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Theo J. Visser - One of the best experts on this subject based on the ideXlab platform.
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impact of oatp1c1 deficiency on Thyroid Hormone Metabolism and action in the mouse brain
Endocrinology, 2012Co-Authors: Steffen Mayerl, Theo J. Visser, Veerle Darras, Sigrun Horn, Heike HeuerAbstract:Organic anion-transporting polypeptide 1c1 (Oatp1c1) (also known as Slco1c1 and Oatp14) belongs to the family of Oatp and has been shown to facilitate the transport of T4. In the rodent brain, Oatp1c1 is highly enriched in capillary endothelial cells and choroid plexus structures where it may mediate the entry of T4 into the central nervous system. Here, we describe the generation and first analysis of Oatp1c1-deficient mice. Oatp1c1 knockout (KO) mice were born with the expected frequency, were not growth retarded, and developed without any overt neurological abnormalities. Serum T3 and T4 concentrations as well as renal and hepatic deiodinase type 1 expression levels were indistinguishable between Oatp1c1 KO mice and control animals. Hypothalamic TRH and pituitary TSH mRNA levels were not affected, but brain T4 and T3 content was decreased in Oatp1c1-deficient animals. Moreover, increased type 2 and decreased type 3 deiodinase activities indicate a mild hypoThyroid situation in the brain of Oatp1c1 KO m...
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bexarotene induced hypoThyroidism bexarotene stimulates the peripheral Metabolism of Thyroid Hormones
The Journal of Clinical Endocrinology and Metabolism, 2007Co-Authors: Johannes W A Smit, Johannes A Romijn, Marcel P M Stokkel, Alberto M Pereira, Theo J. VisserAbstract:Objective: Therapy with the retinoid X receptor agonist bexarotene is associated with hypoThyroidism caused by decreased pituitary TSH secretion. To evaluate the effects of bexarotene on peripheral Thyroid Hormone Metabolism, we performed a study in athyreotic subjects on a fixed substitution dose with l-T4. Design: The design was an open prospective 6-wk intervention study. Methods: Ten athyreotic patients with pulmonary metastases of differentiated Thyroid carcinoma received 6-wk redifferentiation treatment with 300 mg bexarotene/d. l-T4 doses were kept stable. Before and in the sixth week of therapy, serum levels of total T4, free T4 (FT4), T3, reverse T3 (rT3), and TSH were measured. To study nondeiodinase-mediated Thyroid Hormone degradation, serum levels of T4 sulfate (T4S) were measured. Recombinant human TSH was administered before and in the sixth week of bexarotene therapy. Results: Bexarotene induced profound decreases in total T4 (56% of baseline), FT4 (47%), T3 (69%), rT3 (51%), and T4S (70%)...
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euThyroid sick syndrome in meningococcal sepsis the impact of peripheral Thyroid Hormone Metabolism and binding proteins
The Journal of Clinical Endocrinology and Metabolism, 2005Co-Authors: Marieke Den Brinker, Theo J. Visser, Koen F M Joosten, Wim C J Hop, Yolanda B De Rijke, Jan A Hazelzet, Venje Boonstra, Anita C S HokkenkoelegaAbstract:Context and Objectives: The objective of this study was to elucidate the influence of disease severity, deiodination, sulfation, Thyroid Hormone binding, and dopamine use on Thyroid function in euThyroid sick syndrome. Setting: The study was performed at a university-affiliated pediatric intensive care unit (PICU). Design: This was an observational cohort study. Patients: Sixty-nine children with meningococcal sepsis were studied. Main Outcome Measures: Differences in Thyroid function among nonsurvivors, shock survivors, and sepsis survivors on PICU admission were the main outcome measures. Results: The main study group consisted of 45 non-dopamine-treated children. All children had decreased total T3 (TT3)/rT3 ratios without elevated TSH. T4 sulfate levels were decreased in 88%. Nonsurvivors had paradoxically higher TT3/rT3 ratios than shock survivors (0.71 vs. 0.30); this ratio also correlated with shorter duration of disease (r = −0.43). TT4 and T4-binding globulin (TBG) levels declined with increasing...
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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.
