scholarly journals Thyroid hormone transporters

2005 ◽  
Vol 33 (1) ◽  
pp. 228-232 ◽  
Author(s):  
E.C.H. Friesema ◽  
J. Jansen ◽  
T.J Visser
Keyword(s):  
Biological Activity ◽  
Thyroid Hormone ◽  
Thyroid Gland ◽  
Cell Membrane ◽  
Human Chromosome ◽  
Elevated Serum ◽  
Psychomotor Retardation ◽  
Follicular Cells ◽  
Serum T3 ◽  
T3 Receptors

Thyroid hormone is important for development of various tissues, in particular brain, and for regulation of metabolic processes throughout life. The follicular cells of the thyroid gland produce predominantly T4 (thyroxine), but the biological activity of thyroid hormone is largely exerted by T3 (3,3′,5-tri-iodothyronine). The deiodinases involved in T4-to-T3 conversion or T4 and T3 degradation, as well as the T3 receptors, are located intracellularly. Therefore the action and metabolism of thyroid hormone require transport of iodothyronines across the cell membrane via specific transporters. Recently, a number of transporters capable of cellular uptake of iodothyronines have been identified. The most specific transporters identified so far are OATP1C1 and MCT8, which appear to be involved in T4 transport across the blood–brain barrier, and in T3 transport into brain neurons, respectively. The MCT8 gene is located on human chromosome Xq13, and mutations in MCT8 are associated with X-linked severe psychomotor retardation and elevated serum T3 levels.

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 Tissue-Specific Alterations in Thyroid Hormone Homeostasis in Combined Mct10 and Mct8 Deficiency

Endocrinology ◽  
2014 ◽  
Vol 155 (1) ◽  
pp. 315-325 ◽  
Author(s):  
Julia Müller ◽  
Steffen Mayerl ◽  
Theo J. Visser ◽  
Veerle M. Darras ◽  
Anita Boelen ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Gland ◽  
Elevated Serum ◽  
Normal Serum ◽  
Monocarboxylate Transporter ◽  
Cellular Transport ◽  
Tissue Specific ◽  
Serum T3 ◽  
Serum T4 ◽  
Mct8 Deficiency

The monocarboxylate transporter Mct10 (Slc16a10; T-type amino acid transporter) facilitates the cellular transport of thyroid hormone (TH) and shows an overlapping expression with the well-established TH transporter Mct8. Because Mct8 deficiency is associated with distinct tissue-specific alterations in TH transport and metabolism, we speculated that Mct10 inactivation may compromise the tissue-specific TH homeostasis as well. However, analysis of Mct10 knockout (ko) mice revealed normal serum TH levels and tissue TH content in contrast to Mct8 ko mice that are characterized by high serum T3, low serum T4, decreased brain TH content, and increased tissue TH concentrations in the liver, kidneys, and thyroid gland. Surprisingly, mice deficient in both TH transporters (Mct10/Mct8 double knockout [dko] mice) showed normal serum T4 levels in the presence of elevated serum T3, indicating that the additional inactivation of Mct10 partially rescues the phenotype of Mct8 ko mice. As a consequence of the normal serum T4, brain T4 content and hypothalamic TRH expression were found to be normalized in the Mct10/Mct8 dko mice. In contrast, the hyperthyroid situation in liver, kidneys, and thyroid gland of Mct8 ko mice was even more severe in Mct10/Mct8 dko animals, suggesting that in these organs, both transporters contribute to the TH efflux. In summary, our data indicate that Mct10 indeed participates in tissue-specific TH transport and also contributes to the generation of the unusual serum TH profile characteristic for Mct8 deficiency.

