Sterol Regulatory Element-binding Proteins Activate Insulin Gene Promoter Directly and Indirectly through Synergy with BETA2/E47

Amemiya-Kudo, Michiyo; Oka, Junko; Ide, Tomohiro; Matsuzaka, Takashi; Sone, Hirohito; Yoshikawa, Tomohiro; Yahagi, Naoya; Ishibashi, Shun; Osuga, Jun-ichi; Yamada, Nobuhiro; Shimano, Hitoshi

doi:10.1074/jbc.m506718200

Cited by 27 publications

(24 citation statements)

References 50 publications

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“…It is, thus, conceivable that the proximal (GL1/GL2 containing) and distal (GL3 containing) regions of the promoter may physically interact to provide cooperative regulation of transcription. This is in agreement with previous studies that have suggested that insulin responsiveness of glucagon gene expression is dependent on interactions between proximal and distal elements (38), possibly through the formation of a DNA looping structure as found in previous studies (39,40). Finally, expression of a FoxO1.eGFP chimera increased the basal activity of the PPG promoter.…”

Section: Expression Of Foxo1 In Isolated Mousesupporting

confidence: 81%

FoxO1 Is Required for the Regulation of Preproglucagon Gene Expression by Insulin in Pancreatic αTC1-9 Cells

McKinnon

Ravier

Rutter

2006

Journal of Biological Chemistry

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Forkhead/winged helix box gene, group O-1 (FoxO1) is a member of a family of nuclear transcription factors regulated by insulin-dependent phosphorylation and implicated in the development of the endocrine pancreas. We show here firstly that FoxO1 protein is expressed in both primary mouse islet ␣ and ␤ cells. Examined in clonal ␣TC1-9 cells, insulin caused endogenous FoxO1 to translocate from the nucleus to the cytoplasm. Demonstrating the importance of nuclear exclusion of FoxO1 for the inhibition of preproglucagon gene expression, FoxO1 silencing by RNA interference reduced preproglucagon mRNA levels by >40% in the absence of insulin and abolished the decrease in mRNA levels elicited by the hormone. Electrophoretic mobility shift assay and chromatin immunoprecipitation revealed direct binding of FoxO1 to a forkhead consensus binding site, termed GL3, in the preproglucagon gene promoter region, localized ؊1798 bp upstream of the transcriptional start site. Deletion or mutation of this site diminished FoxO1 binding and eliminated transcriptional regulation by glucose or insulin. FoxO1 silencing also abolished the acute regulation by insulin, but not glucose, of glucagon secretion, demonstrating the importance of FoxO1 expression in maintaining the ␣-cell phenotype.The forkhead family of transcription factors is implicated in the control of a wide range of cellular processes (1-5). Thus, members of this family have been shown to either repress or activate transcription after signaling by insulin (6). Insulin stimulates FoxO1 by engaging a phosphatidylinositol 3-kinase-protein kinase B (PKB/Akt) signaling cascade (7) that results in the phosphorylation by PKB of FoxO1 at least three sites, 9). Protein kinase B-mediated phosphorylation at Ser-256 is crucial for the subsequent phosphorylation of Thr-24, which in turn allows nuclear export and sequestration of FoxO1 in the cytosol via binding to 14-3-3 proteins (8).A role for several members of the forkhead family in the development of the endocrine pancreas has previously been described. For example, the forkhead protein Foxa2 (formerly called hepatocyte nuclear factor-3␤) regulates transcription of the pdx-1 (10, 11) and slc2c2 genes (12) in the ␤-cell and is required for the development of a functional ␣-cell population (13). Moreover, mice in which the expression of forkhead protein Foxa1 is disrupted are hypoglycemic and display low levels of circulating glucagon despite lowered levels of insulin and an increase in the levels of cortisol and growth hormone, and proglucagon mRNA levels are depressed in these mice (14 -16). However, the precise role and targets of forkhead proteins within the pancreatic ␣-cell are at present only partly defined.There are at least four enhancer sites within the first 300 bp immediately upstream of the transcriptional start site of the proglucagon promoter, denoted G1-G4 (17-20). The G1 and G2 sites within the rat proglucagon gene bind Foxa proteins, predominantly Foxa2, which act as a repressor of preproglucagon gene expression (18...

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Section: Expression Of Foxo1 In Isolated Mousesupporting

confidence: 81%

FoxO1 Is Required for the Regulation of Preproglucagon Gene Expression by Insulin in Pancreatic αTC1-9 Cells

McKinnon

Ravier

Rutter

2006

Journal of Biological Chemistry

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“…RIP-luciferase reporter plasmid and sterol-regulatory element (SRE)-luciferase reporter plasmid were produced as previously described (22,23).…”

Section: Expression Plasmid and Reporter Plasmidsmentioning

confidence: 99%

Cholesterol accumulation and diabetes in pancreatic β-cell-specific SREBP-2 transgenic mice: a new model for lipotoxicity

