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ORIGINAL RESEARCH article

Front. Endocrinol.
Sec. Cellular Endocrinology
Volume 15 - 2024 | doi: 10.3389/fendo.2024.1400022

Activation of estrogen related receptor γ by calcium and cadmium

Provisionally accepted
Qiaochu Wang Qiaochu Wang 1Nanxi Huang Nanxi Huang 2John B. Psaltis John B. Psaltis 2Reem M. Gahtani Reem M. Gahtani 1Gai Yan Gai Yan 3Dajun Lu Dajun Lu 2Shannon Cahalan Shannon Cahalan 4Xu Shi Xu Shi 1Bassem Haddad Bassem Haddad 2MaryBeth Martin MaryBeth Martin 5*
  • 1 Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, District of Columbia, United States
  • 2 Department of Oncology, Georgetown University, Washington, District of Columbia, United States
  • 3 Department of Onocology, Georgetown University, Washington, District of Columbia, United States
  • 4 Department of Biology, Georgetown University, Washington, District of Columbia, United States
  • 5 Departments of Oncology and Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, United States

The final, formatted version of the article will be published soon.

    Objective: Estrogen related receptor γ (ERRγ) is a metabolic regulator with no identified physiological ligands. This study investigates whether calcium is an ERRγ ligand that mediates the effects of glucagon and whether cadmium, which mimics the effects of calcium, disrupts metabolism through ERRγ.Method: HepG2, MCF-7, and HEK293T transfected with ERRγ were treated with glucagon, calcium, cadmium, ERRγ agonist, or ERRγ inhibitor. Cells were then collected for in vitro assays including real time-qPCR, Western blot, ChIP, immunofluorescence, mutational analysis, or gene set enrichment analysis. Molecular dynamics simulations were performed to study mutation sites.Results: In HepG2 cells, treatment with glucagon, calcium, or cadmium re-localized ERRγ to the cell nucleus, recruited ERRγ to estrogen related response elements, induced the expression of ERRγ regulated genes, and increased extracellular glucose that was blocked by an ERRγ antagonist. In MCF-7 cells and HEK293T cells transfected with ERRγ, similar treatments induced the expression of metabolic genes. Mutational analysis identified S303, T429, and E452 in the ligand binding domain as potential interaction sites. Molecular dynamics simulations showed that calcium induced changes in ERRγ similar to ERRγ agonist.The results suggest that calcium is a potential ligand of ERRγ that mediates the effects of glucagon and cadmium disrupts metabolism through ERRγ.

    Keywords: estrogen related receptor γ, gluconeogenesis, metals, calcium, cadmium Abbreviations 4, 6-diamidino-2-phenylindole, DAPI, 6-phosphofructokinase, liver type, PFKL, bisphenol A, BPA, charcoal stripped calf serum, CCS, chloramphenicol acetyltransferase, CAT, chromatin immunoprecipitation Assay, ChIP, DNA binding domain, DBD, Dulbecco's Modified Eagle's Medium, DMEM

    Received: 12 Mar 2024; Accepted: 16 Sep 2024.

    Copyright: © 2024 Wang, Huang, Psaltis, Gahtani, Yan, Lu, Cahalan, Shi, Haddad and Martin. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: MaryBeth Martin, Departments of Oncology and Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, United States

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