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CC BY-NC-ND 4.0 · Exp Clin Endocrinol Diabetes 2022; 130(08): 498-508
DOI: 10.1055/a-1608-0607
Article

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

Han Yan
1   Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science of the Ministry of Education, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing 100191, China
,
Zhenzhen Chen
2   Hypertension Center, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Beijing 100037, China
,
Haizeng Zhang
2   Hypertension Center, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Beijing 100037, China
,
Weili Yang
1   Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science of the Ministry of Education, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing 100191, China
3   Beijing Key Laboratory of diabetes Research and Care, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
,
Xiangyang Liu
1   Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science of the Ministry of Education, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing 100191, China
,
Yuhong Meng
1   Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science of the Ministry of Education, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing 100191, China
,
Rui Xiang
1   Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science of the Ministry of Education, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing 100191, China
,
Zhe Wu
4   Department of Gastroenterology, Peking University People’s Hospital, Beijing 100044, China
,
Jingjing Ye
4   Department of Gastroenterology, Peking University People’s Hospital, Beijing 100044, China
,
Yujing Chi 
5   Department of Central Laboratory & Institute of Clinical Molecular Biology, Peking University People’s Hospital, Beijing 100044, China
,
Jichun Yang
1   Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science of the Ministry of Education, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing 100191, China
› Institutsangaben
Funding This research was funded by Beijing Natural Science Foundation (7212123/7171006/7204320), the National Natural Science Foundation of China (82070844/81670787/81670748/81471035/818 70551/81800367/81900492), the National Key Research Program of China (2016YFC0903000/2017YFC0909600) and the State Key Laboratory of Cardiovascular Disease Grant (2018fk-02).
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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.

Key words

FAM3A - pancreatic β cells - intracellular ATP - PDX1 - insulin secretion

Supplementary Material



Publikationsverlauf

Eingereicht: 11. April 2021
Eingereicht: 22. Juli 2021

Angenommen: 03. August 2021

Artikel online veröffentlicht:
30. September 2021

© 2021. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).

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