scholarly journals Exendin-4 inhibits glucolipotoxic ER stress in pancreatic β cells via regulation of SREBP1c and C/EBPβ transcription factors

2012 ◽  
Vol 216 (3) ◽  
pp. 343-352 ◽  
Author(s):  
Yoon Sin Oh ◽  
Youn-Jung Lee ◽  
Yup Kang ◽  
Jaeseok Han ◽  
Oh-Kyung Lim ◽  
...  
Keyword(s):  
Er Stress ◽  
Cell Apoptosis ◽  
Molecular Mechanisms ◽  
Prolonged Exposure ◽  
Nuclear Translocation ◽  
Β Cells ◽  
Β Cell ◽  
Stress Markers ◽  
Glucagon Like Peptide 1

Prolonged exposure to high glucose (HG) and palmitate (PA) results in increased ER stress and subsequently induces β-cell apoptosis. Exendin-4, a glucagon-like peptide-1 agonist, is known to protect β cells from toxicity induced by cytokines, HG, or fatty acids by reducing ER stress. However, the detailed molecular mechanisms for this protective effect are still not known. In this study, we investigated the role of exendin-4 in the inhibition of glucolipotoxicity-induced ER stress and β-cell apoptosis. Exendin-4 treatment protected INS-1 β cells from apoptosis in response to HG/PA (25 mM glucose+400 μM PA). HG/PA treatment increased cleaved caspase-3 and induced ER stress maker proteins such as PERK (EIF2AK3), ATF6, and phosphorylated forms of PERK, eIF2α, IRE1α (ERN1), and JNK (MAPK8), and these increases were significantly inhibited by exendin-4 treatment. HG/PA treatment of INS-1 cells increased SREBP1 (SREBF1) protein and induced its nuclear translocation and subsequently increased C/EBPβ (CEBPB) protein and its nuclear translocation. Exendin-4 treatment attenuated this increase. Knockdown ofSREBP1creduced the activation ofC/EBPβand also blocked the expression of ER stress markers induced by HG/PA treatment. Our results indicate that exendin-4 inhibits the activation of SREBP1c and C/EBPβ, which, in turn, may reduce glucolipotoxicity-induced ER stress and β-cell apoptosis.

A novel secretagogin/ATF4 pathway is involved in oxidized LDL-induced endoplasmic reticulum stress and islet β-cell apoptosis

2020 ◽  
Author(s):  
Li Wu ◽  
Yuncheng Lv ◽  
Ying Lv ◽  
Sunmin Xiang ◽  
Zhibo Zhao ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Er Stress ◽  
Cell Apoptosis ◽  
Initiation Factor ◽  
Β Cells ◽  
Β Cell ◽  
Immunoprecipitation Assay ◽  
Min6 Cells ◽  
Stress Markers

Abstract Excessive accumulation of cholesterol in β cells initiates endoplasmic reticulum (ER) stress and associated apoptosis. We have reported that excessive uptake of cholesterol by MIN6 cells decreases the expression of secretagogin (SCGN) and then attenuates insulin secretion. Here, we aimed to determine whether cholesterol-induced SCGN decrease is involved in the modulation of ER stress and apoptosis in pancreatic β cells. In this study, MIN6 cells were treated with oxidized low-density lipoprotein (ox-LDL) for 24 h, and then intracellular lipid droplets and cell apoptosis were quantified, and SCGN and ER stress markers were identified by western blot analysis. Furthermore, small interfer RNA (siRNA)-mediated SCGN knockdown and recombinant plasmid-mediated SCGN restoration experiments were performed to confirm the role of SCGN in ER stress and associated cell apoptosis. Finally, the interaction of SCGN with ATF4 was computationally predicted and then validated by a co-immunoprecipitation assay. We found that ox-LDL treatment increased the levels of ER stress markers, such as phosphorylated protein kinase-like endoplasmic reticulum kinase, phosphorylated eukaryotic initiation factor 2 alpha, activating transcription factor 4 (ATF4), and transcription factor CCAAT-enhancer-binding protein homologous protein, and promoted MIN6 cell apoptosis; in addition, the expression of SCGN was downregulated. siRNA-mediated SCGN knockdown exacerbated β-cell ER stress by increasing ATF4 expression. Pretreatment of MIN6 cells with the recombinant SCGN partly antagonized ox-LDL-induced ER stress and apoptosis. Furthermore, a co-immunoprecipitation assay revealed an interaction between SCGN and ATF4 in MIN6 cells. Taken together, these results demonstrated that pancreatic β-cell apoptosis induced by ox-LDL treatment can be attributed, in part, to an SCGN/ATF4-dependent ER stress response.

