Tyrosol, an olive oil polyphenol, inhibits ER stress-induced apoptosis in pancreatic β-cell through JNK signaling

Chronic exposure to elevated saturated free fatty acid (FFA) levels has been shown to induce endoplasmic reticulum (ER) stress that may contribute to promoting pancreatic β-cell apoptosis. Here, we compared the effects of FFAs on apoptosis and ER stress in human islets and two pancreatic β-cell lines, rat INS-1 and mouse MIN6 cells. Isolated human islets cultured in vitro underwent apoptosis, and markers of ER stress pathways were elevated by chronic palmitate exposure. Palmitate also induced apoptosis in MIN6 and INS-1 cells, although the former were more resistant to both apoptosis and ER stress. MIN6 cells were found to express significantly higher levels of ER chaperone proteins than INS-1 cells, which likely accounts for the ER stress resistance. We attempted to determine the relative contribution that ER stress plays in palmitate-induced β-cell apoptosis. Although overexpressing GRP78 in INS-1 cells partially reduced susceptibility to thapsigargin, this failed to reduce palmitate-induced ER stress or apoptosis. In INS-1 cells, palmitate induced apoptosis at concentrations that did not result in significant ER stress. Finally, MIN6 cells depleted of GRP78 were more susceptible to tunicamycin-induced apoptosis but not to palmitate-induced apoptosis compared with control cells. These results suggest that ER stress is likely not the main mechanism involved in palmitate-induced apoptosis in β-cell lines. Human islets and MIN6 cells were found to express high levels of stearoyl-CoA desaturase-1 compared with INS-1 cells, which may account for the decreased susceptibility of these cells to the cytotoxic effects of palmitate.

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Therapeutic opportunities for pancreatic β-cell ER stress in diabetes mellitus

Nature Reviews Endocrinology ◽

10.1038/s41574-021-00510-4 ◽

2021 ◽

Author(s):

Jing Yong ◽

James D. Johnson ◽

Peter Arvan ◽

Jaeseok Han ◽

Randal J. Kaufman

Keyword(s):

Diabetes Mellitus ◽

Er Stress ◽

Pancreatic Β Cell ◽

Β Cell

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Dexamethasone induces pancreatic β-cell apoptosis through upregulation of TRAIL death receptor

Journal of Molecular Endocrinology ◽

10.1530/jme-20-0238 ◽

2021 ◽

Author(s):

Kanchana Suksri ◽

Namoiy Semprasert ◽

Mutita Junking ◽

Suchanoot Kutpruek ◽

Thawornchai Limjindaporn ◽

...

Keyword(s):

Cell Apoptosis ◽

Molecular Mechanisms ◽

Cultured Cells ◽

Death Receptor ◽

Caspase 8 ◽

Pancreatic Β Cell ◽

Β Cell ◽

Apoptotic Protein ◽

Induced Apoptosis ◽

Trail Death Receptor

Long-term medication with dexamethasone (a synthetic glucocorticoid (GC) drug) results in hyperglycemia, or steroid-induced diabetes. Although recent studies revealed dexamethasone directly induces pancreatic β-cell apoptosis, its molecular mechanisms remain unclear. In our initial analysis of mRNA transcripts, we discovered the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway may be involved in dexamethasone-induced pancreatic β-cell apoptosis. In the present study, a mechanism of dexamethasone-induced pancreatic β-cell apoptosis through the TRAIL pathway was investigated in cultured cells and isolated mouse islets. INS-1 cells were cultured with and without dexamethasone in the presence or absence of a glucocorticoid receptor (GR) inhibitor, RU486. We found that dexamethasone induced pancreatic β-cell apoptosis in association with the upregulation of TRAIL mRNA and protein expression. Moreover, dexamethasone upregulated the TRAIL death receptor (DR5) protein but suppressed the decoy receptor (DcR1) protein. Similar findings were observed in mouse isolated islets: dexamethasone increased TRAIL and DR5 compared to that of control mice. Furthermore, dexamethasone stimulated pro-apoptotic signaling including superoxide production, caspase-8, -9, and -3 activities, NF-B, and Bax, but repressed the anti-apoptotic protein, Bcl-2. All these effects were inhibited by the GR-inhibitor, RU486. Furthermore, knock down DR5 decreased dexamethasone-induced caspase 3 activity. Caspase-8 and caspase-9 inhibitors protected pancreatic β-cells from dexamethasone-induced apoptosis. Taken together, dexamethasone induced pancreatic β-cell apoptosis by binding to the GR and inducing DR5 and TRAIL pathway.

