Subscribe to RSS
Please copy the URL and add it into your RSS Feed Reader.
https://www.thieme-connect.de/rss/thieme/en/10.1055-s-00000017.xml
CC BY-NC-ND 4.0 · Exp Clin Endocrinol Diabetes 2022; 130(08): 498-508
DOI: 10.1055/a-1608-0607
DOI: 10.1055/a-1608-0607
Article
Intracellular ATP Signaling Contributes to FAM3A-Induced PDX1 Upregulation in Pancreatic Beta Cells
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).
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.
Publication History
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/).
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
-
References
- 1 Guariguata L, Whiting DR, Hambleton I. et al. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract 2014; 103: 137-149 DOI: 10.1016/j.diabres.2013.11.002.
- 2 Gerber PA, Rutter GA. The role of oxidative stress and hypoxia in pancreatic beta-cell dysfunction in diabetes mellitus. Antioxid Redox Signal 2017; 26: 501-518 DOI: 10.1089/ars.2016.6755.
- 3 Berchtold LA, Prause M, Størling J. et al. Cytokines and pancreatic β-cell apoptosis. Adv Clin Chem 2016; 75: 99-158 DOI: 10.1016/bs.acc.2016.02.001.
- 4 Marasco MR, Linnemann AK. β-cell autophagy in diabetes pathogenesis. Endocrinology 2018; 159: 2127-2141 DOI: 10.1210/en.2017-03273.
- 5 Helman A, Avrahami D, Klochendler A. et al. Effects of ageing and senescence on pancreatic β-cell function. Diabetes Obes Metab 2016; 18 Suppl 1: 58-62 DOI: 10.1111/dom.12719.
- 6 Gerencser AA. Metabolic activation-driven mitochondrial hyperpolarization predicts insulin secretion in human pancreatic beta-cells. Biochim Biophys Acta Bioenerg 2018; 1859: 817-828 DOI: 10.1016/j.bbabio.2018.06.006.
- 7 Zhang CY, Baffy G, Perret P. et al. Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, β cell dysfunction, and type 2 diabetes. Cell 2001; 105: 745-755 DOI: 10.1016/s0092-8674(01)00378-6.
- 8 Wang C, Geng B, Cui Q. et al. Intracellular and extracellular adenosine triphosphate in regulation of insulin secretion from pancreatic β cells (β). J Diabetes 2014; 6: 113-119 DOI: 10.1111/1753-0407.12098.
- 9 Köhnke R, Mei J, Park M. et al. Fatty acids and glucose in high concentration down-regulates ATP synthase beta-subunit protein expression in INS-1 cells. Nutr Neurosci 2007; 10: 273-278 DOI: 10.1080/10284150701745910.
- 10 Yang J, Chi Y, Burkhardt BR. et al. Leucine metabolism in regulation of insulin secretion from pancreatic beta cells. Nutr Rev 2010; 68: 270-279 DOI: 10.1111/j.1753-4887.2010.00282.x.
- 11 Zhang CY, Parton LE, Ye CP. et al. Genipin inhibits UCP2-mediated proton leak and acutely reverses obesity- and high glucose-induced beta cell dysfunction in isolated pancreatic islets. Cell Metab 2006; 3: 417-427 DOI: 10.1016/j.cmet.2006.04.010.
- 12 Geschwind JF, Hiriart M, Glennon MC. et al. Selective activation of Ca2+ influx by extracellular ATP in a pancreatic beta-cell line (HIT). Biochim Biophys Acta 1989; 1012: 107-115 DOI: 10.1016/0167-4889(89)90018-9.
- 13 Pelegrin P, Surprenant A. Pannexin-1 mediates large pore formation and interleukin-1β release by the ATP-gated P2X7 receptor. EMBO J 2006; 25: 5071-5082 DOI: 10.1038/sj.emboj.7601378.
- 14 Orellana JA, Montero TD, von Bernhardi R. Astrocytes inhibit nitric oxide-dependent Ca(2+) dynamics in activated microglia: involvement of ATP released via pannexin 1 channels. Glia 2013; 61: 2023-2037 DOI: 10.1002/glia.22573.
