y. Zhang, C. Li, W. Li, Y. Zhao, Estrogen regulation of human with-no-lysine (K) kinase-4 gene expression involves AP-1 transcription factor. Mol. Cell Endocrinol. 332, 140–148 (2011)
C.L. Buller, R.D. Loberg, M.H. Fan, Q. Zhu, J.L. Park, E. Vesely et al., A GSK-3/TSC2/mTOR pathway regulates glucose uptake and GLUT1 glucose transporter expression. Am. J. Physiol. Cell Physiol. 295, C836–C843 (2008)
W.J. Boyle, T. Smeal, L.H. Defize, P. Angel, J.R. Woodgett, M. Karin et al., Activation of protein kinase C decreases phosphorylation of c-Jun at sites that negatively regulate its DNA-binding activity. Cell 64, 573–584 (1991)
A. Michau, G. Guillemain, A. Grosfeld, S. Vuillaumier-Barrot, T. Grand, M. Keck et al., Mutations in SLC2A2 gene reveal hGLUT2 function in pancreatic β cell development. J. Biol. Chem. 288, 31080–31092 (2013)
J. Jiang, Z.H. Wang, M. Qu, D. Gao, X.P. Liu, L.Q. Zhu, J.Z. Wang, Stimulation of EphB2 attenuates tau phosphorylation through PI3K/Akt-mediated inactivation of glycogen synthase kinase-3β. Sci. Rep. 29, 11765 (2015)
N.J. Pearce, J.R. Arch, J.C. Clapham, M.P. Coghlan, S.L. Corcoran, C.A. Lister et al., Development of glucose intolerance in male transgenic mice overexpressing human glycogen synthase kinase-3 on a muscle-specific promoter. Metabolism 53, 1322–1330 (2004)
K.P. Hoeflich, J. Luo, E.A. Rubie, M.S. Tsao, O. Jin, J.R. Woodgett, Requirement for glycogen synthase kinase 3ß in cell survival and NF-kappaB activation. Nature 406, 86–90 (2000)
K. Aoyagi, M. Ohara-Imaizumi, C. Nishiwaki, Y. Nakamichi, K. Ueki, T. Kadowaki et al., Acute inhibition of PI3K-PDK1-Akt pathway potentiates insulin secretion through upregulation of newcomer granule fusions in pancreatic β-cells. PLoS One 7, e47381 (2012)
J.C. Bournat, A.M. Brown, A.P. Soler, Wnt-1 dependent activation of the survival factor NF-kappaB in PC12 cells. J. Neurosci. Res. 61, 21–32 (2000)
J.L. Larabee, F.J. Maldonado-Arocho, S. Pacheco, B. France, K. DeGiusti, S.M. Shakir et al., Glycogen synthase kinase 3 activation is important for anthrax edema toxin-induced dendritic cell maturation and anthrax toxin receptor 2 expression in macrophages. Infect. Immun. 79, 3302–3308 (2011)
J.M. Williams, S. Murphy, M. Burke, R.J. Roman, 20-HETE: a new target for the treatment of hypertension. J. Cardiovasc. Pharmacol. 56, 336–344 (2010)
N.C. Ward, K. Chen, C. Li, K.D. Croft, J.F. Keaney Jr., Chronic AMPK activation prevents 20-HETE induced endothelial dysfunction. Clin. Exp. Pharmacol. Physiol. 38, 328–333 (2011)
A.O. Oyekan, Differential effects of 20-hydroxyeicosatetraenoic acid on intrarenal blood flow in the rat. J. Pharmacol. Exp. Ther. 313, 1289–1295 (2005)
X. Liu, J. Wu, H. Liu, G. Lai, Y. Zhao, Disturbed ratio of renal 20-HETE/EETs is involved in androgen-induced hypertension in cytochrome P450 4F2 transgenic mice. Gene 505, 352–359 (2012)
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This work was supported by a grant from the National Natural Science Foundation of China (Grant No. 81270343) and a grant from the Ministry of Education of China (Grant No. 20122104110020).
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Zhang, B., Lai, G., Wu, J. et al. 20-HETE attenuates the response of glucose-stimulated insulin secretion through the AKT/GSK-3β/Glut2 pathway. Endocrine 54, 371–382 (2016). https://doi.org/10.1007/s12020-016-1031-5
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DOI: https://doi.org/10.1007/s12020-016-1031-5