Novel (sulfated) thyroid hormone transporters in the solute carrier 22 family

Zhongli Chen, Robin P. Peeters, Wesley Flach, Linda J. de Rooij, Sena Yildiz, Alexander Teumer, Matthias Nauck, Rosalie B.T.M. Sterenborg, Joost H.W. Rutten, Marco Medici, W. Edward Visser, Marcel E. Meima*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

7 Citations (Scopus)
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Abstract

Objective: Thyroid hormone (TH) transport represents a critical first step in governing intracellular TH regulation. It is still unknown whether the full repertoire of TH transporters has been identified. Members of the solute carrier (SLC) 22 family have substrates in common with the known TH transporters of the organic anion-transporting peptide family. Therefore, we screened the SLC22 family for TH transporters Methods: Uptake of 1 nM of iodothyronines or sulfated iodothyronines in COS1 cells expressing SLC22 proteins was performed. Results: We first tested 25 mouse (m) SLC22 proteins for TH uptake and found that the majority of the organic anion transporter (OAT) clade were capable of 3,3',5-triiodothyronine and/or thyroxine (T4) transport. Based on phylogenetic tree analysis of the mouse and human (h) SLC22 family, we selected eight hSLC22s that grouped with the newly identified mouse TH transporters. Of these, four tested positive for uptake of one or more substrates, particularly hSLC22A11 showed robust (3-fold over control) uptake of T4. Uptake of sulfated iodothyronines was strongly (up to 17-fold) induced by some SLC22s, most notably SLC22A8, hSLC22A9, mSLC22A27 and mSLC22A29. Finally, the zebrafish orthologues of SLC22A6/8 drOatx and drSlc22a6l also transported almost all (sulfated) iodothyronines tested. The OAT inhibitors lesinurad and probenecid inhibited most SLC22 proteins. Conclusions: Our results demonstrated that members of the OAT clade of the SLC22 family constitute a novel, evolutionary conserved group of transporters for (sulfated) iodothyronines. Future studies should reveal the relevance of these transporters in TH homeostasis and physiology.

Original languageEnglish
Article numbere230023
JournalEuropean Thyroid Journal
Volume12
Issue number4
DOIs
Publication statusPublished - Aug 2023

Bibliographical note

Funding Information:
This study is funded by the EU Horizon 2020 program, ATHENA project, grant number 825161, which is gratefully acknowledged. This publication reflects only the authors' view, and the European Commission is not responsible for any use that may be made of the information it contains. SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania, and the network 'Greifswald Approach to Individualized Medicine (GANI_MED)' funded by the Federal Ministry of Education and Research (grant 03IS2061A). Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthineers, Erlangen, Germany and the Federal State of Mecklenburg- West Pomerania. The University of Greifswald is a member of the Caché Campus program of the InterSystems GmbH. The Nijmegen Biomedical Study is a population-based survey conducted at the Department for Health Evidence and the Department of Laboratory Medicine of the Radboud University Medical Center. Principal investigators of the Nijmegen Biomedical Study are L.A.L.M. Kiemeney, A.L.M. Verbeek, D.W. Swinkels, and B. Franke.

Publisher Copyright:
© 2023 the author(s)

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