Peroxisome Proliferator-activated Receptor γ(PPARγ) and Its Target Genes Are Downstream Effectors of FoxO1 Protein in Islet β-Cells
Peroxisome Proliferator-activated Receptor γ(PPARγ) and Its Target Genes Are Downstream Effectors of FoxO1 Protein in Islet β-Cells
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DOI：
10.1074/jbc.m113.486852
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发表时间：
2013-08-30
影响因子：
4.8
通讯作者：
Leahy, Jack L.
中科院分区：
文献类型：
--
作者：
Gupta, Dhananjay;Leahy, Averi A.;Leahy, Jack L.
驱动胰岛β细胞代偿和衰竭的分子机制和信号通路尚未完全解决。我们已经使用体外和体内系统来显示FoxO 1，代谢刺激的整合剂，抑制β细胞中的PPAR γ表达，从而抑制其靶基因（Pdx 1，葡萄糖依赖性促胰岛素多肽（GIP）受体和丙酮酸羧化酶）的转录，这些基因是β细胞功能，存活和补偿的重要调节因子。当上游激活诱导FoxO 1从细胞核转移到细胞质时，FoxO 1对靶基因转录的抑制通常会减轻。证实了这一途径的核心重要性，非糖尿病胰岛素抵抗大鼠的胰岛表达的过氧化物酶体增殖物激活受体γ及其靶基因增强，并显着减少糖尿病诱导。通过胰腺切片的共聚焦显微镜观察，与非糖尿病大鼠的细胞核和细胞质FoxO 1相比，糖尿病大鼠的β细胞中显示出强烈的细胞核FoxO 1免疫染色模式，从而深入了解高血糖症导致的受损的PPAR γ信号传导。这些发现表明FoxO 1/PPAR γ介导的网络作为β细胞适应代谢应激的核心组成部分，FoxO 1活化受损导致这种反应失败或加重糖尿病。
The molecular mechanisms and signaling pathways that drive islet beta-cell compensation and failure are not fully resolved. We have used in vitro and in vivo systems to show that FoxO1, an integrator of metabolic stimuli, inhibits PPAR gamma expression in beta-cells, thus transcription of its target genes (Pdx1, glucose-dependent insulinotropic polypeptide (GIP) receptor, and pyruvate carboxylase) that are important regulators of beta-cell function, survival, and compensation. FoxO1 inhibition of target gene transcription is normally relieved when upstream activation induces its translocation from the nucleus to the cytoplasm. Attesting to the central importance of this pathway, islet expression of PPAR gamma and its target genes was enhanced in nondiabetic insulin-resistant rats and markedly reduced with diabetes induction. Insight into the impaired PPAR gamma signaling with hyperglycemia was obtained with confocal microscopy of pancreas sections that showed an intense nuclear FoxO1 immunostaining pattern in the beta-cells of diabetic rats in contrast to the nuclear and cytoplasmic FoxO1 in nondiabetic rats. These findings suggest a FoxO1/PPAR gamma-mediated network acting as a core component of beta-cell adaptation to metabolic stress, with failure of this response from impaired FoxO1 activation causing or exacerbating diabetes.