The Experts below are selected from a list of 291 Experts worldwide ranked by ideXlab platform
Theo J. Visser - One of the best experts on this subject based on the ideXlab platform.
-
study of the transport of thyroid hormone by transporters of the slc10 family
Molecular and Cellular Endocrinology, 2010Co-Authors: Edward W Visser, Edith C. H. Friesema, Alies Van Mullem, Joachim Geyer, Wing S Wong, Theo J. VisserAbstract:Transport of (sulfated) Iodothyronines across the plasma membrane is required for their intracellular metabolism. Rat Na(+)/taurocholate cotransporting polypeptide (Ntcp; Slc10a1) has been identified as an important transporter protein. We demonstrate that among the 7 members of the solute carrier family SLC10, only human SLC10A1 mediates sodium-dependent transport of the Iodothyronine T4 and Iodothyronine sulfates T3S and T4S. In contrast to SLC10A2-7, cells co-expressing SLC10A1 and the deiodinase D1 demonstrate a dramatic increase in T3S and T4S metabolism. The SLC10A1 substrates taurocholate, DHEAS and E3S inhibit T3S and T4S transport. Furthermore, co-transfection of SLC10A1 with CRYM, a well-known intracellular Iodothyronine-binding protein, results in an enhanced intracellular accumulation of T3S and T4S, indicating that CRYM binds Iodothyronine sulfates. The present findings indicate that the liver-specific transporter SLC10A1 transports (sulfated) Iodothyronines, thereby increasing their intracellular availability. Therefore, SLC10A1 may fulfill a critical step in providing liver D1 with Iodothyronine sulfates for rapid degradation.
-
organic anion transporter 1b1 an important factor in hepatic thyroid hormone and estrogen transport and metabolism
Endocrinology, 2008Co-Authors: Wendy M Van Der Deure, Edith C. H. Friesema, Robin P Peeters, Frank Jan De Jong, Yolanda B De Rijke, Frank H De Jong, Andre G Uitterlinden, Monique M B Breteler, Theo J. VisserAbstract:Sulfation is an important pathway in the metabolism of thyroid hormone and estrogens. Sulfation of estrogens is reversible by estrogen sulfatase, but sulfation of thyroid hormone accelerates its degradation by the type 1 deiodinase in liver. Organic anion transporters (OATPs) are capable of transporting Iodothyronine sulfates such as T4 sulfate (T4S), T3S, and rT3S or estrogen sulfates like estrone sulfate (E1S), but the major hepatic transporter for these conjugates has not been identified. A possible candidate is OATP1B1 because model substrates for this transporter include the bilirubin mimic bromosulfophthalein (BSP) and E1S, and it is highly and specifically expressed in liver. Therefore, OATP1B1-transfected COS1 cells were studied by analysis of BSP, E1S, and Iodothyronine sulfate uptake and metabolism. Two Caucasian populations (155 blood donors and 1012 participants of the Rotterdam Scan Study) were genotyped for the OATP1B1Val174Ala polymorphism and associated with bilirubin, E1S, and T4S levels. OATP1B1-transfected cells strongly induced uptake of BSP, E1S, T4S, T3S, and rT3S compared with mocktransfected cells. Metabolism of Iodothyronine sulfates by cotransfected type 1 deiodinase was greatly augmented in the presence of OATP1B1. OATP1B1-Val 174 showed a 40% higher induction of transport and metabolism of these substrates than OATP1B1-Ala 174 . Carriers of the OATP1B1-Ala 174 allele hadhigherserumbilirubin,E1S,andT4Slevels.Inconclusion, OATP1B1 is an important factor in hepatic transport and metabolism of bilirubin, E1S, and Iodothyronine sulfates. OATP1B1Ala 174 displays decreased transport activity and thereby gives rise to higher bilirubin, E1S, and T4S levels in carriers of this polymorphism. (Endocrinology 149: 4695–4701, 2008)
-
Iodothyronine deiodinase enzyme activities in bone
Bone, 2008Co-Authors: Allan J Williams, Theo J. Visser, Monique H A Kester, Helen Robson, Johannes P T M Van Leeuwen, Stephen M Shalet, Graham R WilliamsAbstract:Euthyroid status is essential for normal skeletal development and maintenance of the adult skeleton, but the mechanisms which control supply of thyroid hormone to bone cells are poorly understood. Thyroid hormones enter target cells via monocarboxylate transporter-8 (MCT8), which provides a functional link between thyroid hormone uptake and metabolism in the regulation of T3-action but has not been investigated in bone. Most circulating active thyroid hormone (T3) is derived from outer ring deiodination of thyroxine (T4) mediated by the type 1 deiodinase enzyme (D1). The D2 isozyme regulates intra-cellular T3 supply and determines saturation of the nuclear T3-receptor (TR), whereas a third enzyme (D3) inactivates T4 and T3 to prevent hormone availability and reduce TR-saturation. The aim of this study was to determine whether MCT8 is expressed in the skeleton and whether chondrocytes, osteoblasts and osteoclasts express functional deiodinases. Gene expression was analyzed by RT-PCR and D1, D2 and D3 function by sensitive and highly specific determination of enzyme activities. MCT8 mRNA was expressed in chondrocytes, osteoblasts and osteoclasts at all stages of cell differentiation. D1 activity was undetectable in all cell types, D2 activity was only present in mature osteoblasts whereas D3 activity was evident throughout chondrocyte, osteoblast and osteoclast differentiation in primary cell cultures. These data suggest that T3 availability especially during skeletal development may be limited by D3-mediated catabolism rather than by MCT8 mediated cellular uptake or D2-dependent T3 production.
