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Intracellular ATP Signaling Contributes to FAM3A-Induced PDX1 Upregulation in Pancreatic Beta CellsFunding 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).
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.
Received: 11 April 2021
Received: 22 July 2021
Accepted: 03 August 2021
Article published online:
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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