β细胞中YY1缺乏会导致小鼠线粒体功能障碍和糖尿病。
YY1 deficiency in β-cells leads to mitochondrial dysfunction and diabetes in mice.
作者信息
Song Dalong, Yang Qi, Jiang Xiuli, Shan Aijing, Nan Jingminjie, Lei Ying, Ji He, Di Wei, Yang Tianxiao, Wang Tiange, Wang Weiqing, Ning Guang, Cao Yanan
机构信息
Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, National Clinical Research Centre for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission, Shanghai Key Laboratory for Endocrine Tumors, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, National Clinical Research Centre for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission, Shanghai Key Laboratory for Endocrine Tumors, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; National Research Center for Translational Medicine, National Key Scientific Infrastructure for Translational Medicine (Shanghai), Shanghai Jiao Tong University, Shanghai, China.
出版信息
Metabolism. 2020 Nov;112:154353. doi: 10.1016/j.metabol.2020.154353. Epub 2020 Sep 8.
BACKGROUND
The transcription factor YY1 is an important regulator for metabolic homeostasis. Activating mutations in YY1 lead to tumorigenesis of pancreatic β-cells, however, the physiological functions of YY1 in β-cells are still unknown. Here, we investigated the effects of YY1 ablation on insulin secretion and glucose metabolism.
METHODS
We established two models of β-cell-specific YY1 knockout mice. The glucose metabolic phenotypes, β-cell mass and β-cell functions were analyzed in the mouse models. Transmission electron microscopy was used to detect the ultrastructure of β-cells. The flow cytometry analysis, measurement of OCR and ROS were performed to investigate the mitochondrial function. Histological analysis, quantitative PCR and ChIP were performed to analyze the target genes of YY1 in β-cells.
RESULTS
Our results showed that loss of YY1 resulted in reduction of insulin production, β-cell mass and glucose tolerance in mice. Ablation of YY1 led to defective ATP production and mitochondrial ROS accumulation in pancreatic β-cells. The inactivation of YY1 impaired the activity of mitochondrial oxidative phosphorylation, induced mitochondrial dysfunction and diabetes in mouse models.
CONCLUSION
Our findings demonstrate that the transcriptional activity of YY1 is essential for the maintenance of mitochondrial functions and insulin secretion in β-cells.
背景
转录因子YY1是代谢稳态的重要调节因子。YY1的激活突变会导致胰腺β细胞发生肿瘤，但YY1在β细胞中的生理功能仍不清楚。在此，我们研究了YY1缺失对胰岛素分泌和葡萄糖代谢的影响。
方法
我们建立了两种β细胞特异性YY1基因敲除小鼠模型。对小鼠模型的葡萄糖代谢表型、β细胞质量和β细胞功能进行了分析。采用透射电子显微镜检测β细胞的超微结构。进行流式细胞术分析、氧耗率（OCR）和活性氧（ROS）测量以研究线粒体功能。进行组织学分析、定量PCR和染色质免疫沉淀（ChIP）以分析YY1在β细胞中的靶基因。
结果
我们的结果表明，YY1缺失导致小鼠胰岛素生成减少、β细胞质量降低和葡萄糖耐量下降。YY1缺失导致胰腺β细胞中ATP生成缺陷和线粒体ROS积累。YY1失活损害了线粒体氧化磷酸化活性，在小鼠模型中诱导了线粒体功能障碍和糖尿病。
结论
我们的研究结果表明，YY1的转录活性对于维持β细胞中的线粒体功能和胰岛素分泌至关重要。
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