-
effective cellular uptake and efflux of thyroid hormone by human monocarboxylate transporter 10
Molecular Endocrinology, 2008Co-Authors: Edith C. H. Friesema, Jurgen Jansen, Monique H A Kester, Janwillem Jachtenberg, Edward W Visser, Theo J. VisserAbstract:Cellular entry of thyroid hormone is mediated by plasma membrane transporters, among others a T-type (aromatic) amino acid transporter. Monocarboxylate transporter 10 (MCT10) has been reported to transport aromatic amino acids but not Iodothyronines. Within the MCT family, MCT10 is most homologous to MCT8, which is a very important Iodothyronine transporter but does not transport amino acids. In view of this paradox, we decided to reinvestigate the possible transport of thyroid hormone by human (h) MCT10 in comparison with hMCT8. Transfection of COS1 cells with hMCT10 cDNA resulted in 1) the production of an approximately 55 kDa protein located to the plasma membrane as shown by immunoblotting and confocal microscopy, 2) a strong increase in the affinity labeling of intracellular type I deiodinase by N-bromoacetyl-[(125)I]T(3), 3) a marked stimulation of cellular T(4) and, particularly, T(3) uptake, 4) a significant inhibition of T(3) uptake by phenylalanine, tyrosine, and tryptophan of 12.5%, 22.2%, and 51.4%, respectively, and 5) a marked increase in the intracellular deiodination of T(4) and T(3) by different deiodinases. Cotransfection studies using the cytosolic thyroid hormone-binding protein micro-crystallin (CRYM) indicated that hMCT10 facilitates both cellular uptake and efflux of T(4) and T(3). In the absence of CRYM, hMCT10 and hMCT8 increased T(3) uptake after 5 min incubation up to 4.0- and 1.9-fold, and in the presence of CRYM up to 6.9- and 5.8-fold, respectively. hMCT10 was less active toward T(4) than hMCT8. These findings establish that hMCT10 is at least as active a thyroid hormone transporter as hMCT8, and that both transporters facilitate Iodothyronine uptake as well as efflux.
-
0013-7227/04/$15.00/0 Endocrinology 145(3):1255–1268 Printed in U.S.A. Copyright © 2004 by The Endocrine Society doi: 10.1210/en.2003-1248
2008Co-Authors: An Ascidian, Willem Klootwijk, Homolog Vertebrate, Iodothyronine Deiodinases, Caroline A. Shepherdley, Kazuhiro W. Makabe, Theo J. VisserAbstract:In all classes of vertebrates, the deiodination of the prohormone T 4 to T 3 represents an essential activation step in thyroid hormone action. The possible presence of Iodothyronine deiodinase activity in protochordates has been demonstrated in vivo. Recent molecular cloning of the genomes and transcripts of several ascidian species allows further investigation into thyroid-related processes in ascidians. A cDNA clone from Halocynthia roretzi (hrDx) was found to have significant homology (30 % amino acid identity) with the Iodothyronine deiodinase gene sequences from vertebrates, including the presence of an in-frame UGA codon that might encode a selenocysteine (SeC) in the active site. Because it was not certain that the 3 � untranslated region (UTR) contained a SeC insertion sequence (SECIS) element essential for SeC incorporation, a chimeric expression vector of the hrDx coding sequenc
Antonio C Bianco - One of the best experts on this subject based on the ideXlab platform.
-
human type 1 Iodothyronine deiodinase dio1 mutations cause abnormal thyroid hormone metabolism
Thyroid, 2020Co-Authors: Monica M Franca, Antonio C Bianco, Samuel Refetoff, Xiao Hui Liao, Alina German, Gustavo W Fernandes, Alexandra M. DumitrescuAbstract:Background: Iodothyronine deiodinase-1 (D1) selenoenzyme regulates the systemic supply of active thyroid hormone (TH). Transient decrease in D1 enzymatic activity is clinically relevant and adaptiv...
-
Induction of Type 2 Iodothyronine Deiodinase After Status Epilepticus Modifies Hippocampal Gene Expression in Male Mice.
