scholarly journals Minireview: Thyroid Hormone Transporters: The Knowns and the Unknowns

2011 ◽  
Vol 25 (1) ◽  
pp. 1-14 ◽  
Author(s):  
W. Edward Visser ◽  
Edith C. H. Friesema ◽  
Theo J. Visser
Keyword(s):  
Thyroid Hormone ◽  
Organic Anion ◽  
Psychomotor Retardation ◽  
Cellular Level ◽  
Monocarboxylate Transporter ◽  
Causative Role ◽  
Organic Anion Transporting Polypeptide ◽  
Neurological Abnormalities ◽  
Knockout Animals

The effects of thyroid hormone (TH) on development and metabolism are exerted at the cellular level. Metabolism and action of TH take place intracellularly, which require transport of the hormone across the plasma membrane. This process is mediated by TH transporter proteins. Many TH transporters have been identified at the molecular level, although a few are classified as specific TH transporters, including monocarboxylate transporter (MCT)8, MCT10, and organic anion-transporting polypeptide 1C1. The importance of TH transporters for physiology has been illustrated dramatically by the causative role of MCT8 mutations in males with psychomotor retardation and abnormal serum TH concentrations. Although Mct8 knockout animals have provided insight in the mechanisms underlying parts of the endocrine phenotype, they lack obvious neurological abnormalities. Thus, the pathogenesis of the neurological abnormalities in males with MCT8 mutations is not fully understood. The prospects of identifying other transporters and transporter-based syndromes promise an exciting future in the TH transporter field.

scholarly journals Thyroid Hormone Transporters

2019 ◽  
Vol 41 (2) ◽  
pp. 146-201 ◽  
Author(s):  
Stefan Groeneweg ◽  
Ferdy S van Geest ◽  
Robin P Peeters ◽  
Heike Heuer ◽  
W Edward Visser
Keyword(s):  
Thyroid Hormone ◽  
Organic Anion ◽  
Treatment Strategies ◽  
Monocarboxylate Transporter ◽  
Organic Anion Transporting Polypeptide ◽  
Clinical Disorders ◽  
Health And Disease ◽  
Mct8 Deficiency ◽  
Insight Into

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 mutational 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 analogue 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.

scholarly journals Evidence for a Homodimeric Structure of Human Monocarboxylate Transporter 8

Endocrinology ◽  
2009 ◽  
Vol 150 (11) ◽  
pp. 5163-5170 ◽  
Author(s):  
W. Edward Visser ◽  
Nancy J. Philp ◽  
Thamar B. van Dijk ◽  
Wim Klootwijk ◽  
Edith C. H. Friesema ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Psychomotor Retardation ◽  
Monocarboxylate Transporter ◽  
Membrane Association ◽  
Transport Function ◽  
Wild Type ◽  
Transfected Cells ◽  
Physiological Relevance ◽  
Dimerization Process

The human monocarboxylate transporter 8 (hMCT8) protein mediates transport of thyroid hormone across the plasma membrane. Association of hMCT8 mutations with severe psychomotor retardation and disturbed thyroid hormone levels has established its physiological relevance, but little is still known about the basic properties of hMCT8. In this study we present evidence that hMCT8 does not form heterodimers with the ancillary proteins basigin, embigin, or neuroplastin, unlike other MCTs. In contrast, it is suggested that MCT8 exists as monomer and homodimer in transiently and stably transfected cells. Apparently hMCT8 forms stable dimers because the complex is resistant to denaturing conditions and dithiothreitol. Cotransfection of wild-type hMCT8 with a mutant lacking amino acids 267–360 resulted in formation of homo-and heterodimers of the variants, indicating that transmembrane domains 4–6 are not involved in the dimerization process. Furthermore, we explored the structural and functional role of the 10 Cys residues in hMCT8. All possible Cys>Ala mutants did not behave differently from wild-type hMCT8 in protein expression, cross-linking experiments with HgCl2 and transport function. Our findings indicate that individual Cys residues are not important for the function of hMCT8 or suggest that hMCT8 has other yet-undiscovered functions in which cysteines play an essential role.

scholarly journals Molecular aspects of thyroid hormone transporters, including MCT8, MCT10, and OATPs, and the effects of genetic variation in these transporters

