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M I N I R E V I E W Minireview: Pathophysiological Importance of Thyroid Hormone Transporters Heike Heuer and Theo J. Visser Neuroendocrinology Group, Leibniz Institute for Age Research/Fritz Lipmann Institute, D-07745 Jena, Germany; and Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands Thyroid hormone metabolism and action are largely intracellular events that require transport of iodothyronines across the plasma membrane. It has been assumed for a long time that this occurs by passive diffusion, but it has become increasingly clear that cellular uptake and efflux of thyroid hormone is mediated by transporter proteins. Recently, several active and specific thyroid hormone transporters have been identified, including monocarboxylate transporter 8 (MCT8), MCT10, and organic anion transporting polypeptide 1C1 (OATP1C1). The latter is expressed predominantly in brain capillaries and transports preferentially T4, whereas MCT8 and MCT10 are expressed in multiple tissues and are capable of transporting different iodothyronines. The pathophysiological importance of thyroid hormone transporters has been established by the demonstration of MCT8 mutations in patients with severe psychomotor retardation and elevated serum T3 levels. MCT8 appears to play an important role in the transport of thyroid hormone in the brain, which is essential for the crucial action of the hormone during brain development. It is expected that more specific thyroid hormone transporters will be discovered in the near future, which will lead to a better understanding of the tissue-specific regulation of thyroid hormone bioavailability. (Endocrinology 150: 1078 –1083, 2009) hyroid hormone is important for the growth and development of various tissues, in particular the brain, and for the regulation of their basal metabolic rate throughout life. Many actions of thyroid hormone are initiated by binding of the active form of the hormone T3 to nuclear receptors in target cells (1). These receptors are associated with the T3-responsive elements in T3-sensitive genes, and binding of T3 to its receptors induces changes in their interaction with corepressor and coactivator proteins, resulting in the stimulation or the repression of gene expression (1). Although T3 is the major receptor-active form of thyroid hormone, T4 is the predominant iodothyronine secreted by the thyroid gland under normal conditions. As a consequence, T4 has to be converted by so-called outer ring deiodination (ORD) to T3. Alternatively, T4 is metabolized by inner ring deiodination (IRD) to receptor-inactive rT3, and by the same reaction, T3 is inactivated to 3,3⬘-T2 (2). The latter is also produced by ORD of rT3. Three iodothyronine deiodinases (D1–3) are involved in these reactions. D1 is expressed in liver, kidney, and T thyroid. Although it has both ORD and IRD activity, the former prevails physiologically, contributing significantly to the production of serum T3 and clearance of serum rT3 (2). D2 is expressed in brain, pituitary, brown adipose tissue, and thyroid and, at least at the mRNA level, in skeletal muscle and heart. D2 has only ORD activity and is important for local production of T3 in brain, pituitary, and brown adipose tissue. D2 in these and other tissues may also contribute to the production of circulating T3. D3 is expressed in adult brain and skin and at high levels in multiple fetal tissues as well as in the placenta and the uterus during pregnancy. It has only IRD activity and is thus important for the negative control of local and systemic T3 levels (2). The biological activity of thyroid hormone is largely determined by the intracellular T3 concentration available for binding to its nuclear receptors, which depends on a number of factors: 1) the circulating concentrations of T3 and its precursor T4, 2) the activities of the deiodinases catalyzing the production or degradation of T3, and 3) the activities of transporters that facilitate ISSN Print 0013-7227 ISSN Online 1945-7170 Printed in U.S.A. Copyright © 2009 by The Endocrine Society doi: 10.1210/en.2008-1518 Received October 30, 2008. Accepted December 15, 2008. First Published Online January 29,2009 Abbreviations: AHDS, Allan-Herndon-Dudley syndrome; CRYM, -crystallin; h, human; IRD, inner ring deiodination; MCT, monocarboxylate transporter; OATP, organic anion transporting polypeptide; ORD, outer ring deiodination; TAT1, T-type amino acid transporter; TLS, translation start site. 1078 endo.endojournals.org Endocrinology, March 2009, 150(3):1078 –1083 Downloaded from