Thyrotrophin-releasing hormone (TRH) and hormone secretion from the follicular and C-cells of perfused dog thyroid lobes

1985 ◽  
Vol 109 (4) ◽  
pp. 499-504 ◽  
Author(s):  
E. Iversen ◽  
P. Laurberg
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Gland ◽  
Hormone Secretion ◽  
Inhibitory Effect ◽  
C Cells ◽  
Follicular Cells ◽  
Thyrotrophin Releasing Hormone ◽  
Releasing Hormone ◽  
Direct Inhibitory Effect ◽  
Thyroid Secretion

Abstract. Recently we found small amounts of TRH immunoreactivity in the thyroid gland of dogs and pigs. In the present study we investigated if exogenous TRH influences the release of T4, T3 and cAMP from the follicular cells, and calcitonin and somatostatin from the C-cells of perfused dog thyroid lobes. 10−5 mol/l TRH inhibited the TSH induced iodothyronine and cAMP release from the thyroid while 10−8 mol/l TRH had no effect. The relative proportions of T4 and T3 in thyroid secretion were not altered by TRH infusion. TRH did not influence the basal or the Ca++ induced release of somatostatin and calcitonin. Hence TRH has a direct inhibitory effect on the hormone secretion from thyroidal follicular cells. This opens the possibility that TRH in the thyroid participate in the regulation of thyroid hormone secretion. Even though the concentration of TRH found to be effective is high our results may indicate that TRH in the thyroid participates in the regulation of thyroid hormone secretion as an antagonist to TSH.

Tissue-Specific Function of Thyroid Hormone Transporters: New Insights from Mouse Models

2019 ◽  
Vol 128 (06/07) ◽  
pp. 423-427 ◽  
Author(s):  
Eva Salveridou ◽  
Steffen Mayerl ◽  
Sivaraj Mohana Sundaram ◽  
Boyka Markova ◽  
Heike Heuer
Keyword(s):  
Thyroid Hormone ◽  
Elevated Serum ◽  
Transport Processes ◽  
Tissue Specific ◽  
Knock Out ◽  
Serum T3 ◽  
A Cell ◽  
Knock Out Mice ◽  
Mct8 Deficiency ◽  
Shed Light

AbstractThyroid hormone (TH) transporters are required for cellular transmembrane passage of TH and are thus mandatory for proper TH metabolism and action. Consequently, inactivating mutations in TH transporters such as MCT8 or OATP1C1 can cause tissue- specific changes in TH homeostasis. As the most prominent example, patients with MCT8 mutations exhibit elevated serum T3 levels, whereas their CNS appear to be in a TH deficient state. Here, we will briefly summarize recent studies of mice lacking Mct8 alone or in combination with the TH transporters Mct10 or Oatp1c1 that shed light on many aspects and pathogenic events underlying global MCT8 deficiency and also underscore the contribution of Mct10 and Oatp1c1 in tissue-specific TH transport processes. Moreover, development of conditional knock-out mice that allow a cell-specific inactivation of TH transporters in distinct tissues, disclosed cell-specific changes in TH signaling, thereby highlighting the pathophysiological significance of local control of TH action.

pax2.1is required for the development of thyroid follicles in zebrafish

Development ◽  
2002 ◽  
Vol 129 (15) ◽  
pp. 3751-3760 ◽  
Author(s):  
Thomas Wendl ◽  
Klaus Lun ◽  
Marina Mione ◽  
Jack Favor ◽  
Michael Brand ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Gland ◽  
Marker Gene ◽  
Follicular Cells ◽  
Hormone Production ◽  
Zebrafish Model ◽  
Hormone Synthesis ◽  
Larval Stages ◽  
Thyroid Follicular Cells ◽  
Thyroid Development