Ishikawa

Iwasaki

Yatoh

et al. 2008

Journal of Lipid Research

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109

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To determine the role of cholesterol synthesis in pancreatic b-cells, a transgenic model of in vivo activation of sterol-regulatory element binding protein 2 (SREBP-2) specifically in b-cells (TgRIP-SREBP-2) was developed and analyzed. Expression of nuclear human SREBP-2 in b-cells resulted in severe diabetes as evidenced by greater than 5-fold elevations in glycohemoglobin compared with C57BL/6 controls. Diabetes in TgRIP-SREBP-2 mice was primarily due to defects in glucose-and potassium-stimulated insulin secretion as determined by glucose tolerance test. Isolated islets of TgSREBP-2 mice were fewer in number, smaller, deformed, and had decreased insulin content. SREBP-2-expressing islets also contained increased esterified cholesterol and unchanged triglycerides with reduced ATP levels. Consistently, these islets exhibited elevated expression of HMG-CoA synthase and reductase and LDL receptor, with suppression of endogenous SREBPs. Genes involved in b-cell differentiation, such as PDX1 and BETA2, were suppressed, explaining loss of b-cell mass, whereas IRS2 expression was not affected. These phenotypes were dependent on the transgene expression. Taken Sterol-regulatory element binding protein 1c (SREBP-1c) is a membrane-bound transcription factor of the basic HLH (bHLH) leucine zipper family and has been established as a nutritional regulator of lipogenic enzymes in the liver (3, 4). Expression of SREBP-1c is highly upregulated by dietary intake of carbohydrates, sugars, and saturated FAs, whereas PUFAs, such as eicosapentaenoic acid, have been shown to inhibit hepatic SREBP-1c through multiple mechanisms (5, 6). These nutritional regulations of SREBP-1c are also observed in a cultured b-cell line and in isolated islets of mice (7,8). SREBP-1c also plays a role in insulin signaling by inhibiting insulin receptor substrate 2 (IRS-2), the major insulin-signaling mediator in the liver and in b-cells (9, 10).As a model for lipotoxicity by endogenous FAs in pancreatic b-cells, we previously developed transgenic mice overexpressing the active form of SREBP-1c under the insulin promoter expression (10). These mice exhibited impaired glucose tolerance in vivo due to both decreased b-cell mass and impaired insulin secretion estimated in isolated islets, which was enhanced by feeding the mice a high-fat, high-sucrose diet. The SREBP-1c-overexpressing islets had ATP depletion caused by enhanced lipogenesis and increased uncoupling protein 2 (UCP-2). Explaining the loss of b-cell mass, these islets had decreased expression of IRS-2 and PDX1. In addition to inhibition of GSIS,

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“…The cells were transfected with a SRE-luciferase reporter plasmid (500 ng) and a pRL-SV40 plasmid (50 ng, Promega) using Lipofectamine 2000 reagent (Invitrogen, Carlsbad, CA) according to the manufacturer's instructions as previously decribed 15) . After 4-hour incubation, the cells were subjected to statin treatment as described above.…”

Section: Transfection and Luciferase Assaysmentioning

confidence: 99%

Distinct Effects of Pravastatin, Atorvastatin, and Simvastatin on Insulin Secretion from a β-cell Line, MIN6 Cells

Ishikawa

Okajima

Inoue

et al. 2006

J Atheroscler Thromb

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In addition to the prevention of cardiovascular diseases by lowering plasma LDL cholesterol, recent studies suggest that statins could have some impact on insulin action. To estimate the direct effects of statins on insulin secretion from pancreatic -cells, MIN6 cells were treated with pravastatin, simvastatin, or atorvastatin. Basal insulin secretion at low glucose concentration was unexpectedly increased at very high doses of simvastatin or atorvastatin after 24-and 48-hour incubation. Insulin secretion at high glucose was not significantly changed, and thus, net glucose-stimulated insulin secretion was apparently decreased by these lipophilic statins. The changes in insulin secretion were highly associated with increased endogenous SREBP activities in response to HMG-CoA inhibition as estimated by SRE-luciferase assays, and finally after 48-hour incubation, accompanied by impaired cell viability as estimated by MTT assays. In contrast, these changes were much less prominent by the addition of pravastatin. Meanwhile, glucose-stimulated insulin secretion of islets isolated from C57BL/6 mice was not significantly changed by any of the statins.

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Sterol Regulatory Element-binding Proteins Activate Insulin Gene Promoter Directly and Indirectly through Synergy with BETA2/E47

Cited by 27 publications

References 50 publications

FoxO1 Is Required for the Regulation of Preproglucagon Gene Expression by Insulin in Pancreatic αTC1-9 Cells

FoxO1 Is Required for the Regulation of Preproglucagon Gene Expression by Insulin in Pancreatic αTC1-9 Cells

Cholesterol accumulation and diabetes in pancreatic β-cell-specific SREBP-2 transgenic mice: a new model for lipotoxicity

Distinct Effects of Pravastatin, Atorvastatin, and Simvastatin on Insulin Secretion from a β-cell Line, MIN6 Cells

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Sterol Regulatory Element-binding Proteins Activate Insulin Gene Promoter Directly and Indirectly through Synergy with BETA2/E47

Cited by 27 publications

References 50 publications

FoxO1 Is Required for the Regulation of Preproglucagon Gene Expression by Insulin in Pancreatic αTC1-9 Cells

FoxO1 Is Required for the Regulation of Preproglucagon Gene Expression by Insulin in Pancreatic αTC1-9 Cells

Cholesterol accumulation and diabetes in pancreatic β-cell-specific SREBP-2 transgenic mice: a new model for lipotoxicity

Distinct Effects of Pravastatin, Atorvastatin, and Simvastatin on Insulin Secretion from a &beta;-cell Line, MIN6 Cells

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Product

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Distinct Effects of Pravastatin, Atorvastatin, and Simvastatin on Insulin Secretion from a β-cell Line, MIN6 Cells