scholarly journals Tissue-Specific Thyroid Hormone Deprivation and Excess in Monocarboxylate Transporter (Mct) 8-Deficient Mice

Endocrinology ◽  
2006 ◽  
Vol 147 (9) ◽  
pp. 4036-4043 ◽  
Author(s):  
Alexandra M. Dumitrescu ◽  
Xiao-Hui Liao ◽  
Roy E. Weiss ◽  
Kathleen Millen ◽  
Samuel Refetoff
Keyword(s):  
Thyroid Hormone ◽  
Monocarboxylate Transporter ◽  
Tissue Specific ◽  
Deficient Mice ◽  
Hormone Deprivation

scholarly journals Tissue Thyroid Hormone Levels in Critical Illness

2005 ◽  
Vol 90 (12) ◽  
pp. 6498-6507 ◽  
Author(s):  
Robin P. Peeters ◽  
Serge van der Geyten ◽  
Pieter J. Wouters ◽  
Veerle M. Darras ◽  
Hans van Toor ◽  
...  
Keyword(s):  
Critical Illness ◽  
Thyroid Hormone ◽  
Hormone Treatment ◽  
Monocarboxylate Transporter ◽  
Total Serum ◽  
Tissue Specific ◽  
Hormone Levels ◽  
Serum T3 ◽  
Serum Thyroid Hormone ◽  
Thyroid Hormone Levels

Context: Pronounced alterations in serum thyroid hormone levels occur during critical illness. T3 decreases and rT3 increases, the magnitudes of which are related to the severity of disease. It is unclear whether these changes are associated with decreased tissue T3 concentrations and, thus, reduced thyroid hormone bioactivity. Patients and Study Questions: We therefore investigated, in 79 patients who died after intensive care and who did or did not receive thyroid hormone treatment, whether total serum thyroid hormone levels correspond to tissue levels in liver and muscle. Furthermore, we investigated the relationship between tissue thyroid hormone levels, deiodinase activities, and monocarboxylate transporter 8 expression. Results: Tissue iodothyronine levels were positively correlated with serum levels, indicating that the decrease in serum T3 during illness is associated with decreased levels of tissue T3. Higher serum T3 levels in patients who received thyroid hormone treatment were accompanied by higher levels of liver and muscle T3, with evidence for tissue-specific regulation. Tissue rT3 and the T3/rT3 ratio were correlated with tissue deiodinase activities. Monocarboxylate transporter 8 expression was not related to the ratio of the serum over tissue concentration of the different iodothyronines. Conclusion: Our results suggest that, in addition to changes in the hypothalamus-pituitary-thyroid axis, tissue-specific mechanisms are involved in the reduced supply of bioactive thyroid hormone in critical illness.

scholarly journals Adeno Associated Virus 9–Based Gene Therapy Delivers a Functional Monocarboxylate Transporter 8, Improving Thyroid Hormone Availability to the Brain of Mct8-Deficient Mice

Thyroid ◽  
2016 ◽  
Vol 26 (9) ◽  
pp. 1311-1319 ◽  
Author(s):  
Hideyuki Iwayama ◽  
Xiao-Hui Liao ◽  
Lyndsey Braun ◽  
Soledad Bárez-López ◽  
Brian Kaspar ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Thyroid Hormone ◽  
Monocarboxylate Transporter ◽  
Adeno Associated Virus ◽  
The Brain ◽  
Deficient Mice

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 High T3, Low T4 Serum Levels in Mct8 Deficiency Are Not Caused by Increased Hepatic Conversion through Type I Deiodinase

2015 ◽  
Vol 4 (Suppl. 1) ◽  
pp. 87-91 ◽  
Author(s):  
Eva K. Wirth ◽  
Eddy Rijntjes ◽  
Franziska Meyer ◽  
Josef Köhrle ◽  
Ulrich Schweizer
Keyword(s):  
Thyroid Hormone ◽  
Serum Levels ◽  
Underlying Mechanism ◽  
Psychomotor Retardation ◽  
Monocarboxylate Transporter ◽  
Type I ◽  
Hormone Levels ◽  
Thyroid Hormone Levels ◽  
Mct8 Deficiency ◽  
Deficient Mice