The thyroid gland is an organ primarily composed of endoderm-derived follicular cells. Although disturbed embryonic development of the thyroid gland leads to congenital hypothyroidism in humans and mammals, the underlying principles of thyroid organogenesis are largely unknown. In this study, we introduce zebrafish as a model to investigate the molecular and genetic mechanisms that control thyroid development. Marker gene expression suggests that the molecular pathways of early thyroid development are essentially conserved between fish and mammals. However during larval stages, we find both conserved and divergent features of development compared with mammals. A major difference is that in fish, we find evidence for hormone production not only in thyroid follicular cells, but also in an anterior non-follicular group of cells.We show that pax2.1 and pax8, members of the zebrafish pax2/5/8 paralogue group, are expressed in the thyroid primordium. Whereas in mice, only Pax8 has a function during thyroid development, analysis of the zebrafish pax2.1 mutant no isthmus (noi–/–) demonstrates that pax2.1 has a role comparable with mouse Pax8 in differentiation of the thyroid follicular cells. Early steps of thyroid development are normal in noi–/–, but later expression of molecular markers is lost and the formation of follicles fails. Interestingly, the anterior non-follicular site of thyroid hormone production is not affected in noi–/–. Thus, in zebrafish, some remaining thyroid hormone synthesis takes place independent of the pathway leading to thyroid follicle formation. We suggest that the noi–/– mutant serves as a new zebrafish model for hypothyroidism.

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 Impact of Monocarboxylate Transporter-8 Deficiency on the Hypothalamus-Pituitary-Thyroid Axis in Mice

Endocrinology ◽  
2010 ◽  
Vol 151 (10) ◽  
pp. 5053-5062 ◽  
Author(s):  
Marija Trajkovic-Arsic ◽  
Julia Müller ◽  
Veerle M. Darras ◽  
Claudia Groba ◽  
Sooyeon Lee ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Gland ◽  
Hormone Replacement ◽  
Hormone Secretion ◽  
High Serum ◽  
Monocarboxylate Transporter ◽  
Neurological Deficits ◽  
Serum Concentrations ◽  
Hormone Production ◽  
Serum T3

In patients, inactivating mutations in the gene encoding the thyroid hormone-transporting monocarboxylate transporter 8 (Mct8) are associated with severe mental and neurological deficits and disturbed thyroid hormone levels. The latter phenotype characterized by high T3 and low T4 serum concentrations is replicated in Mct8 knockout (ko) mice, indicating that MCT8 deficiency interferes with thyroid hormone production and/or metabolism. Our studies of Mct8 ko mice indeed revealed increased thyroidal T3 and T4 concentrations without overt signs of a hyperactive thyroid gland. However, upon TSH stimulation Mct8 ko mice showed decreased T4 and increased T3 secretion compared with wild-type littermates. Moreover, similar changes in the thyroid hormone secretion pattern were observed in Mct8/Trhr1 double-ko mice, which are characterized by normal serum T3 levels and normal hepatic and renal D1 expression in the presence of very low T4 serum concentrations. These data strongly indicate that absence of Mct8 in the thyroid gland affects thyroid hormone efflux by shifting the ratio of the secreted hormones toward T3. To test this hypothesis, we generated Mct8/Pax8 double-mutant mice, which in addition to Mct8 lack a functional thyroid gland and are therefore completely athyroid. Following the injection of these animals with either T4 or T3, serum analysis revealed T3 concentrations similar to those observed in Pax8 ko mice under thyroid hormone replacement, indicating that indeed increased thyroidal T3 secretion in Mct8 ko mice represents an important pathogenic mechanism leading to the high serum T3 levels.

scholarly journals Immunohistochemical localization of thyroid hormone in rat thyroid gland.

1978 ◽  
Vol 26 (12) ◽  
pp. 1121-1124 ◽  
Author(s):  
M Wilson ◽  
K R Hitchcock ◽  
R A DeLellis
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Gland ◽  
Thyroid Hormones ◽  
Parathyroid Gland ◽  
Immunohistochemical Localization ◽  
Follicular Cells ◽  
Adult Rat ◽  
Apical Cytoplasm ◽  
Rat Thyroid ◽  
Rat Thyroid Gland

Direct and indirect immunofluorescence techniques were used to localize the thyroid hormones triidothyronine (T3) and thyroxine (T4) in adult rat thyroid gland. Optimum dilutions of the antisera were established and four tissue fixatives were investigated for usefulness in this technique. Use of antibodies specific for either T3 or T4 resulted in brilliant fluorescence in the colloid pools and apical cytoplasm of follicular cells. In all cases, the adjacent parathyroid gland was devoid of fluorescence. This report demonstrates that these dipeptide hormones can be localized by using immunofluorescence techniques.