endo.endojournals.org at Radcliffe Sci Library Acquisitions Department on February 8, 2010 Endocrinology, March 2009, 150(3):1078 –1083 cellular uptake and/or efflux of the different iodothyronines. It has been thought for a long time that the lipophilic iodothyronines are capable of crossing the plasma membrane by simple diffusion, but it has become increasingly clear that this is impossible without transporters (3). In the last decade, several transporters have been identified that are capable of facilitating the cellular entry and/or efflux of iodothyronine derivatives. These include the Na-taurocholate cotransporting polypeptide (NTCP), different members of the Na-independent organic anion transporting polypeptide (OATP) family, and the L-type amino acid transporters LAT1 and LAT2 (4). We have also shown that fatty acid translocase (FAT) expression in Xenopus oocytes stimulates iodothyronine uptake (5). However, FAT (also known as CD36) is not a true transporter but may function as a cell surface attractant for ligands of neighboring receptors and transporters (6). Most of the above-mentioned organic anion transporters are multispecific, accepting a wide variety of ligands. A notable exception is OATP1C1, which is almost exclusively expressed in brain, in particular in microvessels and the choroid plexus, and shows a high specificity for T4 (7–9). This transporter is thought to be very important for the transport of T4 into the brain. A series of studies by the group of Blondeau and Francon (10, 11) has strongly suggested the involvement of a T-type (aromatic) amino acid transporter in the cellular uptake of iodothyronines, in particular in erythrocytes. In 2001 and 2002, Kim et al. (12, 13) reported on the cloning and characterization of such a transporter in rats and humans, termed TAT1. They noted that this transporter belongs to the family of monocarboxylate transporters (MCTs); it is now better known as MCT10 (or SLC16A10). Although Kim et al. (12, 13) clearly demonstrated transport of the aromatic amino acids Phe, Tyr, and Trp, they could not detect transport of T4 and T3 by MCT10. This led us to hypothesize that another member of the MCT family most homologous to MCT10, namely MCT8, is the long-sought T-type amino acid transporter that also transports thyroid hormone. Indeed, MCT8 (SLC16A2) has been shown to be an active and specific thyroid hormone transporter, but it does not transport aromatic amino acids (14, 15). Remarkably, we have later demonstrated that, in contrast to the results of Kim et al., MCT10 is at least as good as MCT8 in transporting iodothyronines (see below) (16). The MCT family consists of 14 homologous proteins and earned its name because the first four members (MCT1– 4) have been characterized as MCTs that facilitate the proton-dependent cellular uptake and efflux of compounds such as lactate and pyruvate (17, 18). MCT6 has been shown to transport the diuretic bumetadine, but its natural ligands have not been identified yet (19). The function of MCT5, -7, -9, and -11–14 also remains to be elucidated. The proper expression and function of MCT1– 4 in the plasma membrane depends on the oligomerization (e.g. heterotetramer formation) with the ancillary proteins basigin (CD147) or embigin (gp70) (17, 20). This review focuses on the biochemical and pathophysiologial aspects of thyroid hormone transport by MCT8 and MCT10. endo.endojournals.org 1079 Biochemistry of MCT8 The MCT8 gene is located on human (h) chromosome Xq13.2 and consists of six exons and five introns, the first of which is about 100,000 kb in size (17, 21). The mature mRNA is about 4.4 kb large and contains two possible translation start sites (TLSs). Depending on which of these TLSs is used, proteins are generated consisting of 613 or 539 amino acids. The most upstream TLS is absent in most species, including mouse and rat, and the importance of the additional N-terminal sequence in the longer hMCT8 protein is as yet unknown. The N-terminal domain of the shorter hMCT8 protein contains one PEST-domain and the longer hMCT8 protein contains two PEST domains (21). Based on this feature, MCT8 was initially named XPCT (Xlinked PEST-containing transporter). PEST domains are rich in Pro, Glu, Ser and Thr residues and are often associated with rapid protein degradation, but the function of the PEST domain(s) in MCT8 is unknown. As with all other MCTs and irrespective of the length of the N terminus, hMCT8 contains 12 putative transmembrane domains, and both the N and C terminus are located intracellularly. The hMCT8 amino acid sequence does not contain