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serum 3 3 5 triiodothyronine rt3 and 3 5 3 triiodothyronine rt3 are prognostic markers in critically ill patients and are associated with postmortem tissue deiodinase activities
The Journal of Clinical Endocrinology and Metabolism, 2005Co-Authors: Robin P Peeters, Ellen Kaptein, Theo J. Visser, Pieter J Wouters, Hans Van Toor, Greet Van Den BergheAbstract:Introduction and Methods: Critical illness is associated with reduced TSH and Thyroid Hormone secretion, and with changes in peripheral Thyroid Hormone Metabolism, resulting in low serum T3 and high rT3. In 451 critically ill patients who received intensive care for more than 5 d, serum Thyroid parameters were determined on d 1, 5, 15, and last day (LD). All patients had been randomized for intensive or conventional insulin treatment. Seventy-one patients died, and postmortem liver and skeletal muscle biopsies were obtained from 50 of them for analysis of deiodinase (D1–3) activities. Results: Insulin treatment did not affect Thyroid parameters. On d 1, rT3 was higher and T3/rT3 was lower in nonsurvivors as compared with survivors (P = 0.001). Odds ratio for survival of the highest vs. the lowest quartile was 0.3 for rT3 and 2.9 for T3/rT3. TSH, T4, and T3 were lower in nonsurvivors from d 5 until LD (P < 0.001). TSH, T4, T3, and T3/rT3 increased over time in survivors, but decreased or remained unaltered...
Anita Boelen - One of the best experts on this subject based on the ideXlab platform.
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Thyroid Hormone Metabolism in innate immune cells
Journal of Endocrinology, 2017Co-Authors: Anne H Van Der Spek, Eric Fliers, Anita BoelenAbstract:Thyroid Hormone (TH) Metabolism and Thyroid status have been linked to various aspects of the immune response. There is extensive literature available on the effects of Thyroid Hormone on innate immune cells. However, only recently have authors begun to study the mechanisms behind these effects and the role of intracellular TH Metabolism in innate immune cell function during inflammation. This review provides an overview of the molecular machinery of intracellular TH Metabolism present in neutrophils, macrophages and dendritic cells and the role and effects of intracellular TH Metabolism in these cells. Circulating TH levels have a profound effect on neutrophil, macrophage and dendritic cell function. In general, increased TH levels result in an amplification of the pro-inflammatory response of these cells. The mechanisms behind these effects include both genomic and non-genomic effects of TH. Besides a pro-inflammatory effect induced by extracellular TH, the cellular response to pro-inflammatory stimuli appears to be dependent on functional intracellular TH Metabolism. This is illustrated by the fact that the deiodinase enzymes and in some cell types also Thyroid Hormone receptors appear to be crucial for adequate innate immune cell function. This overview of the literature suggests that TH Metabolism plays an important role in the host defence against infection through the modulation of innate immune cell function.
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the classic pathways of Thyroid Hormone Metabolism
Molecular and Cellular Endocrinology, 2017Co-Authors: Anne H Van Der Spek, Eric Fliers, Anita BoelenAbstract:Thyroid Hormones (TH) are crucial for growth and development and play an important role in energy homeostasis. Although serum TH levels are relatively constant in the physiological state, TH bioavailability at the tissue and cellular level is dependent on local TH Metabolism. Circulating TH produced by the Thyroid can be metabolized by a number of different pathways resulting in 1) activation of TH 2) deactivation of TH or 3) excretion of TH and subsequent metabolites. These pathways play an essential role in determining local TH levels and action. The major classical pathways of TH Metabolism are deiodination, sulfation, glucuronidation, and ether-link cleavage. This review provides an overview of these pathways, their relative contributions to TH levels in the serum and in various organs and the changes in these pathways elicited by fasting and illness.
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beyond low plasma t3 local Thyroid Hormone Metabolism during inflammation and infection
Endocrine Reviews, 2011Co-Authors: Anita Boelen, Joan Kwakkel, Eric FliersAbstract:Decreased serum Thyroid Hormone concentrations in severely ill patients were first reported in the 1970s, but the functional meaning of the observed changes in Thyroid Hormone levels, together known as nonThyroidal illness syndrome (NTIS), remains enigmatic. Although the common view was that NTIS results in overall down-regulation of Metabolism in order to save energy, recent work has shown a more complex picture. NTIS comprises marked variation in transcriptional and translational activity of genes involved in Thyroid Hormone Metabolism, ranging from inhibition to activation, dependent on the organ or tissue studied. Illness-induced changes in each of these organs appear to be very different during acute or chronic inflammation, adding an additional level of complexity. Organ- and timing-specific changes in the activity of Thyroid Hormone deiodinating enzymes (deiodinase types 1, 2, and 3) highlight deiodinases as proactive players in the response to illness, whereas the granulocyte is a novel and potentially important cell type involved in NTIS during bacterial infection. Although acute NTIS can be seen as an adaptive response to support the immune response, NTIS may turn disadvantageous when critical illness enters a chronic phase necessitating prolonged life support. For instance, changes in Thyroid Hormone Metabolism in muscle during critical illness may be relevant for the pathogenesis of myopathy associated with prolonged ventilator dependence. This review focuses on NTIS as a timing-related and organ-specific response to illness, occurring independently from the decrease in serum Thyroid Hormone levels and potentially relevant for disease progression.
