title: Free fatty acid induces endoplasmic reticulum stress and apoptosis of β-cells by Ca2+/calpain-2 pathways.
abstract: Dysfunction of β-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 β-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 β-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 β-TC3 cells. We also found that FFA-induced ERS was mediated by the store-operated Ca(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 β-TC3 cells. Together, these results reveal pivotal roles for Ca(2+)/calpain-2 pathways in modulating FFA-induced β-TC3 cell ERS and apoptosis.
authors.affiliation: Department of Endocrinology and Metabolism, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Cui
authors.forename: Jie
authors.initials: J
authors.lastname: Ma
authors.forename: Xingqin
authors.initials: X
authors.lastname: Wang
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Yang
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Qiuhe
authors.initials: Q
authors.lastname: Ji
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology*; D020868:Gene Silencing; D006360:Heat-Shock Proteins / Q000378:metabolism; D047468:Immunoprecipitation; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D051742:Transcription Factor CHOP / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D051702:Activating Transcription Factor 6; D002118:Calcium; D002154:Calpain; D017931:DNA Primers; D000091342:Endoplasmic Reticulum Chaperone BiP; D005230:Fatty Acids, Nonesterified; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D051742:Transcription Factor CHOP; D019892:eIF-2 Kinase; C497112:Atf6 protein, mouse; C497250:Ddit3 protein, mouse; C000717248:Hspa5 protein, mouse; C486556:Ern2 protein, mouse