Liu Yin, He Siyuan, Zhou Ruixue, Zhang Xueping, Yang Shanshan, Deng Dan, Zhang Caixia, Yu Xiaoqian, Chen Yulong, Su Zhiguang
Molecular Medicine Research Center and National Clinical Research Center for Geriatrics, West China Hospital, and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China.
Molecular Medicine Research Center and National Clinical Research Center for Geriatrics, West China Hospital, and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
Diabetes. 2021 Aug;70(8):1703-1716. doi: 10.2337/db20-1238. Epub 2021 May 12.
Pancreatic β-cell mass and insulin secretion are determined by the dynamic change of transcription factor expression levels in response to altered metabolic demand. Nuclear factor-Y (NF-Y) is an evolutionarily conserved transcription factor playing critical roles in multiple cellular processes. However, the physiological role of NF-Y in pancreatic β-cells is poorly understood. The current study was undertaken in a conditional knockout of specifically in pancreatic β-cells ( βKO) to define the essential physiological role of NF-Y in β-cells. βKO mice exhibited glucose intolerance without changes in insulin sensitivity. Reduced β-cell proliferation resulting in decreased β-cell mass was observed in these mice, which was associated with disturbed actin cytoskeleton. NF-Y-deficient β-cells also exhibited impaired insulin secretion with a reduced Ca influx in response to glucose, which was associated with an inefficient glucose uptake into β-cells due to a decreased expression of GLUT2 and a reduction in ATP production resulting from the disruption of mitochondrial integrity. This study is the first to show that NF-Y is critical for pancreatic islet homeostasis and function through regulation in β-cell proliferation, glucose uptake into β-cells, and mitochondrial energy metabolism. Modulating NF-Y expression in β-cells may therefore offer an attractive approach for therapeutic intervention.
胰腺β细胞质量和胰岛素分泌由转录因子表达水平的动态变化决定，以响应代谢需求的改变。核因子-Y（NF-Y）是一种在进化上保守的转录因子，在多个细胞过程中发挥关键作用。然而，NF-Y在胰腺β细胞中的生理作用仍知之甚少。当前的研究在胰腺β细胞特异性条件性敲除（βKO）小鼠中进行，以确定NF-Y在β细胞中的重要生理作用。βKO小鼠表现出葡萄糖不耐受，而胰岛素敏感性没有变化。在这些小鼠中观察到β细胞增殖减少导致β细胞质量下降，这与肌动蛋白细胞骨架紊乱有关。NF-Y缺陷的β细胞还表现出胰岛素分泌受损，对葡萄糖的钙内流减少，这与由于GLUT2表达降低导致的β细胞葡萄糖摄取效率低下以及线粒体完整性破坏导致的ATP生成减少有关。这项研究首次表明，NF-Y通过调节β细胞增殖、β细胞葡萄糖摄取和线粒体能量代谢，对胰岛稳态和功能至关重要。因此，调节β细胞中NF-Y的表达可能为治疗干预提供一种有吸引力的方法。