Endocrinology, 2018Co-Authors: Bruna P. P. Nascimento, Elizabeth A. Mcaninch, Gustavo W Fernandes, Barbara M L C Bocco, Tatiana L. Fonseca, Carolina Vieira Cardoso, Eduardo F Bondan, Renata J Nassif, Roberta Monterazzo Cysneiros, Antonio C BiancoAbstract:Status epilepticus (SE) is an abnormally prolonged seizure that results from either a failure of mechanisms that terminate seizures or from initiating mechanisms that inherently lead to prolonged seizures. Here we report that mice experiencing a 3 hours of SE caused by pilocarpine exhibit a rapid increase in expression of type 2 Iodothyronine deiodinase gene (Dio2) and a decrease in the expression of type 3 Iodothyronine deiodinase gene in hippocampus, amygdala and prefrontal cortex. Type 3 Iodothyronine deiodinase in hippocampal sections was seen concentrated in the neuronal nuclei, typical of ischemic injury of the brain. An unbiased analysis of the hippocampal transcriptome of mice undergoing 3 hours of SE revealed a number of genes, including those involved with response to oxidative stress, cellular homeostasis, cell signaling, and mitochondrial structure. In contrast, in mice with targeted disruption of Dio2 in astrocytes (Astro D2KO mouse), the highly induced genes in the hippocampus were related to inflammation, apoptosis, and cell death. We propose that Dio2 induction caused by SE accelerates production of T3 in different areas of the central nervous system and modifies the hippocampal gene expression profile, affecting the balance between adaptive and maladaptive mechanisms.
-
reawakened interest in type iii Iodothyronine deiodinase in critical illness and injury
Nature Clinical Practice Endocrinology & Metabolism, 2008Co-Authors: Stephen A Huang, Antonio C BiancoAbstract:Type III Iodothyronine deiodinase (D3) is important for thyroid hormone inactivation, but is difficult to detect in normal adult tissue and has therefore been somewhat neglected. This article details studies showing elevated expression in certain tissues during critical illness and tissue injury, which might be significant for normal responses to trauma.
-
Bacterial lipopolysaccharide (LPS)-induced type 2 Iodothyronine deiodinase (D2) activation in the mediobasal hypothalamus (MBH) is independent of the LPS-induced fall in serum thyroid hormone levels.
Brain research, 2005Co-Authors: Csaba Fekete, Marcelo A Christoffolete, Antonio C Bianco, Sumit Sarkar, Charles H. Emerson, Ronald M. LechanAbstract:By administration of bacterial lipopolysaccharide (LPS) to intact and T4-replaced thyroidectomized rats, we demonstrate that in contrast to the cortex and anterior pituitary, there is a persistent increase in type 2 Iodothyronine deiodinase (D2) activity in the mediobasal hypothalamus (MBH). We propose that endotoxin-induced D2 activation in the MBH is independent of circulating levels of thyroid hormone and that this mechanism may contribute to central hypothyroidism associated with infection.
-
type 1 Iodothyronine deiodinase is a sensitive marker of peripheral thyroid status in the mouse
Endocrinology, 2005Co-Authors: Ann Marie Zavacki, Marcelo A Christoffolete, John W Harney, Reed P Larsen, Hao Ying, Goele Aerts, Sheueyann Cheng, Antonio C BiancoAbstract:Mice with one thyroid hormone receptor (TR) alpha-1 allele encoding a dominant negative mutant receptor (TR alpha1(PV/+)) have persistently elevated serum T3 levels (1.9-fold above normal). They also have markedly increased hepatic type 1 Iodothyronine deiodinase (D1) mRNA and enzyme activity (4- to 5-fold), whereas other hepatic T3-responsive genes, such as Spot14 and mitochondrial alpha-glycerol phosphate dehydrogenase (alpha-GPD), are only 0.7-fold and 1.7-fold that of wild-type littermates (TR alpha1+/+). To determine the cause of the disproportionate elevation of D1, TR alpha1+/+ and TR alpha1(PV/+) mice were rendered hypothyroid and then treated with T3. Hypothyroidism decreased hepatic D1, Spot14, and alpha-GPD mRNA to similar levels in TR alpha1+/+ and TR alpha1(PV/+) mice, whereas T3 administration caused an approximately 175-fold elevation of D1 mRNA but only a 3- to 6-fold increases in Spot14 and alpha-GPD mRNAs. Interestingly, the hypothyroidism-induced increase in cerebrocortical type 2 Iodothyronine deiodinase activity was 3 times greater in the TR alpha1(PV/+) mice, and these mice had no T3-dependent induction of type 3 Iodothyronine deiodinase. Thus, the marked responsiveness of hepatic D1 to T3 relative to other genes, such as Spot14 and alpha-GPD, explains the relatively large effect of the modest increase in serum T3 in the TR alpha1(PV/+) mice, and TR alpha plays a key role in T3-dependent positive and negative regulation of the deiodinases in the cerebral cortex.
Edith C. H. Friesema - One of the best experts on this subject based on the ideXlab platform.
