Thyroid hormone entry into cells is facilitated by transmembrane transporters. Mutations of the specific thyroid hormone transporter, MCT8 (Monocarboxylate Transporter 8, SLC16A2) cause an X-linked syndrome of profound neurological impairment and altered thyroid function known as the Allan-Herndon-Dudley syndrome. MCT8 deficiency presumably results in failure of thyroid hormone to reach the neural target cells in adequate amounts to sustain normal brain development. However during the perinatal period the absence of Mct8 in mice induces a state of cerebral cortex hyperthyroidism, indicating increased brain access and/or retention of thyroid hormone. The contribution of other transporters to thyroid hormone metabolism and action, especially in the context of MCT8 deficiency is not clear. We have analyzed the role of the heterodimeric aminoacid transporter Lat2 (Slc7a8), in the presence or absence of Mct8, on thyroid hormone concentrations and on expression of thyroid hormone-dependent cerebral cortex genes. To this end we generated Lat2-/-, and Mct8-/yLat2-/- mice, to compare with wild type and Mct8-/y mice during postnatal development. As described previously the single Mct8 KO neonates had a transient increase of 3,5,3′-triiodothyronine concentration and expression of thyroid hormone target genes in the cerebral cortex. Strikingly the absence of Lat2 in the double Mct8Lat2 KO prevented the effect of Mct8 inactivation in newborns. The Lat2 effect was not observed from postnatal day 5 onwards. On postnatal day 21 the Mct8 KO displayed the typical pattern of thyroid hormone concentrations in plasma, decreased cortex 3,5,3′-triiodothyronine concentration and Hr expression, and concomitant Lat2 inactivation produced little to no modifications. As Lat2 is expressed in neurons and in the choroid plexus, the results support a role for Lat2 in the supply of thyroid hormone to the cerebral cortex during early postnatal development. 相似文献
As a prerequisite for thyroid hormone (TH) metabolism and action TH has to be transported into cells where TH deiodinases and receptors are located. The trans-membrane passage of TH is facilitated by TH transporters of which the monocarboxylate transporter MCT8 has been most intensively studied. Inactivating mutations in the gene encoding MCT8 are associated with a severe form of psychomotor retardation and abnormal serum TH levels (Allan–Herndon–Dudley syndrome). In order to define the underlying pathogenic mechanisms, Mct8 knockout mice have been generated and intensively studied. Most surprisingly, Mct8 ko mice do not show any neurological symptoms but fully replicate the abnormal serum thyroid state.
Scope of review
We will summarize the findings of these mouse studies that shed light on various aspects of Mct8 deficiency and unambiguously demonstrated the pivotal role of Mct8 in mediating TH transport in various tissues. These studies have also revealed the presence of the complex interplay between different pathogenic mechanisms that contribute to the generation of the abnormal TH serum profile.
Major conclusions
Most importantly, studies of Mct8 ko mice indicated the presence of additional TH transporters that act in concert with Mct8. Interesting candidates for such a function are the L-type amino acid transporters Lat1 and Lat2 as well as the organic anion transporting polypeptide Oatp1c1.
General significance
Overall, the analysis of Mct8 deficient mice has greatly expanded our knowledge about the (patho-) physiological function of this transporter and established a sound basis for the characterization of additional TH transporter candidates. This article is part of a Special Issue entitled Thyroid hormone signalling. 相似文献
Monocarboxylate transporter 8 (MCT8) is a well-established thyroid hormone (TH) transporter. In humans, MCT8 mutations result in changes in circulating TH concentrations and X-linked severe global neurodevelopmental delay. MCT8 is expressed in the human placenta throughout gestation, with increased expression in trophoblast cells from growth-restricted pregnancies. We postulate that MCT8 plays an important role in placental development and transplacental TH transport. We investigated the effect of altering MCT8 expression in human trophoblast in vitro and in a Mct8 knockout mouse model. Silencing of endogenous MCT8 reduced T3 uptake into human extravillous trophoblast-like cells (SGHPL-4; 40%, P<0.05) and primary cytotrophoblast (15%, P<0.05). MCT8 over-expression transiently increased T3 uptake (SGHPL-4∶30%, P<0.05; cytotrophoblast: 15%, P<0.05). Silencing MCT8 did not significantly affect SGHPL-4 invasion, but with MCT8 over-expression T3 treatment promoted invasion compared with no T3 (3.3-fold; P<0.05). Furthermore, MCT8 silencing increased cytotrophoblast viability (∼20%, P<0.05) and MCT8 over-expression reduced cytotrophoblast viability independently of T3 (∼20%, P<0.05). In vivo, Mct8 knockout reduced fetal:placental weight ratios compared with wild-type controls at gestational day 18 (25%, P<0.05) but absolute fetal and placental weights were not significantly different. The volume fraction of the labyrinthine zone of the placenta, which facilitates maternal-fetal exchange, was reduced in Mct8 knockout placentae (10%, P<0.05). However, there was no effect on mouse placental cell proliferation in vivo. We conclude that MCT8 makes a significant contribution to T3 uptake into human trophoblast cells and has a role in modulating human trophoblast cell invasion and viability. In mice, Mct8 knockout has subtle effects upon fetoplacental growth and does not significantly affect placental cell viability probably due to compensatory mechanisms in vivo. 相似文献
Iodothyronines are charged amino acid derivatives that cannot passively cross a phospholipid bilayer. Transport of thyroid hormones across plasma membranes is mediated by integral membrane proteins belonging to several gene families. These transporters therefore allow or limit access of thyroid hormones into brain. Since thyroid hormones are essential for brain development and cell differentiation, it is expected that genetic deficiency of such transporters would result in neurodevelopmental derangements.
