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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Activating Transcription Factor 6 / metabolism
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Analysis of Variance
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Animals
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Apoptosis / drug effects
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Apoptosis / physiology*
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Blotting, Western
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Calcium / metabolism
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Calpain / metabolism
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DNA Primers / genetics
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Diabetes Mellitus, Type 2 / physiopathology*
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Endoplasmic Reticulum Chaperone BiP
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Endoplasmic Reticulum Stress / drug effects
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Endoplasmic Reticulum Stress / physiology*
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Fatty Acids, Nonesterified / pharmacology*
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Gene Silencing
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Heat-Shock Proteins / metabolism
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Immunoprecipitation
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Insulin-Secreting Cells / drug effects
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Insulin-Secreting Cells / physiology*
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Membrane Proteins / metabolism
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Mice
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Phosphorylation
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Protein Serine-Threonine Kinases / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / physiology*
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Transcription Factor CHOP / metabolism
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eIF-2 Kinase / metabolism
Substances
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Activating Transcription Factor 6
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Atf6 protein, mouse
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DNA Primers
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Ddit3 protein, mouse
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Endoplasmic Reticulum Chaperone BiP
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Fatty Acids, Nonesterified
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Heat-Shock Proteins
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Hspa5 protein, mouse
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Membrane Proteins
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Transcription Factor CHOP
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Ern2 protein, mouse
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PERK kinase
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Protein Serine-Threonine Kinases
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eIF-2 Kinase
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Calpain
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Calcium
Grants and funding
This work is supported by National Natural Science Foundation of China (30870948). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.