scholarly journals Monocarboxylate Transporter 8 Deficiency: From Pathophysiological Understanding to Therapy Development

2021 ◽  
Vol 12 ◽  
Author(s):  
Ferdy S. van Geest ◽  
Nilhan Gunhanlar ◽  
Stefan Groeneweg ◽  
W. Edward Visser
Keyword(s):  
Thyroid Hormone ◽  
Clinical Stage ◽  
Treatment Options ◽  
Elevated Serum ◽  
Physiological Role ◽  
Monocarboxylate Transporter ◽  
Peripheral Tissues ◽  
Motor Disability ◽  
Serum T3 ◽  
Mct8 Deficiency

Genetic defects in the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) result in MCT8 deficiency. This disorder is characterized by a combination of severe intellectual and motor disability, caused by decreased cerebral thyroid hormone signalling, and a chronic thyrotoxic state in peripheral tissues, caused by exposure to elevated serum T3 concentrations. In particular, MCT8 plays a crucial role in the transport of thyroid hormone across the blood-brain-barrier. The life expectancy of patients with MCT8 deficiency is strongly impaired. Absence of head control and being underweight at a young age, which are considered proxies of the severity of the neurocognitive and peripheral phenotype, respectively, are associated with higher mortality rate. The thyroid hormone analogue triiodothyroacetic acid is able to effectively and safely ameliorate the peripheral thyrotoxicosis; its effect on the neurocognitive phenotype is currently under investigation. Other possible therapies are at a pre-clinical stage. This review provides an overview of the current understanding of the physiological role of MCT8 and the pathophysiology, key clinical characteristics and developing treatment options for MCT8 deficiency.

scholarly journals Functional Analysis of Monocarboxylate Transporter 8 Mutations Identified in Patients with X-Linked Psychomotor Retardation and Elevated Serum Triiodothyronine

2007 ◽  
Vol 92 (6) ◽  
pp. 2378-2381 ◽  
Author(s):  
Jurgen Jansen ◽  
Edith C. H. Friesema ◽  
Monique H. A. Kester ◽  
Carmelina Milici ◽  
Maarten Reeser ◽  
...  
Keyword(s):  
Elevated Serum ◽  
Splice Site Mutation ◽  
Psychomotor Retardation ◽  
Monocarboxylate Transporter ◽  
Missense Mutations ◽  
Wild Type ◽  
Site Mutation ◽  
Central Neurons ◽  
Serum T3 ◽  
Type 3

Abstract Context: T3 action in neurons is essential for brain development. Recent evidence indicates that monocarboxylate transporter 8 (MCT8) is important for neuronal T3 uptake. Hemizygous mutations have been identified in the X-linked MCT8 gene in boys with severe psychomotor retardation and elevated serum T3 levels. Objective: The objective of this study was to determine the functional consequences of MCT8 mutations regarding transport of T3. Design: MCT8 function was studied in wild-type or mutant MCT8-transfected JEG3 cells by analyzing: 1) T3 uptake, 2) T3 metabolism in cells cotransfected with human type 3 deiodinase, 3) immunoblotting, and 4) immunocytochemistry. Results: The mutations identified in MCT8 comprise four deletions (24.5 kb, 2.4 kb, 14 bp, and 3 bp), three missense mutations (Ala224Val, Arg271His, and Leu471Pro), a nonsense mutation (Arg245stop), and a splice site mutation (94 amino acid deletion). All tested mutants were inactive in uptake and metabolism assays, except MCT8 Arg271His, which showed approximately 20% activity vs. wild-type MCT8. Conclusion: These findings support the hypothesis that the severe psychomotor retardation and elevated serum T3 levels in these patients are caused by inactivation of the MCT8 transporter, preventing action and metabolism of T3 in central neurons.

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