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Intermittent-Hypoxia-Induced Autophagy Activation Through the ER-Stress-Related PERK/eIF2α/ATF4 Pathway is a Protective Response to Pancreatic β-Cell Apoptosis

Cellular Physiology and Biochemistry ◽

10.1159/000496047 ◽

2018 ◽

Vol 51 (6) ◽

pp. 2955-2971 ◽

Cited By ~ 16

Author(s):

Shuling Song ◽

Jin Tan ◽

Yuyang Miao ◽

Zuoming Sun ◽

Qiang Zhang

Keyword(s):

Er Stress ◽

Signaling Pathway ◽

Cell Apoptosis ◽

Intermittent Hypoxia ◽

Autophagic Vacuole ◽

Pancreatic Β Cell ◽

Β Cell ◽

Protective Response

Background/Aims: Intermittent hypoxia (IH) causes apoptosis in pancreatic β-cells, but the potential mechanisms remain unclear. Endoplasmic reticulum (ER) stress, autophagy, and apoptosis are interlocked in an extensive crosstalk. Thus, this study aimed to investigate the contributions of ER stress and autophagy to IH-induced pancreatic β-cell apoptosis. Methods: We established animal and cell models of IH, and then inhibited autophagy and ER stress by pharmacology and small interfering RNA (siRNA) in INS-1 cells and rats. The levels of biomarkers for autophagy, ER stress, and apoptosis were evaluated by immunoblotting and immunofluorescence. The number of autophagic vacuoles was observed by transmission electron microscopy. Results: IH induced autophagy activation both in vivo and in vitro, as evidenced by increased autophagic vacuole formation and LC3 turnover, and decreased SQSTM1 level. The levels of ER-stress-related proteins, including GRP78, CHOP, caspase 12, phosphorylated (p)-protein kinase RNA-like ER kinase (PERK), p-eIF2α, and activating transcription factor 4 (ATF4) were increased under IH conditions. Inhibition of ER stress with tauroursodeoxycholic acid or 4-phenylbutyrate partially blocked IH-induced autophagy in INS-1 cells. Furthermore, inhibition of PERK with GSK2606414 or siRNA blocked the ERstress-related PERK/eIF2α/ATF4 signaling pathway and inhibited autophagy induced by IH, which indicates that IH-induced autophagy activation is dependent on this signaling pathway. Promoting autophagy with rapamycin alleviated IH-induced apoptosis, whereas inhibition of autophagy with chloroquine or autophagy-related gene (Atg5 and Atg7) siRNA aggravated pancreatic β-cell apoptosis caused by IH. Conclusion: IH induces autophagy activation through the ER-stress-related PERK/eIF2α/ATF4 signaling pathway, which is a protective response to pancreatic β-cell apoptosis caused by IH.

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

International Journal of Molecular Sciences ◽

10.3390/ijms21218016 ◽

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.

