Review Thyroid Hormone Transporters Stefan Groeneweg,1 Ferdy S. van Geest,1 Robin P. Peeters,1 Heike Heuer,2 and Downloaded from https://academic.oup.com/edrv/article-abstract/41/2/bnz008/5637505 by Erasmus University Rotterdam user on 04 March 2020 W. Edward Visser1 1Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands Academic Center for Thyroid Diseases, Erasmus Medical Center, 3015 GD Rotterdam, the Netherlands; and2 Department of Endocrinology, Diabetes and Metabolism, University Hospital Essen, University Duisburg-Essen, Essen 45122, Germany ORCiD numbers: 0000-0002-5248-863X (W. E. Visser). ABSTRACT Thyroid hormone transporters at the plasma membrane govern intracellular bioavailability of thyroid hormone. Monocarboxylate transporter (MCT) 8 and MCT10, organic anion transporting polypeptide (OATP) 1C1, and SLC17A4 are currently known as transporters displaying the highest specificity toward thyroid hormones. Structure-function studies using homology modeling and muta- tional screens have led to better understanding of the molecular basis of thyroid hormone transport. Mutations in MCT8 and in OATP1C1 have been associated with clinical disorders. Different animal models have provided insight into the functional role of thyroid hormone transporters, in particular MCT8. Different treatment strategies for MCT8 deficiency have been explored, of which thyroid hormone ana- logue therapy is currently applied in patients. Future studies may reveal the identity of as-yet-undiscovered thyroid hormone transporters. Complementary studies employing animal and human models will provide further insight into the role of transporters in health and disease. (Endocrine Reviews 41: 1 – 55, 2020) GRAPHICAL ABSTRACT Thyroid Blood Brain barriers Brain = TSH Astrocyte Oligodendrocyte HEALTH = T4 Neuron = T3 Bone Heart Muscle ISSN Print: 0163-769X ISSN Online: 1945-7189 Thyroid Blood Brain barriers Brain Printed: in USA = TSH Astrocyte Oligodendrocyte © Endocrine Society 2019. Neuron All rights reserved. For T4 DISEASE permissions, please e-mail: [email protected] T3 ISSN Print: 0163-769XISSN Online: 1945-7189Printed: in USA Received: 31 May 2019 Bone Heart Muscle Accepted: 7 November 2019 First Published Online: 22 Key Words: thyroid hormone, thyroid hormone transport, thyroid hormone transporters, MCT8, November 2019 MCT8 deficiency, Allan-Herndon-Dudley syndrome, AHDS, OATP1C1 Corrected and Typeset 13 February 2020. doi: 10.1210/endrev/bnz008 https://academic.oup.com/edrv 1 Review ESSENTIAL POINTS • Thyroid hormones require transporter proteins to facilitate their transport across cell membranes • Among the up to 16 different thyroid hormone transporters belonging to 5 distinct protein families; monocarboxylate transporter 8 (MCT8) is the most specific thyroid hormone transporter identified to date Genetic mutations in MCT8 and organic anion transporting polypeptide (OATP) 1C1 have been associated with clinical • Downloaded from https://academic.oup.com/edrv/article-abstract/41/2/bnz008/5637505 by Erasmus University Rotterdam user on 04 March 2020 syndromes • MCT8 deficiency (Allan-Herndon-Dudley syndrome) is characterized by a neurocognitive (central) entity related to a hypothyroid state in the brain and a peripheral entity due to T3 excess in the circulation • Treatment strategies for MCT8 deficiency that are currently being explored include thyroid hormone analogue therapy, (molecular) chaperones, and gene therapy hyroid hormone, the common name for early studies, providing the basis for a paradigm T the inactive precursor thyroxine (T4) and shift in the field, have been extensively reviewed the active hormone 3,5,3’-tri-iodothyronine (T3), in this Journal by Hennemann et al (2001) (8). The is important for the development of virtually all turn of the millennium marked the time of several tissues and regulation of basal metabolism and discoveries that had a great impact on the field of tissue regeneration throughout life (1, 2). thyroidology. The genomic effects of thyroid hormone are First, several transporters from different pro- exerted through binding of T3 to the nuclear T3 tein families were identified at the molecular receptors (TRs), which are bound to T3-response level as thyroid hormone–transporting proteins. elements (TREs) in the regulatory regions of T3 This was a major breakthrough compared to the target genes and can act as transcription factors (2). decades before when only the general character- The intracellular T3 concentration is governed by istics of thyroid hormone transmembrane pas- the 3 deiodinating enzymes (DIO1-3) that can ei- sage had been studied in nontransfected cells. ther activate or inactivate thyroid hormone, as well The most efficient thyroid hormone transporters as