-
study of the transport of thyroid hormone by transporters of the slc10 family
Molecular and Cellular Endocrinology, 2010Co-Authors: Edward W Visser, Edith C. H. Friesema, Alies Van Mullem, Joachim Geyer, Wing S Wong, Theo J. VisserAbstract:Transport of (sulfated) Iodothyronines across the plasma membrane is required for their intracellular metabolism. Rat Na(+)/taurocholate cotransporting polypeptide (Ntcp; Slc10a1) has been identified as an important transporter protein. We demonstrate that among the 7 members of the solute carrier family SLC10, only human SLC10A1 mediates sodium-dependent transport of the Iodothyronine T4 and Iodothyronine sulfates T3S and T4S. In contrast to SLC10A2-7, cells co-expressing SLC10A1 and the deiodinase D1 demonstrate a dramatic increase in T3S and T4S metabolism. The SLC10A1 substrates taurocholate, DHEAS and E3S inhibit T3S and T4S transport. Furthermore, co-transfection of SLC10A1 with CRYM, a well-known intracellular Iodothyronine-binding protein, results in an enhanced intracellular accumulation of T3S and T4S, indicating that CRYM binds Iodothyronine sulfates. The present findings indicate that the liver-specific transporter SLC10A1 transports (sulfated) Iodothyronines, thereby increasing their intracellular availability. Therefore, SLC10A1 may fulfill a critical step in providing liver D1 with Iodothyronine sulfates for rapid degradation.
-
organic anion transporter 1b1 an important factor in hepatic thyroid hormone and estrogen transport and metabolism
Endocrinology, 2008Co-Authors: Wendy M Van Der Deure, Edith C. H. Friesema, Robin P Peeters, Frank Jan De Jong, Yolanda B De Rijke, Frank H De Jong, Andre G Uitterlinden, Monique M B Breteler, Theo J. VisserAbstract:Sulfation is an important pathway in the metabolism of thyroid hormone and estrogens. Sulfation of estrogens is reversible by estrogen sulfatase, but sulfation of thyroid hormone accelerates its degradation by the type 1 deiodinase in liver. Organic anion transporters (OATPs) are capable of transporting Iodothyronine sulfates such as T4 sulfate (T4S), T3S, and rT3S or estrogen sulfates like estrone sulfate (E1S), but the major hepatic transporter for these conjugates has not been identified. A possible candidate is OATP1B1 because model substrates for this transporter include the bilirubin mimic bromosulfophthalein (BSP) and E1S, and it is highly and specifically expressed in liver. Therefore, OATP1B1-transfected COS1 cells were studied by analysis of BSP, E1S, and Iodothyronine sulfate uptake and metabolism. Two Caucasian populations (155 blood donors and 1012 participants of the Rotterdam Scan Study) were genotyped for the OATP1B1Val174Ala polymorphism and associated with bilirubin, E1S, and T4S levels. OATP1B1-transfected cells strongly induced uptake of BSP, E1S, T4S, T3S, and rT3S compared with mocktransfected cells. Metabolism of Iodothyronine sulfates by cotransfected type 1 deiodinase was greatly augmented in the presence of OATP1B1. OATP1B1-Val 174 showed a 40% higher induction of transport and metabolism of these substrates than OATP1B1-Ala 174 . Carriers of the OATP1B1-Ala 174 allele hadhigherserumbilirubin,E1S,andT4Slevels.Inconclusion, OATP1B1 is an important factor in hepatic transport and metabolism of bilirubin, E1S, and Iodothyronine sulfates. OATP1B1Ala 174 displays decreased transport activity and thereby gives rise to higher bilirubin, E1S, and T4S levels in carriers of this polymorphism. (Endocrinology 149: 4695–4701, 2008)
-
effective cellular uptake and efflux of thyroid hormone by human monocarboxylate transporter 10
Molecular Endocrinology, 2008Co-Authors: Edith C. H. Friesema, Jurgen Jansen, Monique H A Kester, Janwillem Jachtenberg, Edward W Visser, Theo J. VisserAbstract:Cellular entry of thyroid hormone is mediated by plasma membrane transporters, among others a T-type (aromatic) amino acid transporter. Monocarboxylate transporter 10 (MCT10) has been reported to transport aromatic amino acids but not Iodothyronines. Within the MCT family, MCT10 is most homologous to MCT8, which is a very important Iodothyronine transporter but does not transport amino acids. In view of this paradox, we decided to reinvestigate the possible transport of thyroid hormone by human (h) MCT10 in comparison with hMCT8. Transfection of COS1 cells with hMCT10 cDNA resulted in 1) the production of an approximately 55 kDa protein located to the plasma membrane as shown by immunoblotting and confocal microscopy, 2) a strong increase in the affinity labeling of intracellular type I deiodinase by N-bromoacetyl-[(125)I]T(3), 3) a marked stimulation of cellular T(4) and, particularly, T(3) uptake, 4) a significant inhibition of T(3) uptake by phenylalanine, tyrosine, and tryptophan of 12.5%, 22.2%, and 51.4%, respectively, and 5) a marked increase in the intracellular deiodination of T(4) and T(3) by different deiodinases. Cotransfection studies using the cytosolic thyroid hormone-binding protein micro-crystallin (CRYM) indicated that hMCT10 facilitates both cellular uptake and efflux of T(4) and T(3). In the absence of CRYM, hMCT10 and hMCT8 increased T(3) uptake after 5 min incubation up to 4.0- and 1.9-fold, and in the presence of CRYM up to 6.9- and 5.8-fold, respectively. hMCT10 was less active toward T(4) than hMCT8. These findings establish that hMCT10 is at least as active a thyroid hormone transporter as hMCT8, and that both transporters facilitate Iodothyronine uptake as well as efflux.