2009 ◽  
Vol 44 (1) ◽  
pp. 1-11 ◽  
Author(s):  
Wendy M van der Deure ◽  
Robin P Peeters ◽  
Theo J Visser
Keyword(s):  
Genetic Variation ◽  
Thyroid Hormone ◽  
Organic Anion ◽  
Elevated Serum ◽  
Tissue Level ◽  
Psychomotor Retardation ◽  
Monocarboxylate Transporter ◽  
Organic Anion Transporting Polypeptides ◽  
The Central Nervous System ◽  
Molecular Aspects

Thyroid hormone is a pleiotropic hormone with widespread biological actions. For instance, adequate levels of thyroid hormone are critical for the development of different tissues such as the central nervous system, but are also essential for the regulation of metabolic processes throughout life. The biological activity of thyroid hormone depends not only on serum thyroid hormone levels, but is also regulated at the tissue level by the expression and activity of deiodinases, which activate thyroid hormone or mediate its degradation. In addition, thyroid hormone transporters are necessary for the uptake of thyroid hormone into target tissues. With the discovery of monocarboxylate transporter 8 (MCT8) as a specific thyroid hormone transporter and the finding that mutations in this transporter lead to a syndrome of severe psychomotor retardation and elevated serum 3,3′,5-tri-iodothyronine levels known as the Allan–Herndon–Dudley syndrome, the interest in this area of research has greatly increased. In this review, we will focus on the molecular aspects of thyroid hormone transporters, including MCT8, MCT10, organic anion transporting polypeptides, and the effects of genetic variation in these transporters.

scholarly journals Importance of His192 in the Human Thyroid Hormone Transporter MCT8 for Substrate Recognition

Endocrinology ◽  
2013 ◽  
Vol 154 (7) ◽  
pp. 2525-2532 ◽  
Author(s):  
Stefan Groeneweg ◽  
Elaine C. Lima de Souza ◽  
W. Edward Visser ◽  
Robin P. Peeters ◽  
Theo J. Visser
Keyword(s):  
Thyroid Hormone ◽  
Transmembrane Domain ◽  
Substrate Recognition ◽  
Inhibitory Effect ◽  
Psychomotor Retardation ◽  
Site Directed Mutagenesis ◽  
Monocarboxylate Transporter ◽  
Human Thyroid ◽  
Extracellular Loop

Abstract Monocarboxylate transporter 8 (MCT8) facilitates cellular uptake and efflux of thyroid hormone (TH). So far, functional domains within MCT8 are not well defined. Mutations in MCT8 result in severe psychomotor retardation due to impaired neuronal differentiation. One such mutation concerns His192 (H192R), located at the border of transmembrane domain (TMD) 1 and extracellular loop (ECL) 1, suggesting that this His residue is important for efficient TH transport. Here, we studied the role of different His residues, predicted within TMDs or ECLs of MCT8, in substrate recognition and translocation. Therefore, we analyzed the effects of the His-modifying reagent diethylpyrocarbonate (DEPC) and of site-directed mutagenesis of several His residues on TH transport by MCT8. Reaction of MCT8 with DEPC inhibited subsequent uptake of T3 and T4, whereas T3 and T4 efflux were not inhibited. The inhibitory effect of DEPC on TH uptake was prevented in the presence of T3 or T4, suggesting that TH blocks access to DEPC-sensitive residues. Three putative DEPC target His residues were replaced by Ala: H192A, H260A, and H450A. The H260A and H450A mutants showed similar TH transport and DEPC sensitivity as wild-type MCT8. However, the H192A mutant showed a significant reduction in TH uptake and was insensitive to DEPC. Taken together, these results indicate that His192 is sensitive to modification by DEPC and may be located close to a putative substrate recognition site within the MCT8 protein, important for efficient TH uptake.

scholarly journals Role of OAT4 in Uptake of Estriol Precursor 16α-Hydroxydehydroepiandrosterone Sulfate Into Human Placental Syncytiotrophoblasts From Fetus

Endocrinology ◽  
2015 ◽  
Vol 156 (7) ◽  
pp. 2704-2712 ◽  
Author(s):  
Masatoshi Tomi ◽  
Hiromi Eguchi ◽  
Mayuko Ozaki ◽  
Tomohiro Tawara ◽  
Sachika Nishimura ◽  
...  
Keyword(s):  
Fetal Liver ◽  
Organic Anion ◽  
Dehydroepiandrosterone Sulfate ◽  
Cellular Level ◽  
Organic Anion Transporter ◽  
Organic Anion Transporting Polypeptide ◽  
Anion Transporter ◽  
Basal Plasma ◽  
Good Agreement