by the activity of plasma membrane transporter include monocarboxylate transporter (MCT)8, proteins that mediate the cellular uptake and/or ef- MCT10, the organic anion transporting polypep- flux of T4 and T3 in thyroid hormone target cells tide (OATP)1C1 and, recently, SLC17A4 (10–13). (Fig. 1) (3–5). Plasma membrane transporters need Another group of discoveries involved the iden- to be distinguished from serum thyroid hormone– tification of diseases associated with mutations in binding proteins (such as thyroid hormone– thyroid hormone transporters. Mutations in MCT8 binding globulin), which were previously called are associated with severe intellectual disability serum thyroid hormone transporters (6). The accompanied by a specific thyroid hormone fin- transport of thyroid hormones in serum is exten- gerprint in the blood (14, 15). These publications sively reviewed elsewhere (6) and falls beyond the started a new era because they provided ultimate scope of this review. There is increased awareness proof for the physiological relevance of thyroid of nongenomic effects of thyroid hormones whose hormone transporters. Recently, the first case of actions involve receptors in the plasma membrane, OATP1C1 deficiency has been reported presenting mitochondria, or cytoplasm (7). with progressive neurodegeneration and cerebral It had been thought for many decades that hypometabolism (16). thyroid hormones could enter their target cells In addition, different models have been es- through passive diffusion given the lipophilic na- tablished to study the role of thyroid hormone ture of iodothyronines. However, accumulating ev- transporters in health and disease. Particularly, idence published from the 1970s onward provided various experimental models have enlarged the evidence that thyroid hormone transfer across the understanding on the (tissue-specific) contri- plasma membrane requires a carrier-mediated bution of various thyroid hormone transporters mechanism, and that the role of passive diffusion, in the regulation of tissue thyroid hormone if any, is limited (8, 9). These studies indicated that state. Novel global and tissue-specific trans- the transport of thyroid hormone into cells is a porter knock-out (ko) mouse models have been saturable process, may be inhibited by aromatic generated and characterized over recent years and/or aliphatic amino acids, and may depend on (17–27). In addition, zebrafish and chicken are Na+ in some cell types. Yet, the identity of thyroid emerging as complementary vertebrate models to hormone plasma membrane transporter proteins study the role of thyroid hormone transporters. started being elucidated in the late 1990s. These Finally, redifferentiated patient-derived induced 2 Groeneweg et al. Thyroid Hormone Transporters Endocrine Reviews, April 2020, 41(2):1–56 Review Downloaded from https://academic.oup.com/edrv/article-abstract/41/2/bnz008/5637505 by Erasmus University Rotterdam user on 04 March 2020 Figure 1. Transport, metabolism, and action of thyroid hormone in a thyroid hormone target cell. Transport across the plasma mem- brane is facilitated by transporter proteins. Deiodination of thyroid hormones is catalyzed by iodothyronine deiodinases (type 1, D1; type 2, D2; type 3, D3). T3 enters the nucleus, where it binds its receptor (TR) that forms a heterodimer with RXR at T3-responsive elements (TREs) in the promotor regions of T3 target genes. mRNA indicates messenger RNA. pluripotent stem cells (iPSCs) have been em- L-type amino acid transporters (LATs), and ployed as a human model to understand disease monocarboxylate transporters (SLC16 also known (28–32). as MCTs). Drug therapy development programs followed Most thyroid hormone transporters have been the identification of MCT8 deficiency. The identified through in vitro overexpression studies 125 abovementioned models largely facilitated testing in cell lines or Xenopus oocytes, using [ I]–radio- potential therapeutic intervention for transporter labeled iodothyronines to measure cellular thyroid defects. Such preclinical studies indicated that hormone uptake. Such cellular expression systems are the use of thyroid hormone analogues may hold indispensable to ensure proper protein conformation strong therapeutic potential in MCT8 deficiency, and function. The substrate specificity of transporters leading to a phase 2 clinical trial on the application is generally determined in direct uptake studies with of triiodothyroacetic acid (Triac) (33). In addition, the compounds of interest or indirectly in (cis-)inhibi- chemical chaperones and gene therapy are under tion studies. Cellular thyroid hormone homeostasis in active investigation (34–37). these systems depends not only on the overexpressed Here we provide