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Free fatty acid induces endoplasmic reticulum stress and apoptosis of β-cells by Ca2+/calpain-2 pathways.

Dysfunction of [beta]-cells is a major characteristic in the pathogenesis of type 2 diabetes mellitus (T2DM). The combination of obesity and T2DM is associated with elevated plasma free fatty acids (FFAs). However, molecular mechanisms linking FFAs to [beta]-cell dysfunction remain poorly understood... Full description

Journal Title: PloS one 2013, Vol.8(3), p.e59921
Main Author: Cui, Wei
Other Authors: Ma, Jie , Wang, Xingqin , Yang, Wenjuan , Zhang, Jing , Ji, Qiuhe
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1932-6203 ; DOI: 10.1371/journal.pone.0059921
Link: http://search.proquest.com/docview/1319614846/?pq-origsite=primo
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title: Free fatty acid induces endoplasmic reticulum stress and apoptosis of β-cells by Ca2+/calpain-2 pathways.
format: Article
creator:
  • Cui, Wei
  • Ma, Jie
  • Wang, Xingqin
  • Yang, Wenjuan
  • Zhang, Jing
  • Ji, Qiuhe
subjects:
  • Activating Transcription Factor 6–Metabolism
  • Analysis of Variance–Drug Effects
  • Animals–Physiology
  • Apoptosis–Metabolism
  • Blotting, Western–Metabolism
  • Calcium–Genetics
  • Calpain–Physiopathology
  • DNA Primers–Drug Effects
  • Diabetes Mellitus, Type 2–Physiology
  • Endoplasmic Reticulum Stress–Pharmacology
  • Fatty Acids, Nonesterified–Metabolism
  • Gene Silencing–Drug Effects
  • Heat-Shock Proteins–Physiology
  • Immunoprecipitation–Metabolism
  • Insulin-Secreting Cells–Metabolism
  • Membrane Proteins–Physiology
  • Mice–Metabolism
  • Phosphorylation–Metabolism
  • Protein-Serine-Threonine Kinases–Metabolism
  • Reverse Transcriptase Polymerase Chain Reaction–Metabolism
  • Signal Transduction–Metabolism
  • Transcription Factor Chop–Metabolism
  • Eif-2 Kinase–Metabolism
  • Activating Transcription Factor 6
  • Atf6 Protein, Mouse
  • DNA Primers
  • Ddit3 Protein, Mouse
  • Fatty Acids, Nonesterified
  • Heat-Shock Proteins
  • Membrane Proteins
  • Transcription Factor Chop
  • Ern2 Protein, Mouse
  • Perk Kinase
  • Protein-Serine-Threonine Kinases
  • Eif-2 Kinase
  • Calpain
  • Calcium
  • Molecular Chaperone Grp78
ispartof: PloS one, 2013, Vol.8(3), p.e59921
description: Dysfunction of [beta]-cells is a major characteristic in the pathogenesis of type 2 diabetes mellitus (T2DM). The combination of obesity and T2DM is associated with elevated plasma free fatty acids (FFAs). However, molecular mechanisms linking FFAs to [beta]-cell dysfunction remain poorly understood. In the present study, we identified that the major endoplasmic reticulum stress (ERS) marker, Grp78 and ERS-induced apoptotic factor, CHOP, were time-dependently increased by exposure of [beta]-TC3 cells to FFA. The expression of ATF6 and the phosphorylation levels of PERK and IRE1, which trigger ERS signaling, markedly increased after FFA treatments. FFA treatments increased cell apoptosis by inducing ERS in [beta]-TC3 cells. We also found that FFA-induced ERS was mediated by the store-operated Ca.sup.2+ entry through promoting the association of STIM1 and Orai1. Moreover, calpain-2 was required for FFA-induced expression of CHOP and activation of caspase-12 and caspase-3, thus promoting cell apoptosis in [beta]-TC3 cells. Together, these results reveal pivotal roles for Ca.sup.2+ /calpain-2 pathways in modulating FFA-induced [beta]-TC3 cell ERS and apoptosis.
language: eng
source:
identifier: E-ISSN: 1932-6203 ; DOI: 10.1371/journal.pone.0059921
fulltext: fulltext
issn:
  • 19326203
  • 1932-6203
url: Link


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titleFree fatty acid induces endoplasmic reticulum stress and apoptosis of β-cells by Ca2+/calpain-2 pathways.
creatorCui, Wei ; Ma, Jie ; Wang, Xingqin ; Yang, Wenjuan ; Zhang, Jing ; Ji, Qiuhe
contributorCui, Wei (correspondence author) ; Cui, Wei (record owner)
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identifierE-ISSN: 1932-6203 ; DOI: 10.1371/journal.pone.0059921
subjectActivating Transcription Factor 6–Metabolism ; Analysis of Variance–Drug Effects ; Animals–Physiology ; Apoptosis–Metabolism ; Blotting, Western–Metabolism ; Calcium–Genetics ; Calpain–Physiopathology ; DNA Primers–Drug Effects ; Diabetes Mellitus, Type 2–Physiology ; Endoplasmic Reticulum Stress–Pharmacology ; Fatty Acids, Nonesterified–Metabolism ; Gene Silencing–Drug Effects ; Heat-Shock Proteins–Physiology ; Immunoprecipitation–Metabolism ; Insulin-Secreting Cells–Metabolism ; Membrane Proteins–Physiology ; Mice–Metabolism ; Phosphorylation–Metabolism ; Protein-Serine-Threonine Kinases–Metabolism ; Reverse Transcriptase Polymerase Chain Reaction–Metabolism ; Signal Transduction–Metabolism ; Transcription Factor Chop–Metabolism ; Eif-2 Kinase–Metabolism ; Activating Transcription Factor 6 ; Atf6 Protein, Mouse ; DNA Primers ; Ddit3 Protein, Mouse ; Fatty Acids, Nonesterified ; Heat-Shock Proteins ; Membrane Proteins ; Transcription Factor Chop ; Ern2 Protein, Mouse ; Perk Kinase ; Protein-Serine-Threonine Kinases ; Eif-2 Kinase ; Calpain ; Calcium ; Molecular Chaperone Grp78
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descriptionDysfunction of [beta]-cells is a major characteristic in the pathogenesis of type 2 diabetes mellitus (T2DM). The combination of obesity and T2DM is associated with elevated plasma free fatty acids (FFAs). However, molecular mechanisms linking FFAs to [beta]-cell dysfunction remain poorly understood. In the present study, we identified that the major endoplasmic reticulum stress (ERS) marker, Grp78 and ERS-induced apoptotic factor, CHOP, were time-dependently increased by exposure of [beta]-TC3 cells to FFA. The expression of ATF6 and the phosphorylation levels of PERK and IRE1, which trigger ERS signaling, markedly increased after FFA treatments. FFA treatments increased cell apoptosis by inducing ERS in [beta]-TC3 cells. We also found that FFA-induced ERS was mediated by the store-operated Ca.sup.2+ entry through promoting the association of STIM1 and Orai1. Moreover, calpain-2 was required for FFA-induced expression of CHOP and activation of caspase-12 and caspase-3, thus promoting cell apoptosis in [beta]-TC3 cells. Together, these results reveal pivotal roles for Ca.sup.2+ /calpain-2 pathways in modulating FFA-induced [beta]-TC3 cell ERS and apoptosis.
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authorCui, Wei ; Ma, Jie ; Wang, Xingqin ; Yang, Wenjuan ; Zhang, Jing ; Ji, Qiuhe
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