consensus glycosylation sites, and immunoblots of cells transfected with hMCT8 cDNA show a major protein with a molecular mass corresponding to the nonglycosylated protein (15). In addition, a weaker band is observed with a molecular mass suggestive of the homodimer (15). Ancillary proteins such as basigin and embigin do not appear to be required for proper expression of hMCT8 protein in the plasma membrane (Visser, W. E., unpublished results). Initially, MCT8 was characterized as a thyroid hormone transporter in studies where rat MCT8 was expressed in Xenopus oocytes (14). This resulted in an approximately 10-fold increase in the uptake of the iodothyronines T4, T3, rT3, and 3,3⬘T2, but it had no effect on the uptake of T4 sulfate, the aromatic amino acids Phe, Tyr, and Trp, and lactate. Subsequent studies in mammalian cells indicated marked stimulation of T4 and T3 uptake after transient transfection with hMCT8, but the magnitude of the response was much smaller than that observed with rat MCT8 in oocytes (15). This was explained by the high rate of iodothyronine efflux from hMCT8-transfected cells, which could be prevented by cotransfection with the highaffinity cytoplasmic thyroid hormone-binding protein -crystallin (CRYM). In the presence of CRYM, net uptake of T4 and T3 was greatly stimulated by hMCT8 expression in mammalian cells (15). Metabolism of iodothyronines in intact deiodinase-transfected cells is strongly enhanced by cotransfection with hMCT8 (15). This has been shown for T4 metabolism by D2 or D3, for T3 metabolism by D3, for rT3 metabolism by D1 or D2, and for 3,3⬘-T2 metabolism by D3. Although a different topography has been suggested for D3, the active centers of the different deiodinases are localized in the cytoplasm (2). These findings, therefore, demonstrate that hMCT8 greatly increases the intracellular availability of the different iodothyronines. Presumably, MCT8 also facilitates the supply of T3 to its nuclear receptors, but this remains to be demonstrated. Downloaded from endo.endojournals.org at Radcliffe Sci Library Acquisitions Department on February 8, 2010 1080 Heuer and Visser Minireview Endocrinology, March 2009, 150(3):1078 –1083 As demonstrated by Northern blotting and RT-PCR, MCT8 mRNA is widely expressed in human and rat tissues, including brain, heart, liver, kidney, adrenal gland, and thyroid (22, 23). Rat MCT8 protein has been localized by immunohistochemistry in the basolateral membrane of hepatocytes, renal tubule cells, and thyrocytes (Philp, N., unpublished observations). Because little is known about the mechanism of hormone secretion from the thyroid gland, it is unclear whether and how MCT8 plays a role in this process. Analysis of the MCT8 mRNA expression pattern in the mouse brain by in situ hybridization revealed a distinct localization of this transporter in specific neuronal populations known to be highly dependent on proper thyroid hormone supply (24). For instance, pronounced transcript levels were detected in hippocampal pyramidal neurons and granule cells, in layers 2–3 and 5 of the cerebral cortex, in basal ganglia, throughout the amygdala, and in cerebellar Purkinje cells, indicating that MCT8 may play a critical role in the uptake of T3 into neuronal cells (Fig. 1). Moreover, high transcript levels for MCT8 were observed in choroid plexus structures and in capillary endothelial cells, suggesting that MCT8 also contributes to the passage of thyroid hormones via the blood-brain barrier and/or via the blood-cerebrospinal fluid barrier (24, 25) (Fig. 1), a hypothesis that was confirmed by the analysis of MCT8-deficient mice (see below). Clinical Relevance of MCT8 Since 2004, several male patients have been reported in the literature with a particular combination of severe neurological deficits and abnormal serum thyroid hormone levels (26 –36). The neurological phenotype includes in most patients central hypotonia, with poor head control; initially also peripheral hypoto- Oatp1c1 MCT8 T2 D3 T4 ? T4 D2 T3 BBB T3 T3 ? ? astrocyte neuron FIG. 1. A model of the two routes of T3 supply to central neurons. One consists of 1) T4 transport across the blood-brain barrier (BBB) involving OATP1C1, 2) T4 uptake in astrocytes via an unknown transporter, 3) T4 conversion to T3 by D2, 4) T3 release from astrocytes via an unknown transporter, and 5) T3 uptake by neurons via MCT8 or another transporter. The second route consists of 1) T3 transport across the BBB by MCT8 and 2) uptake into neurons by MCT8 or another transporter. Neuronal T3 uptake through other transporters than MCT8 may be