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The NLRP3 inflammasome is dispensable for ER stress-induced pancreatic β-cell damage in Akita mice

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2015.09.009 ◽

2015 ◽

Vol 466 (3) ◽

pp. 300-305 ◽

Cited By ~ 5

Author(s):

Jie Wang ◽

Mi-Young Song ◽

Joo Young Lee ◽

Keun Sang Kwon ◽

Byung-Hyun Park

Keyword(s):

Er Stress ◽

Nlrp3 Inflammasome ◽

Cell Damage ◽

Pancreatic Β Cell ◽

Β Cell ◽

Akita Mice

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The role of casein kinase 2 in ER stress associated pancreatic β cell failure

Diabetes Research and Clinical Practice ◽

10.1016/s0168-8227(16)31000-2 ◽

2016 ◽

Vol 120 ◽

pp. S42

Author(s):

Yuki Matsuura ◽

Tomoko Takai ◽

Tomokazu Matsuda ◽

Emi Terashi ◽

Ayumi Kanno ◽

...

Keyword(s):

Er Stress ◽

Casein Kinase ◽

Casein Kinase 2 ◽

Pancreatic Β Cell ◽

Β Cell

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Transcription factor ATF4 maintains pancreatic β-cell identity during ER stress

Proceedings for Annual Meeting of The Japanese Pharmacological Society ◽

10.1254/jpssuppl.94.0_2-y-e2-1 ◽

2021 ◽

Vol 94 (0) ◽

pp. 2-Y-E2-1

Author(s):

Keisuke Kitakaze ◽

Miho Oyadomari ◽

Jun Zhang ◽

Yoshimasa Hamada ◽

Yasuhiro Takenouchi ◽

...

Keyword(s):

Transcription Factor ◽

Er Stress ◽

Pancreatic Β Cell ◽

Β Cell ◽

Cell Identity

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Chronic activation of GPR40 does not negatively impact upon BRIN-BD11 pancreatic β-cell physiology and function

Pharmacological Reports ◽

10.1007/s43440-020-00101-6 ◽

2020 ◽

Vol 72 (6) ◽

pp. 1725-1737

Author(s):

Eloisa Aparecida Vilas-Boas ◽

Noémie Karabacz ◽

Gabriela Nunes Marsiglio-Librais ◽

Maíra Melo Rezende Valle ◽

Lisa Nalbach ◽

...

Keyword(s):

Insulin Secretion ◽

Er Stress ◽

Cell Physiology ◽

Pancreatic Β Cell ◽

Β Cells ◽

Β Cell ◽

Pancreatic Β Cells ◽

Chronic Activation ◽

And Function

Abstract Background Free fatty acids (FFAs) are known for their dual effects on insulin secretion and pancreatic β-cell survival. Short-term exposure to FFAs, such as palmitate, increases insulin secretion. On the contrary, long-term exposure to saturated FFAs results in decreased insulin secretion, as well as triggering oxidative stress and endoplasmic reticulum (ER) stress, culminating in cell death. The effects of FFAs can be mediated either via their intracellular oxidation and consequent effects on cellular metabolism or via activation of the membrane receptor GPR40. Both pathways are likely to be activated upon both short- and long-term exposure to FFAs. However, the precise role of GPR40 in β-cell physiology, especially upon chronic exposure to FFAs, remains unclear. Methods We used the GPR40 agonist (GW9508) and antagonist (GW1100) to investigate the impact of chronically modulating GPR40 activity on BRIN-BD11 pancreatic β-cells physiology and function. Results We observed that chronic activation of GPR40 did not lead to increased apoptosis, and both proliferation and glucose-induced calcium entry were unchanged compared to control conditions. We also observed no increase in H2O2 or superoxide levels and no increase in the ER stress markers p-eIF2α, CHOP and BIP. As expected, palmitate led to increased H2O2 levels, decreased cell viability and proliferation, as well as decreased metabolism and calcium entry. These changes were not counteracted by the co-treatment of palmitate-exposed cells with the GPR40 antagonist GW1100. Conclusions Chronic activation of GPR40 using GW9508 does not negatively impact upon BRIN-BD11 pancreatic β-cells physiology and function. The GPR40 antagonist GW1100 does not protect against the deleterious effects of chronic palmitate exposure. We conclude that GPR40 is probably not involved in mediating the toxicity associated with chronic palmitate exposure.

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