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chronic local inflammation in mice results in decreased trh and type 3 deiodinase mrna expression in the hypothalamic paraventricular nucleus independently of diminished food intake
Journal of Endocrinology, 2006Co-Authors: Anita Boelen, Joan Kwakkel, Wilmar M Wiersinga, Eric FliersAbstract:During illness, changes in Thyroid Hormone Metabolism occur, known as nonThyroidal illness and characterised by decreased serum triiodothyronine (T3 )a nd thyroxine (T 4) without an increase in TSH. A mouse model of chronic illness is local inflammation, induced by a turpentine injection in each hind limb. Although serum T3 and T4 are markedly decreased in this model, it is unknown whether turpentine administration affects the central part of the hypothalamus‐pituitary‐Thyroid axis (HPT-axis). We therefore studied Thyroid Hormone Metabolism in hypothalamus and pituitary of mice during chronic inflammation induced by turpentine injection. Using pair-fed controls, we could differentiate between the effects of chronic inflammation per se and the effects of restricted food intake as a resultofillness.Chronicinflammationincreasedinterleukin(IL)1bmRNA expression in the hypothalamus more rapidly than in thepituitary.Thishypothalamiccytokineresponsewasassociated witharapidincreaseinlocalD2mRNAexpression.Bycontrast, no changes were present in pituitary D2 expression. TSHb mRNA expression was altered compared with controls. Comparing chronic inflamed mice with pair-fed controls, both preproTSH releasing Hormone (TRH) and D3 mRNA expression in the paraventricular nucleus were significantly lower 48 h after turpentine administration. The timecourse of TSHb mRNA expression was completely different in inflamed mice compared with pair-fed mice. Turpentine administration resultedinsignificantlydecreasedTSHbmRNAexpressiononly after 24 h while later in time it was lower in pair-fed controls. In conclusion, central Thyroid Hormone Metabolism is altered during chronic inflammation and this cannot solely be attributed to diminished food intake.
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simultaneous changes in central and peripheral components of the hypothalamus pituitary Thyroid axis in lipopolysaccharide induced acute illness in mice
Journal of Endocrinology, 2004Co-Authors: Anita Boelen, Joan Kwakkel, Eric Fliers, D C Thijssentimmer, Anneke Alkemade, Wilmar M WiersingaAbstract:During illness, major changes in Thyroid Hormone Metabolism and regulation occur; these are collectively known as non-Thyroidal illness and are characterized by decreased serum triiodothyronine (T 3 ) and thyroxine (T 4 ) without an increase in serum TSH. Whether alterations in the central part of the hypothalamus–pituitary–Thyroid (HPT) axis precede changes in peripheral Thyroid Hormone Metabolism instead of vice versa, or occur simultaneously, is presently unknown. We therefore studied the timecourse of changes in Thyroid Hormone Metabolism in the HPT axis of mice during acute illness induced by bacterial endotoxin (lipopolysaccharide; LPS). LPS rapidly induced interleukin-1 mRNA expression in the hypothalamus, pituitary, Thyroid and liver. This was followed by almost simultaneous changes in the pituitary (decreased expression of Thyroid receptor (TR)-2, TSH and 5-deiodinase (D1) mRNAs), the Thyroid (decreased TSH receptor mRNA) and the liver (decreased TR1 and D1 mRNA). In the hypothalamus, type 2 deiodinase mRNA expression was strongly increased whereas preproTRH mRNA expression did not change after LPS. Serum T 3 and T 4 fell only after 24 h. Our results suggested almost simultaneous involvement of the whole HPT axis in the downregulation of Thyroid Hormone Metabolism during acute illness.
Alexandra M Dumitrescu - One of the best experts on this subject based on the ideXlab platform.
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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...