more important in mice than in humans. Adapted from Heuer et al. (24). nia, which evolves into spastic quadriplegia; inability to sit, stand, or walk independently; severe mental retardation; and absence of speech. For a detailed description of the clinical phenotype, the reader is referred to previous articles (37, 38). This severe form of X-linked psychomotor retardation has already been described in 1944 (39) and since then also named after the original authors as the Allan-Herndon-Dudley syndrome (AHDS). What was not known at that time was the association with abnormal thyroid parameters. Patients with AHDS invariably have markedly elevated serum T3 and low T4, free T4, and rT3 levels. Serum TSH varies between normal and somewhat elevated. The severe neurological impairment in these patients and the elevated serum T3 levels, in view of the well-known importance of thyroid hormone for brain development, suggested that this syndrome represented some form of thyroid hormone resistance. Because the X-linked inheritance of the disorder was not obvious when we encountered this syndrome in 2002 in the first two patients, the THRA and THRB genes, which encode the T3 receptors, were examined for possible pathogenic mutations with negative results (27). Also the DIO1, DIO2, and DIO3 genes, which code for D1, D2, and D3, respectively, were screened for possible mutations that were not found either (27). This prompted us to hypothesize that the AHDS syndrome represents a novel form of thyroid hormone resistance due to a lack of thyroid hormone entry in target cells. Because we had just discovered MCT8 as an active and specific thyroid hormone transporter, which gene is located on the X chromosome, we tested this hypothesis by sequencing the MCT8 gene in the first two patients and, indeed, identified different mutations in this gene. To date, we have demonstrated different mutations in 15 unrelated AHDS families (40), and worldwide over 40 different mutations have been identified. Especially the groups of Schwartz and Refetoff (41, 42) have also contributed considerably to the clinical and genetic investigation of AHDS patients. These mutations include large deletions resulting in the loss of one or more exons, smaller frame-shift deletions, 3-nucleotide (1-amino acid) deletions or insertions, nonsense mutations resulting in truncation of the MCT8 protein, and missense mutations resulting in 1-amino acid substitutions. Many of these mutations are obviously detrimental for hMCT8 function, but for the 1-amino acid deletions, insertions, and substitutions, this is not immediately clear. We have, therefore, introduced a variety of such mutations found in patients into the hMCT8 cDNA and compared the function of mutated and wild-type MCT8 in transfected cells (30, 34, 43). Cells transfected with the MCT8 variants alone were tested for T3 uptake, and cells cotransfected with D3 were tested for T3 metabolism. In both tests, most mutations resulted in a complete inactivation of MCT8 function. However, significant residual activity was observed with a number of MCT8 mutations, and some of these were associated with a milder clinical phenotype (30, 34, 43). There appear to be different mechanisms by which mutations affect MCT8 function. With some mutations, the generation of hMCT8 protein is strongly diminished, perhaps due to incorrect protein processing and rapid protein degradation. With other mutations, hMCT8 protein generation is not dimin- Downloaded from endo.endojournals.org at Radcliffe Sci Library Acquisitions Department on February 8, 2010 Endocrinology, March 2009, 150(3):1078 –1083 ished, but it does not undergo proper trafficking to the plasma membrane. Yet other hMCT8 mutants are expressed at the plasma membrane but appear to have lost their iodothyroninetransporting activity (43). The effects of AHDS-causing mutations on MCT8 transporter function can also be studied in fibroblasts cultured from patients’ skin biopsies (34). Apparently, MCT8 is the major thyroid hormone transporter expressed in these cells, because fibroblasts from AHDS patients show markedly decreased T4 and T3 uptake compared with control fibroblasts. We have studied fibroblasts from four AHDS patients, three of whom had devastating MCT8 mutations, and one had a Phe501del mutation. Fibroblasts from the latter patient showed T3 uptake and efflux rates in between those of the other three patients and the controls. This patient also presented the mildest clinical phenotype and least abnormal serum T4, T3, and rT3 levels in our patient cohort. Results obtained with cells