-
thyroid hormone transport by the human monocarboxylate transporter 8 and its rate limiting role in intracellular metabolism
Molecular Endocrinology, 2006Co-Authors: Edith C. H. Friesema, Theo J. Visser, Jurgen Jansen, George G J M Kuiper, Monique H A KesterAbstract:Cellular entry of thyroid hormone is mediated by plasma membrane transporters. We have identified rat monocarboxylate transporter 8 (MCT8) as an active and specific thyroid hormone transporter. The MCT8 gene is located on the X-chromosome. The physiological relevance of MCT8 has been demonstrated by the identification of hemizygous mutations in this gene in males with severe psychomotor retardation and elevated serum T(3) levels. We have characterized human (h) MCT8 by analysis of Iodothyronine uptake and metabolism in cell lines transiently transfected with hMCT8 cDNA alone or together with cDNA coding for Iodothyronine deiodinase D1, D2, or D3. MCT8 mRNA was detected by RT-PCR in a number of human cell lines as well as in COS1 cells but was low to undetectable in other cell lines, including JEG3 cells. MCT8 protein was not detected in nontransfected cell lines tested by immunoblotting using a polyclonal C-terminal hMCT8 antibody but was detectable in transfected cells at the expected size (61 kDa). Transfection of COS1 and JEG3 cells with hMCT8 cDNA resulted in 2- to 3-fold increases in uptake of T(3) and T(4) but little or no increase in rT(3) or 3,3'-diIodothyronine (3,3'-T(2)) uptake. MCT8 expression produced large increases in T(4) metabolism by cotransfected D2 or D3, T(3) metabolism by D3, rT(3) metabolism by D1 or D2, and 3,3'-T(2) metabolism by D3. Affinity labeling of hMCT8 protein was observed after incubation of intact transfected cells with N-bromoacetyl-[(125)I]T(3). hMCT8 also facilitated affinity labeling of cotransfected D1 by bromoacetyl-T(3). Our findings indicate that hMCT8 mediates plasma membrane transport of Iodothyronines, thus increasing their intracellular availability.
-
mechanisms of disease psychomotor retardation and high t3 levels caused by mutations in monocarboxylate transporter 8
Nature Clinical Practice Endocrinology & Metabolism, 2006Co-Authors: Edith C. H. Friesema, Jurgen Jansen, Heike Heuer, Marija Trajkovic, Karl Bauer, Theo J. VisserAbstract:Thyroid hormone transport across the plasma membrane is essential for hormone functions. As detailed here, novel mutations in monocarboxylate transporter 8 reveal important roles in thyroid hormone access to the brain and might explain the pathogenesis of Allan–Herndon–Dudley syndrome, which is now known to feature thyroid hormone resistance. The actions and the metabolism of thyroid hormone are intracellular events that require the transport of Iodothyronines across the plasma membrane. It is increasingly clear that this process does not occur by simple diffusion, but is facilitated by transport proteins. Only recently have Iodothyronine transporters been identified at the molecular level, of which organic anion transporting polypeptide 1C1 and monocarboxylate transporter 8 (MCT8) deserve special mention, because of their high activity and specificity for Iodothyronines. Organic anion transporting polypeptide 1C1 is almost exclusively expressed in brain capillaries, and may be crucial for the transport of the prohormone T4 across the blood–brain barrier. MCT8 is also expressed in the brain—in particular, in neurons—but also in other tissues. MCT8 seems to be especially important for the uptake of active hormone T3 into neurons, which is essential for optimal brain development. T3 is produced from T4 by type 2 deiodinase in neighboring astrocytes. Neurons express type 3 deiodinase, the enzyme that terminates T3 activity. The SLC16A2 (formerly MCT8) gene is located on chromosome Xq13.2 and has recently been associated with a syndrome combining severe, X-linked, psychomotor retardation and high serum T3 levels. In over 20 families, where affected males have developed this syndrome, several mutations in MCT8 have been identified. The disease mechanism is thought to involve a defect in the neuronal entry of T3 and, therefore, in the action and metabolism of T3 in these cells. This defect results in impaired neurological development and a decrease in T3 clearance.
Monique H A Kester - One of the best experts on this subject based on the ideXlab platform.