Scope of review
We introduce concepts of thyroid hormone transport into the brain and into brain cells. Important thyroid hormone transmembrane transporters are presented along with their expression patterns in different brain cell types. A focus is placed on monocarboxylate transporter 8 (MCT8) which has been identified as an essential thyroid hormone transporter in humans. Mutations in MCT8 underlie one of the first described X-linked mental retardation syndromes, the Allan–Herndon–Dudley syndrome.
Major conclusions
Thyroid hormone transporter molecules are expressed in a developmental and cell type-specific pattern. Any thyroid hormone molecule has to cross consecutively the luminal and abluminal membranes of the capillary endothelium, enter astrocytic foot processes, and leave the astrocyte through the plasma membrane to finally cross another plasma membrane on its way towards its target nucleus.
General significance
We can expect more transporters being involved in or contributing to in neurodevelopmental or neuropsychiatric disease. Due to their expression in cellular components regulating the hypothalamus–pituitary–thyroid axis, mutations and polymorphisms are expected to impact on negative feedback regulation and hormonal setpoints. This article is part of a Special Issue entitled Thyroid hormone signalling. 相似文献
This study was conducted to evaluate the effects of single and combined deficiencies of selenium and iodine on selenoenzyme
activities in sheep. Twenty-four male lambs were assigned to one of four semisynthetic diets: combined deficient A (Se−I), Se-deficient B (Se−I+), I-deficient C (Se+I−), and basal diet D (Se+I+). Thyroid hormones (T3, T4), thyroid stimulating hormone (TSH), and inorganic iodine (PII) were determined in plasma. Selenium and glutathione peroxidase
activity (GSH-Px) were determined in erythrocytes, and tissue samples, including the thyroid, liver, kidney, and brain, were
taken for selenoenzyme analysis. Plasma T3, T4, and TSH concentrations were similar in all groups. Type I deiodinase (ID-I) activity in liver and kidney remained unchanged
in Se or I deficiency. In contrast, hepatic ID-I activity was increased by 70% in combined Se-I deficiency. Thyroidal cystolic
GSH-Px (c-GSH-Px) and phospholipid GSH-Px (ph-GSH-Px) activities remained constant in both Se-deficient groups, whereas thyroidal
c-GSH-Px activity increased (57%) in I deficiency. Type II deiodinase (ID-II) activity was not detectable in the cerebrum
and cerebellum, whereas cerebellum Type III deiodinase (ID-III) activity was decreased in I deficiency and combined Se-I deficiencies.
The results of the present study support a sensitive interaction between Se and I deficiencies in sheep thyroid and brain.