scholarly journals Deficiency of VCP-Interacting Membrane Selenoprotein (VIMP) Leads to G1 Cell Cycle Arrest and Cell Death in MIN6 Insulinoma Cells

2018 ◽  
Vol 51 (5) ◽  
pp. 2185-2197 ◽  
Author(s):  
Lili Men ◽  
Juan Sun ◽  
Decheng Ren
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Insulin Secretion ◽  
Cell Apoptosis ◽  
Β Cells ◽  
Β Cell ◽  
Cycle Arrest ◽  
G1 Cell Cycle Arrest ◽  
Insulinoma Cells

Background/Aims: VCP-interacting membrane selenoprotein (VIMP), an ER resident selenoprotein, is highly expressed in β-cells, however, the role of VIMP in β-cells has not been characterized. In this study, we studied the relationship between VIMP deficiency and β-cell survival in MIN6 insulinoma cells. Methods: To determine the role of VIMP in β-cells, lentiviral VIMP shRNAs were used to knock down (KD) expression of VIMP in MIN6 cells. Cell death was quantified by propidium iodide (PI) staining followed by flow cytometric analyses using a FACS Caliber and FlowJo software. Cell apoptosis and proliferation were determined by TUNEL assay and Ki67 staining, respectively. Cell cycle was analyzed after PI staining. Results: The results show that 1) VIMP suppression induces β-cell apoptosis, which is associated with a decrease in Bcl-xL, and the β-cell apoptosis induced by VIMP suppression can be inhibited by overexpression of Bcl-xL; 2) VIMP knockdown (KD) decreases cell proliferation and G1 cell cycle arrest by accumulating p27 and decreasing E2F1; 3) VIMP KD suppresses unfolded protein response (UPR) activation by regulating the IRE1α and PERK pathways; 4) VIMP KD increases insulin secretion. Conclusion: These results suggest that VIMP may function as a novel regulator to modulate β-cell survival, proliferation, cell cycle, UPR and insulin secretion in MIN6 cells.

scholarly journals ER stress and development of type 1 diabetes

2016 ◽  
Vol 64 (1) ◽  
pp. 2-6 ◽  
Author(s):  
Feyza Engin
Keyword(s):  
Type 1 Diabetes ◽  
Er Stress ◽  
Molecular Mechanisms ◽  
Adaptive Responses ◽  
Β Cell ◽  
Cellular Homeostasis ◽  
Unfolded Protein

Type 1 diabetes (T1D) results from an autoimmune-mediated destruction of pancreatic β cells. The incidence of T1D is on the rise globally around 3% to 5% per year and rapidly increasing incidence in younger children is of the greatest concern. currently, there is no way to cure or prevent T1D; hence, a deeper understanding of the underlying molecular mechanisms of this disease is essential to the development of new effective therapies. The endoplasmic reticulum (ER) is an organelle with multiple functions that are essential for cellular homeostasis. Excessive demand on the ER, chronic inflammation, and environmental factors lead to ER stress and to re-establish cellular homeostasis, the adaptive unfolded protein response (UPR) is triggered. However, chronic ER stress leads to a switch from a prosurvival to a proapoptotic UPR, resulting in cell death. Accumulating data have implicated ER stress and defective UPR in the pathogenesis of inflammatory and autoimmune diseases, and ER stress has been implicated in β-cell failure in type 2 diabetes. However, the role of ER stress and the UPR in β-cell pathophysiology and in the initiation and propagation of the autoimmune responses in T1D remains undefined. This review will highlight the current understanding and recent in vivo data on the role of ER stress and adaptive responses in T1D pathogenesis and the potential therapeutic aspect of enhancing β-cell ER function and restoring UPR defects as novel clinical strategies against this disease.

scholarly journals Enhancer of Zeste Homolog 2 (EZH2) Mediates Glucolipotoxicity-Induced Apoptosis in β-Cells

2020 ◽  
Vol 21 (21) ◽  
pp. 8016
Author(s):  
Tina Dahlby ◽  
Christian Simon ◽  
Marie Balslev Backe ◽  
Mattias Salling Dahllöf ◽  
Edward Holson ◽  
...  
Keyword(s):  
Er Stress ◽  
Molecular Mechanisms ◽  
Selective Inhibition ◽  
Human Islets ◽  
Β Cells ◽  
Β Cell ◽  
Enhancer Of Zeste ◽  
Cell Gene Expression ◽  
Nfκb Pathway ◽  
Induced Apoptosis