transfected with the MCT8-Phe501del mutant were in close agreement with the fibroblast findings. These and other results suggest a genotype-phenotype correlation for AHDScausing mutations in MCT8 (34, 43). Delayed myelinization is often mentioned in magnetic resonance imaging studies of patients with MCT8 mutations, but this appears not to be a general characteristic. Interestingly, however, a study was reported recently in patients with the PelizaeusMerzbacher syndrome, who have X-linked mental retardation because of a myelinization defect. In most patients, this is caused by a mutation in the PLP1 gene, which encodes proteolipid protein 1, an important component of myelin. Vaurs-Barrière et al. (44) screened serum thyroid parameters and the MCT8 gene sequence in 53 patients with Pelizaeus-Merzbacher-like syndrome without mutations in PLP1 and identified six patients with high serum T3 levels and different MCT8 mutations. This study underscores how difficult it is to categorize patients with X-linked mental retardation on the basis of clinical characteristics. It also supports the relevance of screening such patients for high serum T3 levels to identify those with possible mutations in MCT8. endo.endojournals.org 1081 absence of MCT8 in mice results in a strongly diminished uptake of T3 into the brain. As a consequence, the brain was found to be in a rather hypothyroid state as reflected by decreased T4 and T3 concentrations and increased D2 and decreased D3 activities. Because the transport of T4 into the brain of MCT8-null mice is not compromised, an increase in local T3 production is sufficient to provide certain neuronal cells such as cerebellar Purkinje cells with adequate amounts of thyroid hormone, thereby preventing serious neurological damage. Other neurons such as RC3-expressing cells in the striatum exhibit signs of hypothyroidism indicating that either local T3 production or neuronal uptake of T3 into these cells is affected in the absence of MCT8. Furthermore, strongly elevated transcript levels for TRH in the hypothalamic paraventricular nucleus points to a strong hypothyroid state of these cells in the absence of MCT8. This increase in TRH expression can be successfully suppressed with a high dose of T4, demonstrating that paraventricular nucleus neurons still respond to locally produced T3. In comparison with the hypothyroid state of the hypothalamus, the pituitary appears to be surprisingly normal with no alterations in the expression levels of thyroid hormone-responsive genes. Furthermore, TSH levels are only slightly elevated in MCT8-null mice. However, when MCT8-null mice are rendered hypothyroid, only high concentrations of T3 are able to suppress TSH expression, suggesting that not only the hypothalamus but also the pituitary is rather insensitive to the circulating T3 levels. This central resistance to thyroid hormone has also been found in patients with MCT8 mutations (47). However, the underlying mechanism is not understood yet and needs further investigation. The fact that uptake of T3 into the brain is strongly diminished in MCT8-null animals raises the question of why the transport of T4 is not also impaired. We speculate that OATP1C1, which exhibits a striking substrate specificity toward T4 and rT3, is critically involved in the transport of T4 via the blood-brain and blood-cerebrospinal fluid barrier because this transporter is highly enriched in capillary endothelial cells as well as in the choroid plexus (9, 25). This hypothesis, however, needs to be ultimately validated by the analysis of MCT8/OATP1C1-deficient animals. Analysis of MCT8-Null Mice The generation and analysis of mouse mutants deficient in MCT8 provided further information as to the role of this thyroid hormone transporter in specific tissues (45, 46). The most remarkable phenotype of MCT8-null animals is the lack of any overt neurological abnormalities, a rather unexpected finding in light of the severe human phenotype. However, MCT8-null mice exhibit a marked increase in serum T3 and a decrease in serum T4 and rT3. Thus, these mice fully replicate the endocrinological aberrances diagnosed in patients with inactivating MCT8 mutations. How do the abnormal serum thyroid hormone concentrations affect metabolism and function of organs that are dependent on proper thyroid hormone supply? Analysis of the thyroid state of the liver revealed increased D1 activities as well as an increased T3 content in MCT8-null mice, indicating that hepatocytes fully sense the rise in circulating T3 levels. In contrast, MCT10 Of all MCT family members, the MCT10 