Furthermore, the lack of thyroidal ID-I activity, the presservation of the thyroidal antioxidant enzymes, and the increases
in hepatic ID-I indicate that a compensatory mechanism(s) works toward retaining plasma T3 levels, mostly by de novo synthesis of T3 and peripheral deiodination of T4 in Se- and I-deficient sheep. 相似文献
Selenium deficiency impairs thyroid hormone metabolism by inhibiting the synthesis and activity of the iodothyronine deiodinases,
which convert thyroxine (T4) to the more metabolically active 3,3′-5 triiodothyronine (T3). Hepatic type I iodothyronine deiodinase, identified in partially purified cell fractions using affinity labeling with [125I]N-bromoacetyl reverse triiodothyronine, is also labeled with75Se by in vivo treatment of rats with75Se-Na2SeO3. Thus, the type I iodothyronine 5′-deiodinase is a selenoenzyme. In rats, concurrent selenium and iodine deficiency produces
greater increases in thyroid weight and plasma thyrotrophin than iodine deficiency alone. These results indicate that a concurrent
selenium deficiency could be a major determinant of the severity of iodine deficiency. 相似文献
Objective: The Vps10p family member sortilin is expressed in thyroid epithelial cells where it contributes to recycling of the thyroid hormone precursor thyroglobulin (Tg), a process that is thought to render hormone release more effective. Here we investigated the functional impact of sortilin in the thyroid gland using sortilin-deficient mice.Methods: We measured free T4, thyroid-stimulating hormone (TSH) and Tg serum levels and studied thyroid morphology in 14 sortilin-deficient (Sort1)-/-and 12 wildtype (WT) mice.Results: Serum free T4 levels did not differ between Sort1-/-and WT females but were significantly lower in Sort1-/-males compared with WT (P = .0424). Neither serum TSH nor Tg levels differed between Sort1-/-and WT mice, regardless of sex. On the same line, no thyroid histology differences were observed.Conclusion: Our findings seem to exclude a role of sortilin in thyroid hormone secretion, although it is possible that the absence of sortilin may result in a thyroid phenotype if combined with other molecular defects of thyroid hormone synthesis and secretion or under iodine deficiency.Abbreviations: T4 = thyroxine Sort1 = Sortilin 1 Tg = thyroglobulin TSH = thyroid-stimulating hormone WT = wild type 相似文献
The effects of supplementing selenium on thyroid hormone metabolism were studied on mice with excessive iodine exposure. The
serum concentrations of thyroxine (T4) and triiodothyronine (T3) and the activities of iodothyronine 5′ and 5-deiodinase (D2, D3) were measured in the brain of filial mice to study the
influence of selenium on thyroid hormone metabolism. Measurements were carried out on postnatal day 0, 14, and 28. It was
found that selenium supplementation alleviated the adverse effects of excessive iodine on progeny. The serum TT4 level as well as TT4 and TT3 concentrations and D3 activity in cerebrum of progeny decreased, whereas D2 activity increased in the cerebrum of progeny
on postnatal day 0 and 14. Selenium supplementation exerted some favorable effects on thyroid hormone metabolism in cerebrum
of progeny of dam with excessive iodine intake. 相似文献
Allan-Herndon-Dudley syndrome (AHDS) is a severe psychomotor retardation characterized by neurological impairment and abnormal thyroid hormone (TH) levels. Mutations in the TH transporter, monocarboxylate transporter 8 (MCT8), are associated with AHDS. MCT8 knock-out mice exhibit impaired TH levels; however, they lack neurological defects. Here, the zebrafish mct8 gene and promoter were isolated, and mct8 promoter-driven transgenic lines were used to show that, similar to humans, mct8 is primarily expressed in the nervous and vascular systems. Morpholino-based knockdown and rescue experiments revealed that MCT8 is strictly required for neural development in the brain and spinal cord. This study shows that MCT8 is a crucial regulator during embryonic development and establishes the first vertebrate model for MCT8 deficiency that exhibits a neurological phenotype. 相似文献
Selenium deficiency impairs thyroid hormone metabolism by inhibiting the synthesis and activity of the iodothyronine deiodinases,
which convert thyroxine (T4) to the more metabolically active 3,3′–5 triiodothyronine (T3). Hepatic type I iodothyronine deiodinase, identified in partially purified cell fractions using affinity labeling with [125I]N-bromoacetyl reverse triiodothyronine, is also labeled with75Se by in vivo treatment of rats with75Se−Na2SeO3. Thus, the type I iodothyronine 5′-deiodinase is a selenoenzyme. In rats, concurrent selenium and iodine deficiency produces
greater increases in thyroid weight and plasma thyrotrophin than iodine deficiency alone. These results indicate that a concurrent
selenium deficiency could be a major determinant of the severity of iodine deficiency. 相似文献