Estriol biosynthesis in human placenta requires the uptake of a fetal liver-derived estriol precursor, 16α-hydroxydehydroepiandrosterone sulfate (16α-OH DHEAS), by placental syncytiotrophoblasts at their basal plasma membrane (BM), which faces the fetal circulation. The aim of this work is to identify the transporter(s) mediating 16α-OH DHEAS uptake at the fetal side of syncytiotrophoblasts by using human placental BM-enriched vesicles and to examine the contribution of the putative transporter to estriol synthesis at the cellular level, using choriocarcinoma JEG-3 cells. Organic anion transporter (OAT)-4 and organic anion transporting polypeptide 2B1 proteins were enriched in human placental BM vesicles compared with crude membrane fraction. Uptake of [3H]16α-OH DHEAS by BM vesicles was partially inhibited in the absence of sodium but was significantly increased in the absence of chloride and after preloading glutarate. Uptake of [3H]16α-OH DHEAS by BM vesicles was significantly inhibited by OAT4 substrates such as dehydroepiandrosterone sulfate, estrone-3-sulfate, and bromosulfophthalein but not by cyclosporin A, tetraethylammonium, p-aminohippuric acid, or cimetidine. These characteristics of vesicular [3H]16α-OH DHEAS uptake are in good agreement with those of human OAT4-transfected COS-7 cells as well as forskolin-differentiated JEG-3 cells. Estriol secretion from differentiated JEG-3 cells was detected when the cells were incubated with 16α-OH DHEAS for 8 hours but was inhibited in the presence of 50 μM bromosulfophthalein. Our results indicate that OAT4 at the BM of human placental syncytiotrophoblasts plays a predominant role in the uptake of 16α-OH DHEAS for placental estriol synthesis.

scholarly journals Pathophysiological Importance of Thyroid Hormone Transporters

Endocrinology ◽  
2009 ◽  
Vol 150 (3) ◽  
pp. 1078-1083 ◽  
Author(s):  
Heike Heuer ◽  
Theo J. Visser
Keyword(s):  
Thyroid Hormone ◽  
Organic Anion ◽  
Elevated Serum ◽  
Psychomotor Retardation ◽  
Monocarboxylate Transporter ◽  
Tissue Specific ◽  
Thyroid Hormone Metabolism ◽  
Serum T3 ◽  
Specific Regulation ◽  
Near Future

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. Specific thyroid hormone transporters may be discovered in the near future, leading to a better understanding of the tissue-specific regulation of thyroid hormone bioavailability.

scholarly journals Thyroid hormone transporters and deiodinases in the developing human hypothalamus

2012 ◽  
Vol 167 (3) ◽  
pp. 379-386 ◽  
Author(s):  
Edith C H Friesema ◽  
Theo J Visser ◽  
Anke J Borgers ◽  
Andries Kalsbeek ◽  
Dick F Swaab ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Congenital Hypothyroidism ◽  
Organic Anion ◽  
Monocarboxylate Transporter ◽  
Postmortem Brain ◽  
Brain Cells ◽  
Human Hypothalamus ◽  
Organic Anion Transporting Polypeptide ◽  
Coordinated Expression ◽  
D2 Protein

ObjectiveThyroid hormone (TH) signaling in brain cells is dependent on transport of TH across the plasma membrane followed by intracellular deiodination and binding to the nuclear TH receptors. The aim of this study is to investigate the expression of the specific TH transporters monocarboxylate transporter 8 (MCT8 (SLC16A2)), MCT10, organic anion transporting polypeptide 1C1 (OATP1C1 (SLCO1C1)), and the types 2 and 3 deiodinases (D2 and D3) in the developing human hypothalamus.DesignFifteen postmortem brain samples of fetuses and young children ranging between 17 weeks of gestation and 29 months of postnatal age including one child (28 months) with central congenital hypothyroidism were studied.MethodsSections of the different hypothalami were stained with polyclonal rabbit antisera against MCT8, MCT10, OATP1C1, D2, and D3.ResultsWe found MCT8 and D3 but not D2 protein expression to be present in our earliest sample of 17 weeks of gestation, indicating triiodothyronine degradation, but not production at this time of development. At term, expression of TH transporters and D2 decreased and D3 expression increased, suggesting decreased TH signaling just before birth. The child with central congenital hypothyroidism showed higher MCT8 and D2 expression compared with the other children of similar age.ConclusionsThis study reports the developmental timing of expression of components crucial for central TH signaling in the human hypothalamus. In general, during fetal hypothalamic development, the coordinated expression of D2 and D3 in combination with the different TH transporters suggests that proper TH concentrations are regulated to prevent untimely maturation of brain cells.