amino acid sequence is most homologous to that of MCT8, suggesting that they are derived from a common ancestor (16, 17). This is supported by the presence of single genes in different insects that code for proteins highly homologous to MCT8/10 (16). In Drosophila, the gene is known as kar and codes for a putative transporter for Trp or another precursor for an ommochrome pigment; kar is mutated in flies with the karmoisin eye color phenotype (16, 48). The hMCT10 gene is located on human chromosome 6q21-q22 and has the same structure as the hMCT8 gene. The mature mRNA is about 2.6 kb in size, has a single TLS, and codes for a protein of 515 amino acids, containing 12 putative transmembrane domains. Like hMCT8, there is no consensus glycosylation site in the hMCT10 amino acid sequence. Transfection of Downloaded from endo.endojournals.org at Radcliffe Sci Library Acquisitions Department on February 8, 2010 1082 Heuer and Visser Minireview cells with hMCT10 cDNA results in the generation of a major approximately 55-kDa protein, the expected molecular mass for the nonglycosylated protein. Immunoblots also show a higher band, suggestive of the formation of the homodimer (16). Initially, rat and subsequently hMCT10 have been characterized in Xenopus oocytes as a T-type amino acid transporter (TAT1), which facilitates cellular uptake and efflux of aromatic amino acids such as Trp, Phe, Tyr, and 3,4-dihydroxyphenylalanine (DOPA) (12, 13). MCT10 is expressed in different human and rodent tissues, in particular intestine, kidney, liver, skeletal muscle, heart, and placenta (12, 13, 23, 49). MCT10 protein has been localized by immunohistochemistry in the basolateral membranes of perivenous hepatocytes, renal proximal tubule cells, and intestinal villi cells (49). Because MCT10 facilitates the efflux of aromatic amino acids much better than their uptake, the transporter appears to serve an important function in the intestinal and renal resorption of these amino acids by mediating their efflux into the bloodstream (49). Transfection of mammalian cells with hMCT10 cDNA results in a marked induction of iodothyronine uptake, which is strongly augmented if the cells are cotransfected with CRYM (16). The latter is explained by the inhibition of iodothyronine efflux in the presence of the cytosolic thyroid hormone-binding protein. These findings indicate that hMCT10 facilitates both cellular uptake and efflux of the different iodothyronines. As is the case with MCT8, expression of hMCT10 also largely stimulates the deiodination of iodothyronines in cells cotransfected with the different deiodinases through an increase in the intracellular availability of these substrates (16). The physiological relevance of MCT10 for thyroid hormone action and metabolism in different tissues remains to be elucidated. Because MCT10 is at least as active in transporting thyroid hormone as MCT8, it is to be expected that inactivating mutations in MCT10 will also result in significant changes in intracellular thyroid hormone concentrations in different tissues. The magnitude and direction of these changes will not only depend on the expression of MCT10 but also on that of other transporters in these tissues. Conclusion and Perspectives Through the characterization of MCT8, MCT10, and OATP1C1 as active thyroid hormone transporters, and the recognition of the severe clinical phenotype caused by mutations in MCT8, the concept that plasma membrane transporters are essential for action and metabolism of thyroid hormone has been firmly established. It is to be expected that more thyroid hormone transporters will be discovered in the near future. For instance, there is strong evidence for the existence of high-affinity, Na-dependent iodothyronine transporters in the liver, but the identity of these transporters is still elusive. Also, different transporters may be involved in thyroid hormone transport in different cell types and different regions in the brain. Endothelium is a first barrier that has to be crossed in the transfer of thyroid hormone from the blood into the tissues, but very little is still known about the nature of the transporters involved. A lot remains to be investi- Endocrinology, March 2009, 150(3):1078 –1083 gated before we begin to understand all the ins and outs of thyroid hormone transporters. Acknowledgments These studies were supported by grants from the American Thyroid Association and The Netherlands Organization for Scientific Research. Address all correspondence and requests for reprints to: Theo J. 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