- 15 Zhu L, Almaça J, Dadi PK. et al. β-arrestin-2 is an essential regulator of pancreatic β-cell function under physiological and pathophysiological conditions. Nat Commun 2017; 8: 14295 DOI: 10.1038/ncomms14295.
- 16 Alejandro EU, Bozadjieva N, Blandino-Rosano M. et al. Overexpression of kinase-dead mTOR impairs glucose homeostasis by regulating insulin secretion and not β-cell mass. Diabetes 2017; 66: 2150-2162 DOI: 10.2337/db16-1349.
- 17 Zhu Y, Xu G, Patel A. et al. Cloning, expression, and initial characterization of a novel cytokine-like gene family. Genomics 2002; 80: 144-150 DOI: 10.1006/geno.2002.6816.
- 18 Wang C, Chi Y, Li J. et al. FAM3A activates PI3K p110α/Akt signaling to ameliorate hepatic gluconeogenesis and lipogenesis. Hepatology 2014; 59: 1779-1790 DOI: 10.1002/hep.26945.
- 19 Chen Z, Wang J, Yang W. et al. FAM3A mediates PPARγ’s protection in liver ischemia-reperfusion injury by activating Akt survival pathway and repressing inflammation and oxidative stress. Oncotarget 2017; 8: 49882-49896 DOI: 10.18632/oncotarget.17805.
- 20 Song Q, Gou WL, Zhang R. FAM3A protects HT22 cells against hydrogen peroxide-induced oxidative stress through activation of PI3K/Akt but not MEK/ERK pathway. Cell Physiol Biochem 2015; 37: 1431-1441 DOI: 10.1159/000438512.
- 21 Jia S, Chen Z, Li J. et al. FAM3A promotes vascular smooth muscle cell proliferation and migration and exacerbates neointima formation in rat artery after balloon injury. J Mol Cell Cardiol 2014; 74: 173-182 DOI: 10.1016/j.yjmcc.2014.05.011.
- 22 Chi Y, Li J, Li N. et al. FAM3A enhances adipogenesis of 3T3-L1 preadipocytes via activation of ATP-P2 receptor-Akt signaling pathway. Oncotarget 2017; 8: 45862-45873 DOI: 10.18632/oncotarget.17578.
- 23 Ishihara H, Asano T, Tsukuda K. et al. Pancreatic beta cell line MIN6 exhibits characteristics of glucose metabolism and glucose-stimulated insulin secretion similar to those of normal islets. Diabetologia 1993; 36: 1139-1145 DOI: 10.1007/BF00401058.
- 24 Yang W, Chi Y, Meng Y. et al. FAM3A plays crucial roles in controlling PDX1 and insulin expressions in pancreatic beta cells. FASEB J 2020; 34: 3915-3931 DOI: 10.1096/fj.201902368RR.
- 25 Bradley SP, Rastellini C, da Costa MA. et al. Gene silencing in the endocrine pancreas mediated by short-interfering RNA. Pancreas 2005; 31: 373-379 DOI: 10.1097/01.mpa.0000179730.69081.64.
- 26 Kapodistria K, Tsilibary EP, Kotsopoulou E. et al. Liraglutide, a human glucagon-like peptide-1 analogue, stimulates AKT-dependent survival signalling and inhibits pancreatic beta-cell apoptosis. J Cell Mol Med 2018; 22: 2970-2980 DOI: 10.1111/jcmm.13259.
- 27 Wong JC, Vo V, Gorjala P, Fiscus RR. Pancreatic-β-cell survival and proliferation are promoted by protein kinase G type Iα and downstream regulation of AKT/FOXO1. Diab Vasc Dis Res 2017; 14: 434-449 DOI: 10.1177/1479164117713947.
- 28 Li JM, Wang W, Fan CY. et al. Quercetin preserves β-cell mass and function in fructose-induced hyperinsulinemia through modulating pancreatic Akt/FoxO1 activation. Evid Based Complement Alternat Med 2013; 2013: 303902 DOI: 10.1155/2013/303902.