Selective inhibition of histone deacetylase 3 (HDAC3) prevents glucolipotoxicity-induced β-cell dysfunction and apoptosis by alleviation of proapoptotic endoplasmic reticulum (ER) stress-signaling, but the precise molecular mechanisms of alleviation are unexplored. By unbiased microarray analysis of the β-cell gene expression profile of insulin-producing cells exposed to glucolipotoxicity in the presence or absence of a selective HDAC3 inhibitor, we identified Enhancer of zeste homolog 2 (EZH2) as the sole target candidate. β-Cells were protected against glucolipotoxicity-induced ER stress and apoptosis by EZH2 attenuation. Small molecule inhibitors of EZH2 histone methyltransferase activity rescued human islets from glucolipotoxicity-induced apoptosis. Moreover, EZH2 knockdown cells were protected against glucolipotoxicity-induced downregulation of the protective non-canonical Nuclear factor of kappa light polypeptide gene enhancer in B-cells (NFκB) pathway. We conclude that EZH2 deficiency protects from glucolipotoxicity-induced ER stress, apoptosis and downregulation of the non-canonical NFκB pathway, but not from insulin secretory dysfunction. The mechanism likely involves transcriptional regulation via EZH2 functioning as a methyltransferase and/or as a methylation-dependent transcription factor.

scholarly journals The Orphan Nuclear Receptor NR4A1 Protects Pancreatic β-Cells from Endoplasmic Reticulum (ER) Stress-mediated Apoptosis

2015 ◽  
Vol 290 (34) ◽  
pp. 20687-20699 ◽  
Author(s):  
Cong Yu ◽  
Shang Cui ◽  
Chen Zong ◽  
Weina Gao ◽  
Tongfu Xu ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Survivin Promoter ◽  
Min6 Cells ◽  
Chop Expression ◽  
Mouse Islets

The role of NR4A1 in apoptosis is controversial. Pancreatic β-cells often face endoplasmic reticulum (ER) stress under adverse conditions such as high free fatty acid (FFA) concentrations and sustained hyperglycemia. Severe ER stress results in β-cell apoptosis. The aim of this study was to analyze the role of NR4A1 in ER stress-mediated β-cell apoptosis and to characterize the related mechanisms. We confirmed that upon treatment with the ER stress inducers thapsigargin (TG) or palmitic acid (PA), the mRNA and protein levels of NR4A1 rapidly increased in both MIN6 cells and mouse islets. NR4A1 overexpression in MIN6 cells conferred resistance to cell loss induced by TG or PA, as assessed by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, and TUNEL assays indicated that NR4A1 overexpression also protected against ER stress-induced apoptosis. This conclusion was further confirmed by experiments exploiting siRNA to knockdown NR4A1 expression in MIN6 cells or exploiting NR4A1 knock-out mice. NR4A1 overexpression in MIN6 cells reduced C/EBP homologous protein (CHOP) expression and Caspase3 activation induced by TG or PA. NR4A1 overexpression in MIN6 cells or mouse islets resulted in Survivin up-regulation. A critical regulatory element was identified in Survivin promoter (−1872 bp to −1866 bp) with a putative NR4A1 binding site; ChIP assays demonstrated that NR4A1 physically associates with the Survivin promoter. In conclusion, NR4A1 protects pancreatic β-cells against ER stress-mediated apoptosis by up-regulating Survivin expression and down-regulating CHOP expression, which we termed as “positive and negative regulation.”

scholarly journals Imeglimin Ameliorates β-cell Apoptosis by Modulating the Endoplasmic Reticulum Homeostasis Pathway

2021 ◽  
Author(s):  
Jinghe Li ◽  
Ryota Inoue ◽  
Yu Togashi ◽  
Tomoko Okuyama ◽  
Aoi Satoh ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Cell Survival ◽  
Cell Apoptosis ◽  
Cell Function ◽  
Cell Mass ◽  
Β Cells ◽  
Β Cell ◽  
Akita Mice ◽  
The Impact