-
Iodothyronine deiodinase enzyme activities in bone
Bone, 2008Co-Authors: Allan J Williams, Theo J. Visser, Monique H A Kester, Helen Robson, Johannes P T M Van Leeuwen, Stephen M Shalet, Graham R WilliamsAbstract:Euthyroid status is essential for normal skeletal development and maintenance of the adult skeleton, but the mechanisms which control supply of thyroid hormone to bone cells are poorly understood. Thyroid hormones enter target cells via monocarboxylate transporter-8 (MCT8), which provides a functional link between thyroid hormone uptake and metabolism in the regulation of T3-action but has not been investigated in bone. Most circulating active thyroid hormone (T3) is derived from outer ring deiodination of thyroxine (T4) mediated by the type 1 deiodinase enzyme (D1). The D2 isozyme regulates intra-cellular T3 supply and determines saturation of the nuclear T3-receptor (TR), whereas a third enzyme (D3) inactivates T4 and T3 to prevent hormone availability and reduce TR-saturation. The aim of this study was to determine whether MCT8 is expressed in the skeleton and whether chondrocytes, osteoblasts and osteoclasts express functional deiodinases. Gene expression was analyzed by RT-PCR and D1, D2 and D3 function by sensitive and highly specific determination of enzyme activities. MCT8 mRNA was expressed in chondrocytes, osteoblasts and osteoclasts at all stages of cell differentiation. D1 activity was undetectable in all cell types, D2 activity was only present in mature osteoblasts whereas D3 activity was evident throughout chondrocyte, osteoblast and osteoclast differentiation in primary cell cultures. These data suggest that T3 availability especially during skeletal development may be limited by D3-mediated catabolism rather than by MCT8 mediated cellular uptake or D2-dependent T3 production.
-
effective cellular uptake and efflux of thyroid hormone by human monocarboxylate transporter 10
Molecular Endocrinology, 2008Co-Authors: Edith C. H. Friesema, Jurgen Jansen, Monique H A Kester, Janwillem Jachtenberg, Edward W Visser, Theo J. VisserAbstract:Cellular entry of thyroid hormone is mediated by plasma membrane transporters, among others a T-type (aromatic) amino acid transporter. Monocarboxylate transporter 10 (MCT10) has been reported to transport aromatic amino acids but not Iodothyronines. Within the MCT family, MCT10 is most homologous to MCT8, which is a very important Iodothyronine transporter but does not transport amino acids. In view of this paradox, we decided to reinvestigate the possible transport of thyroid hormone by human (h) MCT10 in comparison with hMCT8. Transfection of COS1 cells with hMCT10 cDNA resulted in 1) the production of an approximately 55 kDa protein located to the plasma membrane as shown by immunoblotting and confocal microscopy, 2) a strong increase in the affinity labeling of intracellular type I deiodinase by N-bromoacetyl-[(125)I]T(3), 3) a marked stimulation of cellular T(4) and, particularly, T(3) uptake, 4) a significant inhibition of T(3) uptake by phenylalanine, tyrosine, and tryptophan of 12.5%, 22.2%, and 51.4%, respectively, and 5) a marked increase in the intracellular deiodination of T(4) and T(3) by different deiodinases. Cotransfection studies using the cytosolic thyroid hormone-binding protein micro-crystallin (CRYM) indicated that hMCT10 facilitates both cellular uptake and efflux of T(4) and T(3). In the absence of CRYM, hMCT10 and hMCT8 increased T(3) uptake after 5 min incubation up to 4.0- and 1.9-fold, and in the presence of CRYM up to 6.9- and 5.8-fold, respectively. hMCT10 was less active toward T(4) than hMCT8. These findings establish that hMCT10 is at least as active a thyroid hormone transporter as hMCT8, and that both transporters facilitate Iodothyronine uptake as well as efflux.
-
thyroid hormone transport by the human monocarboxylate transporter 8 and its rate limiting role in intracellular metabolism
Molecular Endocrinology, 2006Co-Authors: Edith C. H. Friesema, Theo J. Visser, Jurgen Jansen, George G J M Kuiper, Monique H A KesterAbstract:Cellular entry of thyroid hormone is mediated by plasma membrane transporters. We have identified rat monocarboxylate transporter 8 (MCT8) as an active and specific thyroid hormone transporter. The MCT8 gene is located on the X-chromosome. The physiological relevance of MCT8 has been demonstrated by the identification of hemizygous mutations in this gene in males with severe psychomotor retardation and elevated serum T(3) levels. We have characterized human (h) MCT8 by analysis of Iodothyronine uptake and metabolism in cell lines transiently transfected with hMCT8 cDNA alone or together with cDNA coding for Iodothyronine deiodinase D1, D2, or D3. MCT8 mRNA was detected by RT-PCR in a number of human cell lines as well as in COS1 cells but was low to undetectable in other cell lines, including JEG3 cells. MCT8 protein was not detected in nontransfected cell lines tested by immunoblotting using a polyclonal C-terminal hMCT8 antibody but was detectable in transfected cells at the expected size (61 kDa). Transfection of COS1 and JEG3 cells with hMCT8 cDNA resulted in 2- to 3-fold increases in uptake of T(3) and T(4) but little or no increase in rT(3) or 3,3'-diIodothyronine (3,3'-T(2)) uptake. MCT8 expression produced large increases in T(4) metabolism by cotransfected D2 or D3, T(3) metabolism by D3, rT(3) metabolism by D1 or D2, and 3,3'-T(2) metabolism by D3. Affinity labeling of hMCT8 protein was observed after incubation of intact transfected cells with N-bromoacetyl-[(125)I]T(3). hMCT8 also facilitated affinity labeling of cotransfected D1 by bromoacetyl-T(3). Our findings indicate that hMCT8 mediates plasma membrane transport of Iodothyronines, thus increasing their intracellular availability.
