Intracellular ATP Signaling Contributes to FAM3A-Induced PDX1 Upregulation in Pancreatic Beta Cells.

IF 1.6 4区 医学 Q4 ENDOCRINOLOGY & METABOLISM Experimental and Clinical Endocrinology & Diabetes Pub Date : 2022-08-01 Epub Date: 2021-09-30 DOI:10.1055/a-1608-0607
Han Yan, Zhenzhen Chen, Haizeng Zhang, Weili Yang, Xiangyang Liu, Yuhong Meng, Rui Xiang, Zhe Wu, Jingjing Ye, Yujing Chi, Jichun Yang
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引用次数: 5

Abstract

FAM3A is a recently identified mitochondrial protein that stimulates pancreatic-duodenal homeobox 1 (PDX1) and insulin expressions by promoting ATP release in islet β cells. In this study, the role of intracellular ATP in FAM3A-induced PDX1 expression in pancreatic β cells was further examined. Acute FAM3A inhibition using siRNA transfection in mouse pancreatic islets significantly reduced PDX1 expression, impaired insulin secretion, and caused glucose intolerance in normal mice. In vitro, FAM3A overexpression elevated both intracellular and extracellular ATP contents and promoted PDX1 expression and insulin secretion. FAM3A-induced increase in cellular calcium (Ca2+) levels, PDX1 expression, and insulin secretion, while these were significantly repressed by inhibitors of P2 receptors or the L-type Ca2+ channels. FAM3A-induced PDX1 expression was abolished by a calmodulin inhibitor. Likewise, FAM3A-induced β-cell proliferation was also inhibited by a P2 receptor inhibitor and an L-type Ca2+ channels inhibitor. Both intracellular and extracellular ATP contributed to FAM3A-induced PDX1 expression, insulin secretion, and proliferation of pancreatic β cells.

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细胞内ATP信号参与fam3a诱导的胰腺β细胞PDX1上调。
FAM3A是最近发现的一种线粒体蛋白,通过促进胰岛β细胞ATP的释放来刺激胰十二指肠同源盒1 (PDX1)和胰岛素的表达。本研究进一步探讨了细胞内ATP在fam3a诱导的胰腺β细胞PDX1表达中的作用。用siRNA转染小鼠胰岛急性FAM3A抑制可显著降低正常小鼠的PDX1表达,胰岛素分泌受损,并引起葡萄糖耐受不良。在体外,FAM3A过表达可提高细胞内和细胞外ATP含量,促进PDX1表达和胰岛素分泌。fam3a诱导细胞钙(Ca2+)水平、PDX1表达和胰岛素分泌增加,而这些被P2受体或l型Ca2+通道抑制剂显著抑制。fam3a诱导的PDX1表达被钙调素抑制剂消除。同样,fam3a诱导的β细胞增殖也被P2受体抑制剂和l型Ca2+通道抑制剂抑制。细胞内和细胞外ATP都有助于fam3a诱导的PDX1表达、胰岛素分泌和胰腺β细胞的增殖。
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来源期刊
CiteScore
4.10
自引率
5.60%
发文量
72
审稿时长
3 months
期刊介绍: Publishing outstanding articles from all fields of endocrinology and diabetology, from molecular biology to clinical research, this journal is a brilliant resource. Since being published in English in 1983, the popularity of this journal has grown steadily, reflecting the importance of this publication within its field. Original contributions and short communications appear in each issue along with reviews addressing current topics. In addition, supplementary issues are published each year presenting abstracts or proceedings of national and international scientific meetings. The journal was initially published in German and is still the oldest endocrinological periodical in the German-language market!
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