- 29 Wang Y, Wang H, Liu Y. et al. Antihyperglycemic effect of ginsenoside Rh2 by inducing islet β-cell regeneration in mice. Horm Metab Res 2012; 44: 33-40 DOI: 10.1055/s-0031-1295416.
- 30 Li Z, Shangguan Z, Liu Y. et al. Puerarin protects pancreatic β-cell survival via PI3K/Akt signaling pathway. J Mol Endocrinol 2014; 53: 71-79 DOI: 10.1530/JME-13-0302.
- 31 Bastidas-Ponce A, Roscioni SS, Burtscher I. et al. Foxa2 and Pdx1 cooperatively regulate postnatal maturation of pancreatic β-cells. Mol Metab 2017; 6: 524-534 DOI: 10.1016/j.molmet.2017.03.007.
- 32 Kitamura T, Nakae J, Kitamura Y. et al. The forkhead transcription factor FoxO1 links insulin signaling to Pdx1 regulation of pancreatic βcell growth. J Clin Invest 2002; 110: 1839-1847 DOI: 10.1172/JCI16857.
- 33 Zhu P, Ma Z, Guo L. et al. Short body length phenotype is compensated by the upregulation of nidogen family members in a deleterious nid1a mutation of zebrafish. J Genet Genomics 2017; 44: 553-556 DOI: 10.1016/j.jgg.2017.09.011.
- 34 Ma Z, Zhu P, Shi H. et al. PTC-bearing mRNA elicits a genetic compensation response via Upf3a and COMPASS components. Nature 2019; 568: 259-263 DOI: 10.1038/s41586-019-1057-y.
- 35 El-Brolosy MA, Kontarakis Z, Rossi A. et al. Genetic compensation triggered by mutant mRNA degradation. Nature 2019; 568: 193-197 DOI: 10.1038/s41586-019-1064-z.
- 36 Crooke ST, Witztum JL, Bennett CF. et al. RNA-Targeted Therapeutics. Cell Metab 2018; 27: 714-739 DOI: 10.1016/j.cmet.2018.03.004.
- 37 Faas MM, Sáez T, de Vos P. Extracellular ATP and adenosine: The Yin and Yang in immune responses?. Mol Aspects Med 2017; 55: 9-19 DOI: 10.1016/j.mam.2017.01.002.
- 38 Di Virgilio F, Sarti AC, Falzoni S. et al. Extracellular ATP and P2 purinergic signalling in the tumour microenvironment. Nat Rev Cancer 2018; 18: 601-618 DOI: 10.1038/s41568-018-0037-0.
- 39 Emmett DS, Feranchak A, Kilic G. et al. Characterization of ionotrophic purinergic receptors in hepatocytes. Hepatology 2008; 47: 698-705 DOI: 10.1002/hep.22035.
- 40 MacDonald PE, El-Kholy W, Riedel MJ. et al. The multiple actions of GLP-1 on the process of glucose-stimulated insulin secretion. Diabetes 2002; 51: S434-S442 DOI: 10.2337/diabetes.51.2007.s434.
- 41 Yang J, Wong RK, Wang X. et al. Leucine culture reveals that ATP synthase functions as a fuel sensor in pancreatic β-cells. J Biol Chem 2004; 279: 53915-53923 DOI: 10.1074/jbc.M405309200.
- 42 Tang S, Xin Y, Yang M. et al. Osteoprotegerin promotes islet β cell proliferation in intrauterine growth retardation rats through the PI3K/AKT/FoxO1 pathway. Int J Clin Exp Pathol 2019; 12: 2324-2338
- 43 Ahlgren U, Jonsson J, Edlund H. The morphogenesis of the pancreatic mesenchyme is uncoupled from that of the pancreatic epithelium in IPF1/PDX1-deficient mice. Development 1996; 122: 1409-1416
- 44 Horiguchi M, Yoshida M, Hirata K. et al. Senescence caused by inactivation of the homeodomain transcription factor Pdx1 in adult pancreatic acinar cells in mice. FEBS Lett 2019; 593: 2226-2234 DOI: 10.1002/1873-3468.13504.