scholarly journals Parallel Regulation of Thyroid Hormone Transporters OATP1c1 and MCT8 During and After Endotoxemia at the Blood-Brain Barrier of Male Rodents

Endocrinology ◽  
2015 ◽  
Vol 156 (4) ◽  
pp. 1552-1564 ◽  
Author(s):  
Gábor Wittmann ◽  
Judit Szabon ◽  
Petra Mohácsik ◽  
Shira S. Nouriel ◽  
Balázs Gereben ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Blood Brain Barrier ◽  
Organic Anion ◽  
Brain Barrier ◽  
Monocarboxylate Transporter ◽  
Mrna Levels ◽  
Brain Vessels ◽  
Altered Expression ◽  
Protein Levels ◽  
Blood Brain

Abstract There is increasing evidence that local thyroid hormone (TH) availability changes profoundly in inflammatory conditions due to altered expression of deiodinases that metabolize TH. It is largely unknown, however, how inflammation affects TH availability via the expression of TH transporters. In this study we examined the effect of bacterial lipopolysaccharide (LPS) administration on two TH transporters that are critically important for brain TH homeostasis, organic anion-transporting polypeptide 1c1 (OATP1c1), and monocarboxylate transporter 8 (MCT8). MRNA levels were studied by in situ hybridization and qPCR as well as protein levels by immunofluorescence in both the rat and mouse forebrain. The mRNA of both transporters decreased robustly in the first 9 hours after LPS injection, specifically in brain blood vessels; OATP1c1 mRNA in astrocytes and MCT8 mRNA in neurons remained unchanged. At 24 and/or 48 hours after LPS administration, OATP1c1 and MCT8 mRNAs increased markedly above control levels in brain vessels. OATP1c1 protein decreased markedly in vessels by 24 hours whereas MCT8 protein levels did not decrease significantly. These changes were highly similar in mice and rats. The data demonstrate that OATP1c1 and MCT8 expression are regulated in a parallel manner during inflammation at the blood-brain barrier of rodents. Given the indispensable role of both transporters in allowing TH access to the brain, the results suggest reduced brain TH uptake during systemic inflammation.

scholarly journals Septic shock non-thyroidal illness syndrome causes hypothyroidism and conditions for reduced sensitivity to thyroid hormone

2013 ◽  
Vol 50 (2) ◽  
pp. 255-266 ◽  
Author(s):  
Isabel Castro ◽  
Leah Quisenberry ◽  
Rosa-Maria Calvo ◽  
Maria-Jesus Obregon ◽  
Joaquin Lado-Abeal
Keyword(s):  
Gene Expression ◽  
Septic Shock ◽  
Thyroid Hormone ◽  
Tissue Level ◽  
Binding Activity ◽  
Monocarboxylate Transporter ◽  
Kidney Cortex ◽  
Liver And Kidney ◽  
Response To Stress

Non-thyroidal illness syndrome (NTIS) is part of the neuroendocrine response to stress, but the significance of this syndrome remains uncertain. The aim of this study was to investigate the effect of lipopolysaccharide (LPS)-induced NTIS on thyroid hormone (TH) levels and TH molecular targets, as well as the relationship between septic shock nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) activation and TH receptor β (THRB) gene expression at a multi-tissue level in a pig model. Prepubertal domestic pigs were given i.v. saline or LPS for 48 h. Serum and tissue TH was measured by chemiluminescence and RIA. Expression of THRs and cofactors was measured by real-time PCR, and deiodinase (DIO) activity was measured by enzyme assays. Tissue NF-kB nuclear binding activity was evaluated by EMSA. LPS-treated pigs had decreased TH levels in serum and most tissues. DIO1 expression in liver and kidney and DIO1 activity in kidney decreased after LPS. No changes in DIO2 activity were observed between groups. LPS induced an increase in hypothalamus, thyroid, and liver DIO3 activity. Among the other studied genes, monocarboxylate transporter 8 and THRB were the most commonly repressed in endotoxemic pigs. LPS-induced NF-kB activation was associated with a decrease in THRB gene expression only in frontal lobe, adrenal gland, and kidney cortex. We conclude that LPS-induced NTIS in pigs is characterized by hypothyroidism and tissue-specific reduced TH sensitivity. The role of NF-kB in regulating THRB expression during endotoxemia, if any, is restricted to a limited number of tissues.

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