Reduced Luminal Calcium and Chaperone Function in Response to Elevated Free Fatty Acids in Liver Cells
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Chronic exposure to elevated free fatty acids, in particular long chain saturated fatty acids, provokes endoplasmic reticulum (ER) stress, activation of the unfolded protein response (UPR) and cell death in a number of cell types. The perturbations to the ER that instigate ER stress and activation of the unfolded protein response to fatty acids in hepatocytes have not been identified. The present study employed H4IIE liver cells and primary rat hepatocytes to examine the hypothesis that saturated fatty acids induce ER stress via effects on ER luminal calcium stores and reduced chaperone function. Exposure of H4IIE liver cells and primary hepatocytes to palmitate and stearate reduced thapsigargin‐sensitive calcium stores and induced multiple markers of ER stress and UPR activation over similar time courses (6h). Increased cell death was observed following 16h of exposure. Co‐incubation with oleate prevented the reduction in calcium stores, induction of ER stress markers and cell death. Since several ER molecular chaperones function in a calcium‐dependent manner, the effects of chemical chaperones on palmitate‐mediated ER stress and cell death was examined. The chemical chaperones, 4‐phenyl butyric acid and taurine‐conjugated ursodeoxycholic acid, reduced palmitate‐mediated ER stress and cell death. These data suggest that reduced ER luminal calcium and protein folding capacity contribute to long chain saturated fatty acid‐mediated perturbations in the ER.Keywords:
Chemical chaperone
Thapsigargin
Calcium in biology
The endoplasmic reticulum (ER) plays important roles in coordinating protein biosynthesis and secretion in the cell. Accumulation of misfolded and/or unfolded proteins in the ER causes ER stress and the so-called unfolded protein response (UPR). The UPR alleviates ER stress through blocking protein synthesis and activating expression of chaperone genes, whereas prolonged UPR could induce cell death. Recent research has showed that ER stress and UPR are involved in hearing loss. Accordingly, animal experiments showed that chemical chaperones or ER stress inducers alleviate environment-related hearing loss, whereas ER stress inhibitor has been used to treat certain types of hereditary deafness. Further investigations are needed to fully understand the detailed mechanisms of how ER stress contributes to the loss of auditory function, which will help us to eventually develop ER-stress-related treatment of various types of deafness.
Chemical chaperone
Chaperone (clinical)
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【Unfolded protein response (UPR) is an important genomic response to endoplasmic reticulum (ER) stress. The ER response is characterized by changes in specific proteins, induction of ER chaperones and degradation of misfolded proteins. Also, the pathogenesis of several diseases like Alzheimer's disease, neuronal degenerative diseases, and diabetes reveal the role of ER stress as one of the causative mechanisms. Borneolum has been used for neuronal disease in oriental medicine. In the present study, the protective effect of borneolum on thapsigargin-induced apoptosis in rat C6 glial cells. Treatment with C6 glial cells with 5 uM thapsigargin caused the loss of cell viability, and morphological change, which was associated with the elevation of intracellular $Ca^{++}$ level, the increase in Grp78 and CHOP and cleavage of pro-caspase 12 Furthermore, thapsigargin induced Grp98, XBP1, and ATF4 protein expression in C6 glial cells. Borneolum reduced thapsigargin-induced apoptosis through ER pathways. In the ER pathway, borneolum attenuated thapsigargin-induced elevations in Grp78, CHOP, ATF4, and XBP1 as well as reductions in pro-caspase 12 levels. Also, our data showed that borneolum protected thapsigargin-induced cytotoxicity in astrocytes from rat (P3) brain. Taken together, our data suggest that borneolum is neuroprotective against thapsigargin-induced ER stress in C6 glial cells and astrocytes. Accordingly, borneolum may be therapeutically useful for the treatment of thapsigargin-induced apoptosis in central nervous system.】
Thapsigargin
XBP1
ATF4
Gliosis
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OBJECTIVE: To summarize the advances of domestic and foreign research on reticulum stress and unfolded protein response,to review its molecular mechanism and the pathways of the cell survival and apoptosis associated with reticulum stress.METHODS:The full text database of PubMed and CNKI were searched,and the words endoplasmic reticulum stress/unfolded protein response/apoptosis were used as Key words:.To retrieve the literature about reticulum stress and unfolded protein response from Jan.1990 to Jan.2010,and then 24 were used in analysis at last.RESULTS:The reticulum(ER),an important intracellular organelle of eukary-ocyte,is the factory for folding and maturation of newly synthesized transmembrane and secretory proteins.Accumulation of unfolded or misfolded proteins in ER leads to ER stress and triggers the unfolded protein response(UPR).UPR is a highly conserved self-protective mechanism by ameliorating the accumulation of unfolded or misfolded proteins in the ER;however if ER stress is severe or protracted,cell apoptosis may be induced.CONCLUSION:Though the molecular mechanism of reticulum stress and unfolded protein response is clear,there are still present some questions,and so it needs further study.
Endoplasmic-reticulum-associated protein degradation
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Endoplasmic-reticulum-associated protein degradation
Homeostasis
Chaperone (clinical)
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Thapsigargin
SERCA
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Thapsigargin
Chemical chaperone
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Homeostasis
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Unfolded protein response (UPR) is an adaptive response, allowing the endoplasmic reticulum (ER) responds to an accumulation of unfolded proteins in its lumen, also known as ER stress. The ER reacts to ER stress through ER transmembrane protein sensors, thus activating intracellular signal transduction pathways. The UPR is interconnected with inflammation through reactive oxygen species production, activation of nuclear factor-kB (NF-kB) and JUN N-terminal kinase (JNK) via inositol-requiring enzyme 1 (IRE1) and induction of acute-phase response. LCN2 is one of the acute phase proteins that are induced under inflammatory conditions and up-regulated during ER stress. We therefore examined the ER stress responses in LCN2-/- condition.
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