Background: The Allan-Herndon-Dudley syndrome is a severe psychomotor retardation accompanied by specific changes in circulating thyroid hormone levels (high T3, low T4). These are caused by mutations in the thyroid hormone transmembrane transport protein monocarboxylate transporter 8 (MCT8). Objective: To test the hypothesis that circulating low T4 and high T3 levels are caused by enhanced conversion of T4 via increased activity of hepatic type I deiodinase (Dio1). Methods: We crossed mice deficient in Mct8 with mice lacking Dio1 activity in hepatocytes. Translation of the selenoenzyme Dio1 was abrogated by hepatocyte-specific inactivation of selenoprotein biosynthesis. Results: Inactivation of Dio1 activity in the livers of global Mct8-deficient mice does not restore normal circulating thyroid hormone levels. Conclusions: Our data suggest that although hepatic Dio1 activity is increased in Mct8-deficient mice, it does not cause the observed abnormal circulating thyroid hormone levels. Since global inactivation of Dio1 in Mct8-deficient mice does normalize circulating thyroid hormone levels, the underlying mechanism and relevant tissues involved remain to be elucidated.

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.

scholarly journals Generation and Characterization of dickkopf3 Mutant Mice

2006 ◽  
Vol 26 (6) ◽  
pp. 2317-2326 ◽  
Author(s):  
Ivan del Barco Barrantes ◽  
Ana Montero-Pedrazuela ◽  
Ana Guadaño-Ferraz ◽  
Maria-Jesus Obregon ◽  
Raquel Martinez de Mena ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Clinical Chemistry ◽  
Lung Ventilation ◽  
Immunoglobulin M ◽  
Mutant Mice ◽  
Phenotypic Analysis ◽  
Thyroid Hormone Metabolism ◽  
Hormone Binding Protein ◽  
Deficient Mice

ABSTRACT dickkopf (dkk) genes encode a small family of secreted Wnt antagonists, except for dkk3, which is divergent and whose function is poorly understood. Here, we describe the generation and characterization of dkk3 mutant mice. dkk3-deficient mice are viable and fertile. Phenotypic analysis shows no major alterations in organ morphology, physiology, and most clinical chemistry parameters. Since Dkk3 was proposed to function as thyroid hormone binding protein, we have analyzed deiodinase activities, as well as thyroid hormone levels. Mutant mice are euthyroid, and the data do not support a relationship of dkk3 with thyroid hormone metabolism. Altered phenotypes in dkk3 mutant mice were observed in the frequency of NK cells, immunoglobulin M, hemoglobin, and hematocrit levels, as well as lung ventilation. Furthermore, dkk3-deficient mice display hyperactivity.

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 Tissue-specific expression of B7x protects from CD4 T cell–mediated autoimmunity

2011 ◽  
Vol 208 (8) ◽  
pp. 1683-1694 ◽  
Author(s):  
Joyce Wei ◽  
P’ng Loke ◽  
Xingxing Zang ◽  
James P. Allison
Keyword(s):  
T Cells ◽  
Pancreatic Islets ◽  
Peripheral Tolerance ◽  
Wild Type ◽  
Autoimmune Encephalomyelitis ◽  
Specific Expression ◽  
Tissue Specific ◽  
Disease Induction ◽  
Deficient Mice ◽  
Experimental Autoimmune

B7x, an inhibitory member of the B7/CD28 superfamily, is highly expressed in a broad range of nonhematopoietic organs, suggesting a role in maintaining peripheral tolerance. As endogenous B7x protein is expressed in pancreatic islets, we investigated whether the molecule inhibits diabetogenic responses. Transfer of disease-inducing BDC2.5 T cells into B7x-deficient mice resulted in a more aggressive form of diabetes than in wild-type animals. This exacerbation of disease correlated with higher frequencies of islet-infiltrating Th1 and Th17 cells. Conversely, local B7x overexpression inhibited the development of autoimmunity, as crossing diabetes-susceptible BDC2.5/B6g7 mice to animals overexpressing B7x in pancreatic islets abrogated disease induction. This protection was caused by the inhibition of IFN-γ production by CD4 T cells and not to a skewing or expansion of Th2 or regulatory T cells. The suppressive function of B7x was also supported by observations from another autoimmune model, experimental autoimmune encephalomyelitis, in which B7x-deficient mice developed exacerbated disease in comparison with wild-type animals. Analysis of central nervous system–infiltrating immune cells revealed that the loss of endogenous B7x resulted in expanded Th1 and Th17 responses. Data from these two autoimmune models provide evidence that B7x expression in the periphery acts as an immune checkpoint to prevent tissue-specific autoimmunity.

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