Differential regulation of the endoplasmic reticulum stress response in pancreatic β-cells exposed to long-chain saturated and monounsaturated fatty acids
Differential regulation of the endoplasmic reticulum stress response in pancreatic β-cells exposed to long-chain saturated and monounsaturated fatty acids
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DOI：
10.1677/joe-08-0041
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发表时间：
2008-06-01
影响因子：
4
通讯作者：
Morgan, Noel G.
中科院分区：
文献类型：
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作者：
Diakogiannaki, Eleftheria;Welters, Hannah J.;Morgan, Noel G.
胰腺β细胞暴露于长链脂肪酸导致内质网（ER）应激途径的某些组分活化，这种机制可能是某些脂肪酸促进β细胞死亡的能力的基础。我们研究了BRIN-BD 11 β细胞暴露于饱和脂肪酸棕榈酸酯（C16：0）或单不饱和棕榈油酸酯（C16：1）的ER应激。棕榈酸（0-025-0-25 mM）诱导ER应激的RNA依赖性蛋白激酶样ER真核起始因子2 α（eIF 2 α）激酶（PERK）依赖性途径（磷酸-eIF 2 α; ATF 4，激活转录因子4和C/EBP同源蛋白（CHOP-10））的各种标志物的表达，尽管它未能促进ER伴侣GRP 78的表达。相比之下，棕榈油酸酯没有诱导任何标志物的ER应激途径，即使在浓度高达1 mM。当棕榈酸酯和棕榈油酸酯组合添加时，ER应激反应发生显着衰减。在这些条件下，磷酸-eIF 2 α、ATF 4和CHOP-10的水平降低至低于对照细胞中发现的水平。棕榈酸酯也减弱了ER应激反应的蛋白质糖基化抑制剂，衣霉素，并提高了细胞的活力暴露于这种代理。BRIN-BD 11细胞在不存在脂肪酸的情况下暴露于蛋白磷酸酶抑制剂salubrinal导致eIF 2 α磷酸化增加，但与palinitoleate共孵育可消除这种情况。我们的结论是，饱和脂肪酸激活P细胞中PERK依赖性ER应激途径的组分，最终导致细胞凋亡增加。这种作用被单不饱和化合物拮抗，所述单不饱和化合物可以通过调节参与介导eIF 2 α磷酸化的一种或多种激酶的活性来发挥其抗凋亡作用。
Exposure of pancreatic beta-cells to long-chain fatty acids leads to the activation of some components of the endoplasmic reticulum (ER) stress pathway and this mechanism may underlie the ability of certain fatty acids to promote beta-cell death. We have studied ER stress in BRIN-BD11 beta-cells exposed to either the saturated fatty acid palmitate (C16:0) or the monounsaturated palmitoleate (C16:1). Palmitate (0-025-0-25 mM) induced the expression of various markers of the RNA-dependent protein kinase-like ER eukaryotic initiation factor 2 alpha (eIf2 alpha) kinase (PERK) -dependent pathway of ER stress (phospho-eIF2 alpha; ATF4, activating transcription factor 4 and C/EBP homologous protein (CHOP-10)) although it failed to promote the expression of the ER chaperone GRP78. By contrast, palmitoleate did not induce any markers of the ER stress pathway even at concentrations as high as I mM. When palmitate and palmitoleate were added in combination, a marked attenuation of the ER stress response occurred. Under these conditions, the levels of phospho-eIF2 alpha, ATF4 and CHOP-10 were reduced to less than those found in control cells. Palmitoleate also attenuated the ER stress response to the protein glycosylation inhibitor, tunicamycin, and improved the viability of the cells exposed to this agent. Exposure of the BRIN-BD11 cells to the protein phosphatase inhibitor, salubrinal, in the absence of fatty acids resulted in increased eIF2 alpha phosphorylation but this was abolished by co-incubation with palinitoleate. We conclude that saturated fatty acids activate components of the PERK-dependent ER stress pathway in P-cells, ultimately leading to increased apoptosis. This effect is antagonised by monounsaturates that may exert their anti-apoptotic actions by regulating the activity of one or more kinase enzymes involved in mediating the phosphorylation of eIF2 alpha.