Martinez Sara C, Tanabe Katsuya, Cras-Méneur Corentin, Abumrad Nada A, Bernal-Mizrachi Ernesto, Permutt M Alan
Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8127, St. Louis, MO 63110, USA.
Diabetes. 2008 Apr;57(4):846-59. doi: 10.2337/db07-0595. Epub 2008 Jan 3.
beta-Cells are particularly susceptible to fatty acid-induced apoptosis associated with decreased insulin receptor/phosphatidylinositol-3 kinase/Akt signaling and the activation of stress kinases. We examined the mechanism of fatty acid-induced apoptosis of mouse beta-cells especially as related to the role played by endoplasmic reticulum (ER) stress-induced Foxo1 activation and whether decreasing Foxo1 activity could enhance cell survival.
Mouse insulinoma (MIN6) cells were administered with fatty acids, and the role of Foxo1 in mediating effects on signaling pathways and apoptosis was examined by measuring Foxo1 activity and using dominant-negative Foxo1.
Increasing fatty acid concentrations (100-400 micromol/l palmitate or oleate) led to early Jun NH(2)-terminal kinase (JNK) activation that preceded induction of ER stress markers and apoptosis. Foxo1 activity was increased with fatty acid administration and by pharmacological inducers of ER stress, and this increase was prevented by JNK inhibition. Fatty acids induced nuclear localization of Foxo1 at 4 h when Akt activity was increased, indicating that FoxO1 activation was not mediated by JNK inhibition of Akt. In contrast, fatty acid administration for 24 h was associated with decreased insulin signaling. A dominant-negative Foxo1 adenovirus (Adv-DNFoxo) conferred cells with protection from ER stress and fatty acid-mediated apoptosis. Microarray analysis revealed that fatty acid induction of gene expression was in most cases reversed by Adv-DNFoxo, including the proapoptotic transcription factor CHOP (C/EBP [CCAAT/enhancer binding protein] homologous protein).
Early induction of JNK and Foxo1 activation plays an important role in fatty acid-induced apoptosis. Expressing a dominant-negative allele of Foxo1 reduces expression of apoptotic and ER stress markers and promotes beta-cell survival from fatty acid and ER stress, identifying a potential therapeutic target for preserving beta-cells in type 2 diabetes.
β细胞对脂肪酸诱导的凋亡特别敏感，这与胰岛素受体/磷脂酰肌醇-3激酶/Akt信号通路降低以及应激激酶的激活有关。我们研究了脂肪酸诱导小鼠β细胞凋亡的机制，特别是与内质网（ER）应激诱导的Foxo1激活所起的作用相关，以及降低Foxo1活性是否能提高细胞存活率。
给小鼠胰岛素瘤（MIN6）细胞施用脂肪酸，并通过测量Foxo1活性和使用显性负性Foxo1来研究Foxo1在介导对信号通路和凋亡的影响中的作用。
脂肪酸浓度增加（100 - 400微摩尔/升棕榈酸或油酸）导致早期Jun NH2末端激酶（JNK）激活，这发生在内质网应激标志物诱导和凋亡之前。施用脂肪酸以及内质网应激的药理学诱导剂可增加Foxo1活性，而JNK抑制可阻止这种增加。脂肪酸在4小时时诱导Foxo1核定位，此时Akt活性增加，表明FoxO1激活不是由JNK对Akt的抑制介导的。相反，施用脂肪酸24小时与胰岛素信号通路降低有关。显性负性Foxo1腺病毒（Adv-DNFoxo）赋予细胞免受内质网应激和脂肪酸介导的凋亡的保护作用。微阵列分析显示，在大多数情况下，Adv-DNFoxo可逆转脂肪酸诱导的基因表达，包括促凋亡转录因子CHOP（C/EBP [CCAAT/增强子结合蛋白]同源蛋白）。
JNK和Foxo1激活的早期诱导在脂肪酸诱导的凋亡中起重要作用。表达Foxo1的显性负性等位基因可降低凋亡和内质网应激标志物的表达，并促进β细胞在脂肪酸和内质网应激下的存活，从而确定了在2型糖尿病中保护β细胞的潜在治疗靶点。