In this study we have examined whether rat brain nuclear thyroid hormone receptors bind T4 or metabolites of T4 and whether there is a developmental change in brain T4 metabolism and binding. Developing animals were injected with trace [125I]3,5-tetraiodothyronine ([125I]T4) and after sacrifice brain nuclear and cytoplasmic fractions were examined to determine whether their radioactivity was represented by the injected [125I]T4 or any of its metabolites. Of the radiothyronines specifically bound to the nucleus, 90% was found to be triiodothyronine ([125I] T3) and 10% was [125I]T4. Of the cytoplasmic, protamine sulfate-precipitable fraction, 40% was [125I]T4 and 60% [125I]T3. Inasmuch as the percentage of [125I] T3 found in plasma during the same postinjection interval was similar to that present as contaminant of the injected material, it was concluded that brain [125I] T3 derives from local monodeiodination of T4 to T3. The main developmental change observed was a marked decline in the total cytoplasmic and nuclear [125I] T4 uptake. However, with development, the T3/T4 ratio remained constant in the nuclear fraction while it decreased in the cytoplasmic fraction. It is concluded that although T3, deriving from monodeiodianation of T4, is the main form of thyroid hormone that regulates brain development by its binding to brain nuclear receptors, the fact that T4 is the most available from during the critical period makes it, indirectly, very important to brain development. Further, the decline observed with development in T4 uptake and monodeiodination to T3, may contribute to the concomitantly declining role of thyroid hormones on brain tissue. 相似文献
The objective of this investigation was to quantify how thyroid hormone receptors of the sockeye salmon, Oncorhynchus nerka, respond to salinity changes from freshwater (FW) to seawater (SW) conditions. Thyroid hormone receptors (TRs) mRNA and protein expressions levels significantly increased when the fish were transferred from FW to SW, and the plasma T3 and T4 levels were significantly highest at 50 % SW and then maintained as control. Moreover, these parameters were significantly lower in the cortisol-injected groups than in the control. Hence, TRs, T3, and T4 may play a role in SW adaptation, when the fish migrate from FW to SW environments. We showed a negative correlation between cortisol and thyroid hormone levels, and a significant increase in plasma K+ levels in the kidney when the fish were transferred to SW, with levels being significantly lower in the cortisol-injected group. Hence, cortisol appears to be a stress hormone, and the plasma Na+ and Cl- levels significantly increased when the fish were transferred to SW, with levels being significantly lower in the cortisol-injected group. These results indicate that cortisol modulates ion transportation in the plasma. 相似文献
The effects of thyroxine (T4) and triiodothyronine (T3) treatment upon the formation of [2-14C]flavins bound covalently to tissue proteins in liver and cerebrum were measured 1 h after a subcutaneous injection of [2-14C]riboflavin in male rats of different ages. In livers of rats of ages 2, 3, and 12 months, T4 (100 μg/100 g body wt) and T3 (25 μg/100 g body wt) in daily intraperitoneal doses for 7 days each increased incorporation into covalently bound flavins 50% above that in saline-treated controls. In newborn rats, T4 in doses of 10 μg/rat for 7 days increased incorporation similarly to that in adults. In adult rats doses of T3 from 2.5 to 25 μg/100 g body wt were nearly as effective as larger doses of T3 and T4 in increasing the formation of covalently bound flavins in liver. In cerebra of newborn rats, T4 was ineffective in increasing the formation of covalently bound flavins. However, in cerebra of rats of ages 2, 3, and 12 months, both T3 and T4 consistently increased the formation of covalently bound flavins. Doses of T3 from 2.5 to 25 μg/100 g body wt produced significant increases. These findings are of interest in view of our previous demonstration that the formation of flavin adenine dinucleotide, the major tissue flavin, is not increased in rat brain even by massive doses of thyroid hormones. The present results indicate that the formation of the fraction of flavins bound covalently to tissue proteins differs from the usual pattern of brain metabolism of adult rats in being subject to control by thyroid hormones. 相似文献
Transport of thyroid hormone across the cell membrane is required for its action and metabolism. Recently, a T-type amino acid transporter was cloned which transports aromatic amino acids but not iodothyronines. This transporter belongs to the monocarboxylate transporter (MCT) family and is most homologous with MCT8 (SLC16A2). Therefore, we cloned rat MCT8 and tested it for thyroid hormone transport in Xenopus laevis oocytes. Oocytes were injected with rat MCT8 cRNA, and after 3 days immunofluorescence microscopy demonstrated expression of the protein at the plasma membrane. MCT8 cRNA induced an approximately 10-fold increase in uptake of 10 nM 125I-labeled thyroxine (T4), 3,3',5-triiodothyronine (T3), 3,3',5'-triiodothyronine (rT3) and 3,3'-diiodothyronine. Because of the rapid uptake of the ligands, transport was only linear with time for <4 min. MCT8 did not transport Leu, Phe, Trp, or Tyr. [125I]T4 transport was strongly inhibited by L-T4, D-T4, L-T3, D-T3, 3,3',5-triiodothyroacetic acid, N-bromoacetyl-T3, and bromosulfophthalein. T3 transport was less affected by these inhibitors. Iodothyronine uptake in uninjected oocytes was reduced by albumin, but the stimulation induced by MCT8 was markedly increased. Saturation analysis provided apparent Km values of 2-5 microM for T4, T3, and rT3. Immunohistochemistry showed high expression in liver, kidney, brain, and heart. In conclusion, we have identified MCT8 as a very active and specific thyroid hormone transporter. 相似文献