The effects of imeglimin, a novel anti-diabetes agent, on β-cell function remain unclear. Here, we unveiled the impact of imeglimin on β-cell survival. Treatment with imeglimin augmented mitochondrial function, enhanced insulin secretion, promoted β-cell proliferation, and improved β-cell survival in mouse islets. Imeglimin upregulated the expression of endoplasmic reticulum (ER)-related molecules including <i>Chop (Ddit3),</i> <i>Gadd34</i> (<i>Ppp1r15a</i>), <i>Atf3</i>, and <i>Sdf2l1</i>, and decreased eIF2α phosphorylation, after treatment with thapsigargin, and restored global protein synthesis in β-cells under ER stress. Imeglimin failed to protect ER stress-induced β-cell apoptosis in CHOP-deficient islets or in the presence of GADD34 inhibitor. Treatment with imeglimin showed a significant decrease in the number of apoptotic β-cells and increased β-cell mass in Akita mice. Imeglimin also protected against β-cell apoptosis in both human islets and human pluripotent stem cell (<a>hPSC)-derived β-like cells</a>. <a>Taken together, imeglimin modulates ER homeostasis pathway, which results in the prevention of β-cell apoptosis both <i>in vitro</i> and <i>in vivo</i>.</a>

scholarly journals Emerging role of testosterone in pancreatic β cell function and insulin secretion

2019 ◽  
Vol 240 (3) ◽  
pp. R97-R105 ◽  
Author(s):  
Weiwei Xu ◽  
Jamie Morford ◽  
Franck Mauvais-Jarvis
Keyword(s):  
Insulin Secretion ◽  
Metabolic Regulation ◽  
Cell Function ◽  
Visceral Obesity ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function ◽  
Glucagon Like Peptide 1 ◽  
Glucose Stimulated Insulin Secretion

One of the most sexually dimorphic aspects of metabolic regulation is the bidirectional modulation of glucose homeostasis by testosterone in male and females. Severe testosterone deficiency predisposes men to type 2 diabetes (T2D), while in contrast, androgen excess predisposes women to hyperglycemia. The role of androgen deficiency and excess in promoting visceral obesity and insulin resistance in men and women respectively is well established. However, although it is established that hyperglycemia requires β cell dysfunction to develop, the role of testosterone in β cell function is less understood. This review discusses recent evidence that the androgen receptor (AR) is present in male and female β cells. In males, testosterone action on AR in β cells enhances glucose-stimulated insulin secretion by potentiating the insulinotropic action of glucagon-like peptide-1. In females, excess testosterone action via AR in β cells promotes insulin hypersecretion leading to oxidative injury, which in turn predisposes to T2D.

D4F alleviates the C/EBP homologous protein-mediated apoptosis in glycated high-density lipoprotein-treated macrophages by facilitating autophagy

2021 ◽  
pp. 153537022110453
Author(s):  
Hua Tian ◽  
Zhaoqiang Zhang ◽  
Xiaoyan Han ◽  
Tianqi Pan ◽  
Geru Tao ◽  
...  
Keyword(s):  
High Density Lipoprotein ◽  
Er Stress ◽  
Cell Apoptosis ◽  
Nuclear Translocation ◽  
Density Lipoprotein ◽  
High Density ◽  
Beclin 1 ◽  
Homologous Protein ◽  
Raw264.7 Macrophages

The present study aimed to investigate the role of D4F, an apolipoprotein A-I mimetic peptide, in macrophage apoptosis induced by the glycated high-density lipoprotein (gly-HDL)-induced endoplasmic reticulum (ER) stress C/EBP homologous protein (CHOP) pathway, and unravel the regulatory role of autophagy in this process. Our results revealed that except for suppressing the accumulation of lipids within RAW264.7 macrophages caused by gly-HDL, D4F inhibited gly-HDL-induced decrease in the cell viability and increase in lactate dehydrogenase leakage and cell apoptosis, which were similar to 4-phenylbutyric acid (PBA, an ER stress inhibitor). Besides, similar to PBA, D4F inhibited gly-HDL-induced ER stress response activation evaluated through the decreased PERK and eIF2α phosphorylation, together with reduced ATF6 nuclear translocation as well as the downregulation of GRP78 and CHOP. Interestingly, D4F facilitated gly-HDL-triggered activation of autophagy, measured as elevated levels of beclin-1, LC3-II, and ATG5 expressions in macrophages. Furthermore, the inhibition effect of D4F on gly-HDL-induced ER stress-CHOP-induced apoptosis of macrophages was restrained after beclin-1 siRNA and 3-methyladenine (3-MA, an inhibitor of autophagy) treatments, while this effect was further reinforced after rapamycin (Rapa, an inducer of autophagy) treatment. Furthermore, administering D4F or Rapa to T2DM mice upregulated LC3-II and attenuated CHOP expression, cell apoptosis, and atherosclerotic lesions. However, the opposite results were obtained when 3-MA was administered to these mice. These results support that D4F effectively protects macrophages against gly-HDL-induced ER stress-CHOP-mediated apoptosis by promoting autophagy.