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a novel homozygous selenocysteine insertion sequence binding protein 2 secisbp2 sbp2 gene mutation in a turkish boy
Thyroid, 2018Co-Authors: Gonul Catli, Haruki Fujisawa, Ozgur Kirbiyik, Mizuho S Mimoto, Pinar Gencpinar, Taha Resid Ozdemir, Bumin Dundar, Alexandra M DumitrescuAbstract:SECISBP2 is an essential factor in selenoprotein synthesis, and its mutations result in a multiorgan syndrome, including abnormal Thyroid Hormone Metabolism. A 10-year-old obese Turkish boy born to consanguineous parents presented with high thyroxine, low triiodothyronine, high reverse triiodothyronine, and normal or slightly elevated thyrotropin. He also had attention-deficit disorder and muscle weakness but no delay in growth or bone age. Sequencing of genomic DNA revealed a novel c.800_801insA, p.K267Kfs*2 mutation, homozygous in the proband and heterozygous in both parents and his brother. Studies showed reduction in several selenoproteins in serum and fibroblasts.
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Mutations in SECISBP2 result in abnormal Thyroid Hormone Metabolism
Nature Genetics, 2005Co-Authors: Alexandra M Dumitrescu, Xiao-hui Liao, Mohamed S Y Abdullah, Joaquin Lado-abeal, Fathia Abdul Majed, Lars C Moeller, Gerard Boran, Lutz Schomburg, Roy E Weiss, Samuel RefetoffAbstract:Incorporation of selenocysteine (Sec), through recoding of the UGA stop codon, creates a unique class of proteins. Mice lacking tRNA^Sec die in utero ^ 1 , but the in vivo role of other components involved in selenoprotein synthesis is unknown, and Sec incorporation defects have not been described in humans. Deiodinases (DIOs) are selenoproteins involved in Thyroid Hormone Metabolism. We identified three of seven siblings with clinical evidence of abnormal Thyroid Hormone Metabolism. Their fibroblasts showed decreased DIO2 enzymatic activity not linked to the DIO2 locus. Systematic linkage analysis of genes involved in DIO2 synthesis and degradation led to the identification of an inherited Sec incorporation defect, caused by a homozygous missense mutation in SECISBP2 (also called SBP2 ). An unrelated child with a similar phenotype was compound heterozygous with respect to mutations in SECISBP2 . Because SBP2 is epistatic to selenoprotein synthesis, these defects had a generalized effect on selenoproteins. Incomplete loss of SBP2 function probably causes the mild phenotype.
Katarzyna Hryniewicz - One of the best experts on this subject based on the ideXlab platform.
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Thyroid Hormone Metabolism in patients with congestive heart failure the low triiodothyronine state
Thyroid, 2002Co-Authors: Deborah D Ascheim, Katarzyna HryniewiczAbstract:Thyroid Hormone has multiple effects on the cardiovascular system, ranging from molecular and cellular effects to the consequent hemodynamic alterations. Consequently, Thyroid function has been evaluated in small cohorts of patients with advanced heart failure that indicate a significant prevalence of morphologic or functional Thyroid disorders. We sought to determine the prevalence of altered Thyroid Hormone Metabolism in a broad spectrum of ambulatory heart failure patients. Thyroid function tests were evaluated in 132 ambulatory patients (98 males, 32 females, mean age, 67 years) with left ventricular systolic dysfunction (EF 4.25 U/mL and low triiodothyronine (T3) state was defined as T3 levels < 80 ng/dL, with normal thyroxine (T4) and TSH level. Seven percent of patients were found to have primary hypoThyroidism and 34% have a low T3 state. Of patients receiving a...
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Thyroid Hormone Metabolism in patients with congestive heart failure the low triiodothyronine state
Thyroid, 2002Co-Authors: Deborah D Ascheim, Katarzyna HryniewiczAbstract:Thyroid Hormone has multiple effects on the cardiovascular system, ranging from molecular and cellular effects to the consequent hemodynamic alterations. Consequently, Thyroid function has been evaluated in small cohorts of patients with advanced heart failure that indicate a significant prevalence of morphologic or functional Thyroid disorders. We sought to determine the prevalence of altered Thyroid Hormone Metabolism in a broad spectrum of ambulatory heart failure patients. Thyroid function tests were evaluated in 132 ambulatory patients (98 males, 32 females, mean age, 67 years) with left ventricular systolic dysfunction (EF 4.25 U/mL and low triiodothyronine (T3) state was defined as T3 levels < 80 ng/dL, with normal thyroxine (T4) and TSH level. Seven percent of patients were found to have primary hypoThyroidism and 34% have a low T3 state. Of patients receiving amiodarone, 21% had elevated TSH levels and 76% had low T3 levels. The prevalence of abnormal Thyroid function correlated with NYHA class. There is an unexpectedly high risk of hypoThyroidism and low T3 syndrome in patients regardless of treatment with amiodarone, which appears to correlate with disease severity that requires further investigation.
