Department of Endocrinology, First Hospital of China Medical University, No. 155, Nanjingbei Street, Heping District, Shenyang 110001, Liaoning, China.
Peptides. 2010 Feb;31(2):307-14. doi: 10.1016/j.peptides.2009.11.011. Epub 2009 Nov 26.
Ghrelin is a 28-amino-acid peptide secreted predominantly by X/A-like cells of the gastric fundus. Ghrelin increases pancreatic beta-cell proliferation and survival via sequential activation of phosphatidylinositol-3 kinase (PI3K) and Akt. The transcription regulator Foxo1 is a prominent effector of PI3K/Akt; when it is inhibited, pancreatic beta-cells are protected against fatty-acid-induced apoptosis. We investigated the role of Foxo1 in the protective effect of ghrelin under lipotoxic conditions in the MIN6 pancreatic beta-cell line. Results showed that ghrelin promoted cell proliferation and attenuated palmitate-induced apoptosis in cultured MIN6 cells. Nuclear exclusion of Foxo1 was necessary for the function of ghrelin. Treatment of MIN6 cells with palmitate and ghrelin-induced rapid nuclear exclusion and phosphorylation of Foxo1. Unlike the JNK inhibitor SP600125, Akt inhibitor IV blocked the anti-lipotoxic effect of ghrelin and stimulated Foxo1 nuclear translocation. In addition, treatment with ghrelin combined with SP600125 showed a synergistic antiapoptotic effect in palmitate-treated MIN6 cells. Ghrelin also inhibited the endoplasmic reticulum stress pathway of apoptosis in MIN6 cells, decreased expression of cytoplasmic triglyceride, and downregulated gene expression of Bcl-2-associated X (BAX), sterol-response element-binding protein 1c (SREBP1c), and C/EBP homologous protein (CHOP-10). These findings suggest that ghrelin protects pancreatic beta-cells from lipotoxicity by inhibiting the nuclear translocation of Foxo1.
胃饥饿素是一种由胃底的 X/A 样细胞主要分泌的 28 个氨基酸肽。胃饥饿素通过顺序激活磷脂酰肌醇-3 激酶（PI3K）和 Akt 增加胰岛β细胞的增殖和存活。转录调节因子 Foxo1 是 PI3K/Akt 的主要效应物；当它被抑制时，胰岛β细胞可免受脂肪酸诱导的凋亡。我们研究了 Foxo1 在 MIN6 胰岛β细胞系中脂毒性条件下胃饥饿素的保护作用中的作用。结果表明，胃饥饿素促进细胞增殖并减轻培养的 MIN6 细胞中棕榈酸诱导的凋亡。Foxo1 的核排斥是胃饥饿素发挥作用所必需的。用棕榈酸和胃饥饿素处理 MIN6 细胞可迅速引起 Foxo1 的核排斥和磷酸化。与 JNK 抑制剂 SP600125 不同，Akt 抑制剂 IV 阻断了胃饥饿素的抗脂毒性作用并刺激了 Foxo1 的核转位。此外，用胃饥饿素联合 SP600125 处理可在棕榈酸处理的 MIN6 细胞中显示出协同的抗凋亡作用。胃饥饿素还抑制了 MIN6 细胞中的内质网应激凋亡途径，降低了细胞质甘油三酯的表达，并下调了 Bcl-2 相关 X（BAX）、固醇调节元件结合蛋白 1c（SREBP1c）和 C/EBP 同源蛋白（CHOP-10）的基因表达。这些发现表明，胃饥饿素通过抑制 Foxo1 的核转位来保护胰岛β细胞免受脂毒性。
