Dipalmitoleoylphosphoethanolamine as a PP2A Enhancer Obstructs Insulin Signaling by Promoting Ser/Thr Dephosphorylation of Akt

Tsuchiya, Ayako; Kanno, Takeshi; Nishizaki, Tomoyuki

doi:10.1159/000363027

Cited by 3 publications

(3 citation statements)

References 23 publications

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“…In our earlier study, 1,2-dipalmitoleoyl-sn-glycero-3-phosphoethanolamine (DPPE), which contains palmitoleic acid on the α and β position, induced apoptosis of malignant pleural mesothelioma (MPM) cells by enhancing activities of protein phosphatase 2A (PP2A) and protein tyrosine phosphatase 1B (PTP1B) [12]. Another phosphatidylethanolamine 1,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine (DLPE), which contains linoleic acid on the α and β position, also enhanced PP2A and PTP1B activities, but such effect was not obtained with 1,2-diarachidonoylsn-glycero-3-phosphoethanolamine (DAPE), which contains arachidonic acid on the α and β position, or 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), which contains oleic acid on the α and β position [13].…”

Section: Introductionmentioning

confidence: 99%

Diarachidonoylphosphoethanolamine induces necrosis/necroptosis of malignant pleural mesothelioma cells

Kaku

Tsuchiya

Kanno

et al. 2015

Cellular Signalling

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Section: Introductionmentioning

confidence: 99%

Diarachidonoylphosphoethanolamine induces necrosis/necroptosis of malignant pleural mesothelioma cells

Kaku

Tsuchiya

Kanno

et al. 2015

Cellular Signalling

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“…Glucose uptake assay was carried out by the method as described previously 1 13 14 . Differentiated 3T3-L1-GLUT4myc adipocytes without and with IR knock-down were incubated in a Krebs-Ringer-HEPES buffer containing 0.2% (w/v) BSA supplemented with 10 mM glucose at 37 °C for 1 h. Then, cells were not treated and treated with diDCP-LA-PE or insulin in phosphate-buffered saline supplemented with 10 mM glucose at 37 °C for 2 h. After treatment, extracellular solution was collected and glucose was labeled with p -aminobenzoic ethyl ester (ABEE), followed by HPLC.…”

Section: Methodsmentioning

confidence: 99%

The phosphatidylethanolamine derivative diDCP-LA-PE mimics intracellular insulin signaling

Nishizaki¹,

Gotoh

Shimizu

et al. 2016

Sci Rep

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Insulin facilitates glucose uptake into cells by translocating the glucose transporter GLUT4 towards the cell surface through a pathway along an insulin receptor (IR)/IR substrate 1 (IRS-1)/phosphatidylinositol 3 kinase (PI3K)/3-phosphoinositide-dependent protein kinase-1 (PDK1)/Akt axis. The newly synthesized phosphatidylethanolamine derivative 1,2-O-bis-[8-{2-(2-pentyl-cyclopropylmethyl)-cyclopropyl}-octanoyl]-sn-glycero-3-phosphatidylethanolamine (diDCP-LA-PE) has the potential to inhibit protein tyrosine phosphatase 1B (PTP1B) and to directly activate PKCζ, an atypical isozyme, and PKCε, a novel isozyme. PTP1B inhibition enhanced insulin signaling cascades downstream IR/IRS-1 by preventing tyrosine dephosphorylation. PKCζ and PKCε directly activated Akt2 by phosphorylating at Thr309 and Ser474, respectively. diDCP-LA-PE increased cell surface localization of GLUT4 and stimulated glucose uptake into differentiated 3T3-L1 adipocytes, still with knocking-down IR or in the absence of insulin. Moreover, diDCP-LA-PE effectively reduced serum glucose levels in type 1 diabetes (DM) model mice. diDCP-LA-PE, thus, may enable type 1 DM therapy without insulin injection.

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“…PE is shown to regulate membrane fusion, cell cycle, autophagy, apoptosis, cognitive function, and glucose homeostasis [5-10]. We have earlier found that the PE derivative 1, 2- O -bis-[8-{2-(2-pentyl-cyclopropylmethyl)-cyclopropyl}-octanoyl]- sn - glycero-3-phosphatidylethanolamine (diDCP-LA-PE) is capable of mimicking intracellular insulin signaling [11].…”

Section: Introductionmentioning

confidence: 99%

Dioleoylphosphoethanolamine Retains Cell Surface GLUT4 by Inhibiting PKCα-Driven Internalization

Nishizaki¹

2018

Cell Physiol Biochem

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Background/Aims: Phosphatidylethanolamine, a component of the plasma membrane, regulates diverse cellular processes. The present study investigated the role of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) in the trafficking of the glucose transporter GLUT4 and the glucose homeostasis. Methods: Monitoring of GLUT4 trafficking, GLUT4 internalization assay, and glucose uptake assay were carried out using differentiated 3T3-L1-GLUT4myc adipocytes. Akt1/2 and PKC isozymes were knocked-down by transfecting each siRNA. Cell-free PKC assay and in situ PKCα assay with a FRET probe were carried out. Oral glucose tolerance test (OGTT) was performed using BKS.Cg-+Lep^db/+Leb^db/Jcl mice, an animal model of type 2 diabetes mellitus (DM). Results: DOPE increased cell surface localization of the glucose transporter GLUT4 in differentiated 3T3-L1-GLUT4myc adipocytes, regardless of Akt activation. Likewise, PKCα deficiency increased cell surface localization of GLUT4, that occludes the effect of DOPE. DOPE clearly suppressed phorbol 12-myristate 13-acetate-induced PKCα activation in the cell-free and in situ PKC assay. DOPE and PKCα deficiency cancelled endocytic internalization of GLUT4 localized on the plasma membrane after insulin stimulation. DOPE significantly enhanced glucose uptake into cells. A similar effect was obtained by knocking-down PKCα, that occludes the effect of DOPE. In OGTT, oral administration with DOPE effectively restricted an increase in the blood glucose levels after glucose loading in type 2 DM model mice. Conclusion: The results of the present study show that DOPE retains cell surface GLUT4 by suppressing PKCα-driven endocytic internalization of GLUT4, to enhance glucose uptake into cells and restrict an increase in the blood glucose levels after glucose loading in type 2 DM.

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Dipalmitoleoylphosphoethanolamine as a PP2A Enhancer Obstructs Insulin Signaling by Promoting Ser/Thr Dephosphorylation of Akt

Cited by 3 publications

References 23 publications

Diarachidonoylphosphoethanolamine induces necrosis/necroptosis of malignant pleural mesothelioma cells

Diarachidonoylphosphoethanolamine induces necrosis/necroptosis of malignant pleural mesothelioma cells

The phosphatidylethanolamine derivative diDCP-LA-PE mimics intracellular insulin signaling

Dioleoylphosphoethanolamine Retains Cell Surface GLUT4 by Inhibiting PKCα-Driven Internalization

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