Samuel Refetoff - One of the best experts on this subject based on the ideXlab platform.
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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...
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unique regulation of Thyroid Hormone Metabolism during fasting in the house musk shrew suncus murinus insectivora soricidae
General and Comparative Endocrinology, 2006Co-Authors: Yoko Takeuchi, Daisuke Suzuki, Samuel Refetoff, Koji Seki, Katsuhiko Tsunekawa, Takayuki Kasahara, Masami Murakami, Yoshiharu MurataAbstract:Abstract The active Hormone, 3,3′,5-triiodothyronine (T 3 ) is derived from thyroxine (T 4 ) by the action of iodothyronine 5′-deiodinases (5′-D). By now two types of 5′-D have been identified; Type 1 (D1) and type 2 (D2). A relative contribution of these isotypes to the circulating T 3 levels in the human remains to be determined whereas a number of reports indicate that, under physiological conditions, D1 plays a major role in maintaining circulating T 3 levels in rodents. In both human and rodents, sickness and starvation reduce serum T 3 concentration mainly through decrease in D1 activity. Recently, we found that the house musk shrew ( Suncus murinus , Insectivora: Soricidae) has a different tissue distribution of D1 activity. Because compared to rodents D1 activity in the shrew was found only in liver at a much reduced level, D2 rather than D1 may play a role in the maintenance of serum T 3 . Therefore, we questioned how D1 and D2 activities change in fasted shrews and how these changes affect circulating Thyroid Hormone levels. We thus starved shrews for 24, 48 or 72 h and measured changes in serum concentration of T 3 , T 4 , and 3,3′,5′-triiodothyronine (reverse T 3 , rT 3 ) and D1 activities as well as its mRNA expression in liver. D2 activities were also measured in brown adipose tissue (BAT) and cerebral cortex of shrews. Unlike in human and rodents, T 3 levels in shrews remained constant during fasting while T 4 levels tended to decrease, resulting in an increase in its T 3 /T 4 ratio. On the other hand, changes in rT 3 levels were similar to those in human and rodents, being elevated with fasting. D1 mRNA and its activity were significantly reduced in the liver whereas D2 activities in BAT and cerebral cortex were increased by fasting. These results indicated that fasting in shrews also reduced hepatic D1 activity but it did not affect circulating T 3 levels. The increased T 3 /T 4 ratio together with increased D2 activity in BAT and cerebral cortex with fasting suggest that D2 rather than D1 is responsible for the maintenance of T 3 levels in the house musk shrew.
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Mutations in SECISBP2 result in abnormal Thyroid Hormone Metabolism
Nature Genetics, 2005Co-Authors: Alexandra M Dumitrescu, Xiao-hui Liao, Mohamed S Y Abdullah, Joaquin Lado-abeal, Fathia Abdul Majed, Lars C Moeller, Gerard Boran, Lutz Schomburg, Roy E Weiss, Samuel RefetoffAbstract:Incorporation of selenocysteine (Sec), through recoding of the UGA stop codon, creates a unique class of proteins. Mice lacking tRNA^Sec die in utero ^ 1 , but the in vivo role of other components involved in selenoprotein synthesis is unknown, and Sec incorporation defects have not been described in humans. Deiodinases (DIOs) are selenoproteins involved in Thyroid Hormone Metabolism. We identified three of seven siblings with clinical evidence of abnormal Thyroid Hormone Metabolism. Their fibroblasts showed decreased DIO2 enzymatic activity not linked to the DIO2 locus. Systematic linkage analysis of genes involved in DIO2 synthesis and degradation led to the identification of an inherited Sec incorporation defect, caused by a homozygous missense mutation in SECISBP2 (also called SBP2 ). An unrelated child with a similar phenotype was compound heterozygous with respect to mutations in SECISBP2 . Because SBP2 is epistatic to selenoprotein synthesis, these defects had a generalized effect on selenoproteins. Incomplete loss of SBP2 function probably causes the mild phenotype.