Selenium (Se) influences the metabolism of thyroid hormones in mammals. However, the role of Se deficiency in the regulation of thyroid hormones in chickens is not well known. In the present study, we examined the levels of thyroidal triiodothyronine (T3), thyroidal thyroxine (T4), free triiodothyronine, free thyroxine (FT4), and thyroid-stimulating hormone in the serum and the mRNA expression levels of 25 selenoproteins in chicken thyroids. Then, principal component analysis (PCA) was performed to analyze the relationships between the selenoproteins. The results indicated that Se deficiency influenced the conversion of T4 to T3 and induced the accumulation of T4 and FT4. In addition, the mRNA expression levels of the selenoproteins were generally decreased by Se deficiency. The PCA showed that eight selenoproteins (deiodinase 1 (Dio1), Dio2, Dio3, thioredoxin reductase 2 (Txnrd2), selenoprotein i (Seli), selenoprotein u (Selu), glutathione peroxidase 1 (Gpx1), and Gpx2) have similar trends, which indicated that they may play similar roles in the metabolism of thyroid hormones. The results showed that Se deficiency inhibited the conversion of T4 to T3 and decreased the levels of the crucial metabolic enzymes of the thyroid hormones, Dio1, Dio2, and Dio3, in chickens. In addition, the decreased selenoproteins (Dio1, Dio2, Dio3, Txnrd2, Seli, Selu, Gpx1, and Gpx2) induced by Se deficiency may indirectly limit the conversion of T4 to T3 in chicken thyroids. The information presented in this study is helpful to understand the role of Se in the thyroid function of chickens. 相似文献
Summary In the eel, ovine prolactin (oPrl) treatment (0.018 IU/day·g body weight), for 8 to 13 days modifies neither iodide absorption from the water nor excretion, extrathyroidal metabolism and plasma level of iodide.Thyroid activity, evaluated by epithelial cell height, radioiodine uptake and absolute iodide uptake is approximately twice that of controls. However, the amounts of total iodine, thyroxine (T4) and triiodothyronine (T3) in thyroid are unaltered by oPrl. Therefore, the decrease of plasma T4 and the increase of plasma T3, previously observed in oPrl-treated eels, do not result from a preferential thyroidal secretion of T3, but only from a stimulation of peripheral conversion of T4 to T3. Furthermore, the increased thyroid activity probably originates from a decreased feedback inhibition following the fall of circulating T4 induced by oPrl.Abbreviations
oPrl
ovine prolactin
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T4
Thyroxine
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T3
3.5.3 triiodothyronine
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TRH
thyrotropin releasing hormone
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TSH
thyroid stimulating hormone
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PBI
protein bound iodine 相似文献
Energy metabolism supports both inhibitory and excitatory neurotransmission processes. This study investigated the specific contribution of astrocytic metabolism to γ‐aminobutyric acid (GABA) synthesis and inhibitory GABAergic neurotransmission that remained to be ilucidated in vivo. Therefore, we measured 13C incorporation into brain metabolites by dynamic 13C nuclear magnetic resonance spectroscopy at 14.1 T in rats under α‐chloralose anaesthesia during infusion of [1,6‐13C]glucose. The enhanced sensitivity at 14.1 T allowed to quantify incorporation of 13C into the three aliphatic carbons of GABA non‐invasively. Metabolic fluxes were determined with a mathematical model of brain metabolism comprising glial, glutamatergic and GABAergic compartments. GABA synthesis rate was 0.11 ± 0.01 μmol/g/min. GABA‐glutamine cycle was 0.053 ± 0.003 μmol/g/min and accounted for 22 ± 1% of total neurotransmitter cycling between neurons and glia. Cerebral glucose oxidation was 0.47 ± 0.02 μmol/g/min, of which 35 ± 1% and 7 ± 1% was diverted to the glutamatergic and GABAergic tricarboxylic acid cycles, respectively. The remaining fraction of glucose oxidation was in glia, where 12 ± 1% of the TCA cycle flux was dedicated to oxidation of GABA. 16 ± 2% of glutamine synthesis was provided to GABAergic neurons. We conclude that substantial metabolic activity occurs in GABAergic neurons and that glial metabolism supports both glutamatergic and GABAergic neurons in the living rat brain.