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

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 transp...

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Published in:European thyroid journal 2023-08, Vol.12 (4), p.1-11
Main Authors: Chen, Zhongli, Peeters, Robin P, Flach, Wesley, de Rooij, Linda J, Yildiz, Sena, Teumer, Alexander, Nauck, Matthias, Sterenborg, Rosalie B T M, Rutten, Joost H W, Medici, Marco, Edward Visser, W, Meima, Marcel E
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container_issue 4
container_start_page 1
container_title European thyroid journal
container_volume 12
creator Chen, Zhongli
Peeters, Robin P
Flach, Wesley
de Rooij, Linda J
Yildiz, Sena
Teumer, Alexander
Nauck, Matthias
Sterenborg, Rosalie B T M
Rutten, Joost H W
Medici, Marco
Edward Visser, W
Meima, Marcel E
description 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.
doi_str_mv 10.1530/ETJ-23-0023
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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.</description><identifier>ISSN: 2235-0802</identifier><identifier>ISSN: 2235-0640</identifier><identifier>EISSN: 2235-0802</identifier><identifier>DOI: 10.1530/ETJ-23-0023</identifier><identifier>PMID: 37074673</identifier><language>eng</language><publisher>England: Bioscientifica Ltd</publisher><subject>Animals ; Humans ; lesinurad ; Membrane Transport Proteins - genetics ; Mice ; oat3 ; oat4 ; oat7 ; organic anion transporter ; Organic Anion Transporters - genetics ; Phylogeny ; probenecid ; solute carrier 22 family ; Sulfates - metabolism ; thyroid hormone ; thyroid hormone sulfate ; Thyroid Hormones ; transporter ; Zebrafish - metabolism</subject><ispartof>European thyroid journal, 2023-08, Vol.12 (4), p.1-11</ispartof><rights>the author(s)</rights><rights>the author(s) 2023 the author(s)</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-b490t-d31493c543d3a7d61082f04b4aceaf6951d7eddadacef17e0db51d763c1f86233</citedby><orcidid>0000-0002-5392-0519 ; 0000-0002-3366-6015 ; 0000-0002-7271-7858 ; 0000-0002-5248-863X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10305468/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10305468/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37074673$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chen, Zhongli</creatorcontrib><creatorcontrib>Peeters, Robin P</creatorcontrib><creatorcontrib>Flach, Wesley</creatorcontrib><creatorcontrib>de Rooij, Linda J</creatorcontrib><creatorcontrib>Yildiz, Sena</creatorcontrib><creatorcontrib>Teumer, Alexander</creatorcontrib><creatorcontrib>Nauck, Matthias</creatorcontrib><creatorcontrib>Sterenborg, Rosalie B T M</creatorcontrib><creatorcontrib>Rutten, Joost H W</creatorcontrib><creatorcontrib>Medici, Marco</creatorcontrib><creatorcontrib>Edward Visser, W</creatorcontrib><creatorcontrib>Meima, Marcel E</creatorcontrib><title>Novel (sulfated) thyroid hormone transporters in the solute carrier 22 family</title><title>European thyroid journal</title><addtitle>Eur Thyroid J</addtitle><description>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. 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Peeters, Robin P ; Flach, Wesley ; de Rooij, Linda J ; Yildiz, Sena ; Teumer, Alexander ; Nauck, Matthias ; Sterenborg, Rosalie B T M ; Rutten, Joost H W ; Medici, Marco ; Edward Visser, W ; Meima, Marcel E</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-b490t-d31493c543d3a7d61082f04b4aceaf6951d7eddadacef17e0db51d763c1f86233</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Animals</topic><topic>Humans</topic><topic>lesinurad</topic><topic>Membrane Transport Proteins - genetics</topic><topic>Mice</topic><topic>oat3</topic><topic>oat4</topic><topic>oat7</topic><topic>organic anion transporter</topic><topic>Organic Anion Transporters - genetics</topic><topic>Phylogeny</topic><topic>probenecid</topic><topic>solute carrier 22 family</topic><topic>Sulfates - metabolism</topic><topic>thyroid hormone</topic><topic>thyroid hormone sulfate</topic><topic>Thyroid Hormones</topic><topic>transporter</topic><topic>Zebrafish - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chen, Zhongli</creatorcontrib><creatorcontrib>Peeters, Robin P</creatorcontrib><creatorcontrib>Flach, Wesley</creatorcontrib><creatorcontrib>de Rooij, Linda J</creatorcontrib><creatorcontrib>Yildiz, Sena</creatorcontrib><creatorcontrib>Teumer, Alexander</creatorcontrib><creatorcontrib>Nauck, Matthias</creatorcontrib><creatorcontrib>Sterenborg, Rosalie B T M</creatorcontrib><creatorcontrib>Rutten, Joost H W</creatorcontrib><creatorcontrib>Medici, Marco</creatorcontrib><creatorcontrib>Edward Visser, W</creatorcontrib><creatorcontrib>Meima, Marcel E</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>Directory of Open Access Journals</collection><jtitle>European thyroid journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chen, Zhongli</au><au>Peeters, Robin P</au><au>Flach, Wesley</au><au>de Rooij, Linda J</au><au>Yildiz, Sena</au><au>Teumer, Alexander</au><au>Nauck, Matthias</au><au>Sterenborg, Rosalie B T M</au><au>Rutten, Joost H W</au><au>Medici, Marco</au><au>Edward Visser, W</au><au>Meima, Marcel E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Novel (sulfated) thyroid hormone transporters in the solute carrier 22 family</atitle><jtitle>European thyroid journal</jtitle><addtitle>Eur Thyroid J</addtitle><date>2023-08-01</date><risdate>2023</risdate><volume>12</volume><issue>4</issue><spage>1</spage><epage>11</epage><pages>1-11</pages><issn>2235-0802</issn><issn>2235-0640</issn><eissn>2235-0802</eissn><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.</abstract><cop>England</cop><pub>Bioscientifica Ltd</pub><pmid>37074673</pmid><doi>10.1530/ETJ-23-0023</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0002-5392-0519</orcidid><orcidid>https://orcid.org/0000-0002-3366-6015</orcidid><orcidid>https://orcid.org/0000-0002-7271-7858</orcidid><orcidid>https://orcid.org/0000-0002-5248-863X</orcidid><oa>free_for_read</oa></addata></record>
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subjects Animals
Humans
lesinurad
Membrane Transport Proteins - genetics
Mice
oat3
oat4
oat7
organic anion transporter
Organic Anion Transporters - genetics
Phylogeny
probenecid
solute carrier 22 family
Sulfates - metabolism
thyroid hormone
thyroid hormone sulfate
Thyroid Hormones
transporter
Zebrafish - metabolism
title Novel (sulfated) thyroid hormone transporters in the solute carrier 22 family
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