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【bio-news】抑制FOXO1：保护胰岛细胞免受游离脂肪
Objective: β-cells are particularly susceptible to fatty acid (FA) induced apoptosis associated with decreased insulin receptor/PI3-kinase/Akt signaling and the activation of stress kinases. We examined the mechanism of FA induced apoptosis of mouse â-cells especially as related to the role played by ER stress-induced Foxo1 activation and whether decreasing Foxo1 activity could enhance cell survival.
Research Design and Methods: Mouse insulinoma (MIN6) cells were treated with FA and the role of Foxo1 in mediating effects on signaling pathways and apoptosis was examined by measuring Foxo1 activity and using dominant negative Foxo1.
Results: Increasing FA concentrations (100-400 µM palmitate or oleate) led to early Jun-N-terminal kinase (JNK) activation that preceded induction of ER stress markers and apoptosis. Foxo1 activity was increased with FA treatment and by pharmacologic inducers of ER-stress and this increase was prevented by JNK inhibition. FA induced nuclear localization of Foxo1 at 4 hours when Akt activity was increased indicating that FoxO1 activation was not mediated by JNK inhibition of Akt. In contrast, FA treatment for 24 hours was associated with decreased insulin signaling. A dominant-negative Foxo1 adenovirus (Adv-DNFoxo) conferred cells with protection from ER stress and FA mediated apoptosis. Microarray analysis revealed that FA induction of gene expression was in most cases reversed by Adv-DNFoxo, including the pro-apoptotic transcription factor, CHOP.
Conclusions: Early induction of JNK and Foxo1 activation play an important role in FA-induced apoptosis. Expressing a dominant-negative allele of Foxo1 reduces expression of apoptotic and ER stress markers and promotes β-cell survival from FA and ER-stress, identifying a potential therapeutic target for preserving β-cells in type 2 diabetes.
http://diabetes.diabetesjournals.org/cgi/content/abstract/db07-0595v2 FoxO家族是转录调节因子，也是INS／IGF-1信号通路中的关键分子。FoxO基因在进化上高度保守，其氨基酸序列中含有3个高度保守PKB磷酸化基序。FoxO受P13K／PKB磷酸化级联通路的调节，其活性与磷酸化状态直接相关。FoxO对细胞增殖、细胞凋亡等生理过程有重要调节作用，并可能在免疫系统发育中对免疫细胞的凋亡及亚群间的平衡起一定调节作用。
转自生物谷 Inhibition of Foxo1 Protects Pancreatic Islet ®-Cells Against Fatty Acid and ER-Stress Induced Apoptosis
抑制FoxO1（Forkhead转录因子）对由游离脂肪酸引起及内质网应激(ER-Stress)引起的胰岛细胞凋亡有保护作用
Objective: β-cells are particularly susceptible to fatty acid (FA) induced apoptosis associated with decreased insulin receptor/PI3-kinase/Akt signaling and the activation of stress kinases. We examined the mechanism of FA induced apoptosis of mouse â-cells especially as related to the role played by ER stress-induced Foxo1 activation and whether decreasing Foxo1 activity could enhance cell survival.
目的：β细胞对游离脂肪酸引起的细胞凋亡特别敏感，可能与胰岛素受体/磷脂酰肌醇3/蛋白激酶B(InsR －PI3K-Akt信号通路)下调以及激酶应激的活化有关。我们试图验证，在小鼠的β细胞中，游离脂肪酸诱导的细胞凋亡的机制与内质网应激诱导FoxO1激活是否有重要关系，抑制FoxO1活性对于增加β细胞的存活是否有影响。
Research Design and Methods: Mouse insulinoma (MIN6) cells were treated with FA and the role of Foxo1 in mediating effects on signaling pathways and apoptosis was examined by measuring Foxo1 activity and using dominant negative Foxo1.
研究设计与试验方法：小鼠胰岛细胞瘤细胞（MIN6）在存在游离脂肪酸的培养基中培养，FoxO1在信号通路中的调节作用以及对细胞凋亡的影响通过检测FoxO1的活性以及Foxo1显性负相测定。
Results: Increasing FA concentrations (100-400 µM palmitate or oleate) led to early Jun-N-terminal kinase (JNK) activation that preceded induction of ER stress markers and apoptosis. Foxo1 activity was increased with FA treatment and by pharmacologic inducers of ER-stress and this increase was prevented by JNK inhibition. FA induced nuclear localization of Foxo1 at 4 hours when Akt activity was increased indicating that FoxO1 activation was not mediated by JNK inhibition of Akt. In contrast, FA treatment for 24 hours was associated with decreased insulin signaling. A dominant-negative Foxo1 adenovirus (Adv-DNFoxo) conferred cells with protection from ER stress and FA mediated apoptosis. Microarray analysis revealed that FA induction of gene expression was in most cases reversed by Adv-DNFoxo, including the pro-apoptotic transcription factor, CHOP.
结果：提高游离脂肪酸的浓度（100-400 µM棕榈酸酯或油酸），导致早期的c-jun氨基末端激酶激活，进而诱导产生内质网应激标记物和细胞凋亡。经过游离脂肪酸和内质网应激药物诱导剂处理后，小鼠胰岛细胞瘤细胞（MIN6）中Foxo1活性增加，而这种活性的增加可以被c-jun氨基末端激酶的抑制剂所抑制保护。游离脂肪酸处理4小时后，能诱导Foxo1的核定位，同时蛋白激酶B的活性也增加，这显示：FoxO1的活性不被蛋白激酶B的JUK抑制剂所调控。与之相反的是，游离脂肪酸处理24小时与胰岛素信号通路的下调有关。显性负相的Foxo1腺病毒显示其对游离脂肪酸及内质网应激调控的细胞凋亡有保护作用。生物芯片分析显示：在大多数的情况中，由游离脂肪酸诱导的基因表达被显性负相的Foxo1腺病毒逆转，包括促进凋亡的转录因子，CHOP。
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作者:admin@医学,生命科学 2011-08-31 05:19
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