-
biochemical mechanisms of thyroid hormone deiodination
Thyroid, 2005Co-Authors: George G J M Kuiper, Monique H A Kester, Robin P Peeters, Theo J. VisserAbstract:Deiodination is the foremost pathway of thyroid hormone metabolism not only in quantitative terms but also because thyroxine (T4) is activated by outer ring deiodination (ORD) to 3,3',5-triIodothyronine (T3), whereas both T4 and T3 are inactivated by inner ring deiodination (IRD) to 3,3',5-triIodothyronine and 3,3'- diIodothyronine, respectively. These reactions are catalyzed by three Iodothyronine deiodinases, D1-3. Although they are homologous selenoproteins, they differ in important respects such as catalysis of ORD and/or IRD, deiodination of sulfated Iodothyronines, inhibition by the thyrostatic drug propylthiouracil, and regulation during fetal and neonatal development, by thyroid state, and during illness. In this review we will briefly discuss recent developments in these different areas. These have resulted in the emerging view that the biological activity of thyroid hormone is regulated locally by tissue-specific regulation of the different deiodinases.
-
Iodothyronine levels in the human developing brain major regulatory roles of Iodothyronine deiodinases in different areas
The Journal of Clinical Endocrinology and Metabolism, 2004Co-Authors: Monique H A Kester, Theo J. Visser, Raquel Martinez De Mena, Maria Jesus Obregon, Danijela Marinkovic, Allan G Howatson, Robert Hume, Gabriella Morreale De EscobarAbstract:Thyroid hormones are required for human brain development, but data on local regulation are limited. We describe the ontogenic changes in T4, T3, and rT3 and in the activities of the types I, II, and III Iodothyronine deiodinases (D1, D2, and D3) in different brain regions in normal fetuses (13–20 wk postmenstrual age) and premature infants (24–42 wk postmenstrual age). D1 activity was undetectable. The developmental changes in the concentrations of the Iodothyronines and D2 and D3 activities showed spatial and temporal specificity but with divergence in the cerebral cortex and cerebellum. T3 increased in the cortex between 13 and 20 wk to levels higher than adults, unexpected given the low circulating T3. Considerable D2 activity was found in the cortex, which correlated positively with T4 (r = 0.65). Cortex D3 activity was very low, as was D3 activity in germinal eminence and choroid plexus. In contrast, cerebellar T3 was very low and increased only after midgestation. Cerebellum D3 activities were the ...
George G J M Kuiper - One of the best experts on this subject based on the ideXlab platform.
-
thyroid hormone transport by the human monocarboxylate transporter 8 and its rate limiting role in intracellular metabolism
Molecular Endocrinology, 2006Co-Authors: Edith C. H. Friesema, Theo J. Visser, Jurgen Jansen, George G J M Kuiper, Monique H A KesterAbstract:Cellular entry of thyroid hormone is mediated by plasma membrane transporters. We have identified rat monocarboxylate transporter 8 (MCT8) as an active and specific thyroid hormone transporter. The MCT8 gene is located on the X-chromosome. The physiological relevance of MCT8 has been demonstrated by the identification of hemizygous mutations in this gene in males with severe psychomotor retardation and elevated serum T(3) levels. We have characterized human (h) MCT8 by analysis of Iodothyronine uptake and metabolism in cell lines transiently transfected with hMCT8 cDNA alone or together with cDNA coding for Iodothyronine deiodinase D1, D2, or D3. MCT8 mRNA was detected by RT-PCR in a number of human cell lines as well as in COS1 cells but was low to undetectable in other cell lines, including JEG3 cells. MCT8 protein was not detected in nontransfected cell lines tested by immunoblotting using a polyclonal C-terminal hMCT8 antibody but was detectable in transfected cells at the expected size (61 kDa). Transfection of COS1 and JEG3 cells with hMCT8 cDNA resulted in 2- to 3-fold increases in uptake of T(3) and T(4) but little or no increase in rT(3) or 3,3'-diIodothyronine (3,3'-T(2)) uptake. MCT8 expression produced large increases in T(4) metabolism by cotransfected D2 or D3, T(3) metabolism by D3, rT(3) metabolism by D1 or D2, and 3,3'-T(2) metabolism by D3. Affinity labeling of hMCT8 protein was observed after incubation of intact transfected cells with N-bromoacetyl-[(125)I]T(3). hMCT8 also facilitated affinity labeling of cotransfected D1 by bromoacetyl-T(3). Our findings indicate that hMCT8 mediates plasma membrane transport of Iodothyronines, thus increasing their intracellular availability.