scholarly journals Role of calcium-independent phospholipase A2β in human pancreatic islet β-cell apoptosis

2012 ◽  
Vol 303 (11) ◽  
pp. E1386-E1395 ◽  
Author(s):  
Xiaoyong Lei ◽  
Sheng Zhang ◽  
Alan Bohrer ◽  
Suzanne E. Barbour ◽  
Sasanka Ramanadham
Keyword(s):  
Er Stress ◽  
Cell Apoptosis ◽  
Caspase 3 ◽  
Apoptotic Cell ◽  
Human Islet ◽  
Β Cells ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Β Protein ◽  
Insulinoma Cells

Death of β-cells due to apoptosis is an important contributor to β-cell dysfunction in both type 1 and type 2 diabetes mellitus. Previously, we described participation of the Group VIA Ca2+-independent phospholipase A2 (iPLA2β) in apoptosis of insulinoma cells due to ER stress. To examine whether islet β-cells are similarly susceptible to ER stress and undergo iPLA2β-mediated apoptosis, we assessed the ER stress response in human pancreatic islets. Here, we report that the iPLA2β protein is expressed predominantly in the β-cells of human islets and that thapsigargin-induced ER stress promotes β-cell apoptosis, as reflected by increases in activated caspase-3 in the β-cells. Furthermore, we demonstrate that ER stress is associated with increases in islet iPLA2β message, protein, and activity, iPLA2β-dependent induction of neutral sphingomyelinase and ceramide accumulation, and subsequent loss of mitochondrial membrane potential. We also observe that basal activated caspase-3 increases with age, raising the possibility that β-cells in older human subjects have a greater susceptibility to undergo apoptotic cell death. These findings reveal for the first time expression of iPLA2β protein in human islet β-cells and that induction of iPLA2β during ER stress contributes to human islet β-cell apoptosis. We hypothesize that modulation of iPLA2β activity might reduce β-cell apoptosis and this would be beneficial in delaying or preventing β-cell dysfunction associated with diabetes.

scholarly journals CHOP Contributes to, But Is Not the Only Mediator of, IAPP Induced β-Cell Apoptosis

2016 ◽  
Vol 30 (4) ◽  
pp. 446-454 ◽  
Author(s):  
T. Gurlo ◽  
J. F. Rivera ◽  
A. E. Butler ◽  
M. Cory ◽  
J. Hoang ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Er Stress ◽  
Cell Apoptosis ◽  
Protein Misfolding ◽  
Nuclear Translocation ◽  
Cell Mass ◽  
Cell Loss ◽  
Β Cell ◽  
Islet Amyloid

The islet in type 2 diabetes is characterized by β-cell loss, increased β-cell apoptosis, and islet amyloid derived from islet amyloid polypeptide (IAPP). When protein misfolding protective mechanisms are overcome, human IAPP (h-IAPP) forms membrane permeant toxic oligomers that induce β-cell dysfunction and apoptosis. In humans with type 2 diabetes (T2D) and mice transgenic for h-IAPP, endoplasmic reticulum (ER) stress has been inferred from nuclear translocation of CCAAT/enhancer-binding protein homologous protein (CHOP), an established mediator of ER stress. To establish whether h-IAPP toxicity is mediated by ER stress, we evaluated diabetes onset and β-cell mass in h-IAPP transgenic (h-TG) mice with and without deletion of CHOP in comparison with wild-type controls. Diabetes was delayed in h-TG CHOP−/− mice, with relatively preserved β-cell mass and decreased β-cell apoptosis. Deletion of CHOP attenuates dysfunction of the autophagy/lysosomal pathway in β-cells of h-TG mice, uncovering a role for CHOP in mediating h-IAPP-induced dysfunction of autophagy. As deletion of CHOP delayed but did not prevent h-IAPP-induced β-cell loss and diabetes, we examined CHOP-independent stress pathways. JNK, a target of the IRE-1pTRAF2 complex, and the Bcl-2 family proapoptotic mediator BIM, a target of ATF4, were comparably activated by h-IAPP expression in the presence and absence of CHOP. Therefore, although these studies affirm that CHOP is a mediator of h-IAPP-induced ER stress, it is not the only one. Therefore, suppression of CHOP alone is unlikely to be a durable therapeutic strategy to protect against h-IAPP toxicity because multiple stress pathways are activated.

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