-
biochemical mechanisms of thyroid hormone deiodination
Thyroid, 2005Co-Authors: George G J M Kuiper, Monique H A Kester, Robin P Peeters, Theo J. VisserAbstract:Deiodination is the foremost pathway of thyroid hormone metabolism not only in quantitative terms but also because thyroxine (T4) is activated by outer ring deiodination (ORD) to 3,3',5-triIodothyronine (T3), whereas both T4 and T3 are inactivated by inner ring deiodination (IRD) to 3,3',5-triIodothyronine and 3,3'- diIodothyronine, respectively. These reactions are catalyzed by three Iodothyronine deiodinases, D1-3. Although they are homologous selenoproteins, they differ in important respects such as catalysis of ORD and/or IRD, deiodination of sulfated Iodothyronines, inhibition by the thyrostatic drug propylthiouracil, and regulation during fetal and neonatal development, by thyroid state, and during illness. In this review we will briefly discuss recent developments in these different areas. These have resulted in the emerging view that the biological activity of thyroid hormone is regulated locally by tissue-specific regulation of the different deiodinases.
-
a new polymorphism in the type ii deiodinase gene is associated with circulating thyroid hormone parameters
American Journal of Physiology-endocrinology and Metabolism, 2005Co-Authors: Robin P Peeters, George G J M Kuiper, Yolanda B De Rijke, Andre G Uitterlinden, Annewieke W Van Den Beld, Hayat Attalki, Hans Van Toor, Steven W J Lamberts, Joop A M J L Janssen, Theo J. VisserAbstract:Type II deiodinase (D2) is important in the regulation of local thyroid hormone bioactivity in certain tissues. D2 in skeletal muscle may also play a role in serum triIodothyronine (T(3)) production. In this study, we identified a polymorphism in the 5'-UTR of the D2 gene (D2-ORFa-Gly3Asp). We investigated the association of D2-ORFa-Gly3Asp, and of the previously identified D2-Thr92Ala polymorphism, with serum Iodothyronine levels. D2-ORFa-Gly3Asp was identified by sequencing the 5'-UTR of 15 randomly selected individuals. Genotypes for D2-ORFa-Gly3Asp were determined in 156 healthy blood donors (age 46.3 +/- 12.2 yr) and 349 ambulant elderly men (age 77.7 +/- 3.5 yr) and related to serum Iodothyronine and TSH levels. D2-ORFa-Asp(3) had an allele frequency of 33.9% in blood bank donors and was associated with serum thyroxine (T(4); Gly/Gly vs. Gly/Asp vs. Asp/Asp = 7.06 +/- 0.14 vs. 6.74 +/- 0.15 vs. 6.29 +/- 0.27 microg/dl, P = 0.01), free T(4) (1.22 +/- 0.02 vs. 1.16 +/- 0.02 vs. 1.06 +/- 0.04 ng/dl, P = 0.001), reverse T(3) (P = 0.01), and T(3)/T(4) ratio (P = 0.002) in a dose-dependent manner, but not with serum T(3) (P = 0.59). In elderly men, D2-ORFa-Asp(3) had a similar frequency but was not associated with serum Iodothyronine levels. This new polymorphism in the 5'-UTR of D2 is associated with Iodothyronine levels in blood donors but not in elderly men. We hypothesize that this might be explained by the decline in skeletal muscle size during aging, resulting in a relative decrease in the contribution of D2 to serum T(3) production.
-
substitution of cysteine for selenocysteine in the catalytic center of type iii Iodothyronine deiodinase reduces catalytic efficiency and alters substrate preference
Endocrinology, 2003Co-Authors: George G J M Kuiper, Willem Klootwijk, Theo J. VisserAbstract:Human type III Iodothyronine deiodinase (D3) catalyzes the conversion of T4 to rT3 and of T3 to 3, 3′-diIodothyronine (T2) by inner-ring deiodination. Like types I and II Iodothyronine deiodinases, D3 protein contains selenocysteine (SeC) in the highly conserved core catalytic center at amino acid position 144. To evaluate the contribution of SeC144 to the catalytic properties of D3 enzyme, we generated mutants in which cysteine (D3Cys) or alanine (D3Ala) replaces SeC144 (D3wt). COS cells were transfected with expression vectors encoding D3wt, D3Cys, or D3Ala protein. Kinetic analysis was performed on homogenates with dithiothreitol as reducing cofactor. The Michaelis constant of T3 was 5-fold higher for D3Cys than for D3wt protein. In contrast, the Michaelis constant of T4 increased 100-fold. The D3Ala protein was enzymatically inactive. Semiquantitative immunoblotting of homogenates with a D3 antiserum revealed that about 50-fold higher amounts of D3Cys and D3Ala protein are expressed relative to D3wt p...
