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Journal Cover   European Thyroid Journal
   Full-text available via subscription Subscription journal
   ISSN (Print) 2235-0640 - ISSN (Online) 2235-0802
   Published by Karger Homepage  [104 journals]
  • Evolutionary Conservation of 3-Iodothyronamine as Agonist at the Trace
           Amine-Associated Receptor 1
    • Abstract: Objectives: The trace amine-associated receptor 1 (Taar1) is a Gs protein-coupled receptor activated by trace amines, such as β-phenylethylamine (β-PEA) and 3-iodothyronamine (T1AM). T1AM is an endogenous biogenic amine and thyroid hormone derivative that exerts several biological functions. However, the physiological relevance of T1AM acting via Taar1 is still under discussion. Therefore, we studied the structural and functional evolution of Taar1 in vertebrates to provide evidence for a conserved Taar1-mediated T1AM function. Study Design: We mined public sequence databases to retrieve Taar1 sequence information from vertebrates. We cloned and functionally characterized Taar1 from selected vertebrate species using cAMP assays to determine the evolutionary conservation of T1AM action at Taar1. Results: We found intact open reading frames of Taar1 in more than 100 vertebrate species, including mammals, sauropsids, and amphibians. Evolutionary conservation analyses of Taar1 protein sequences revealed high variation in amino acid residues proposed to be involved in agonist binding, especially in rodent Taar1 orthologs. Functional characterization showed that T1AM, β-PEA and p-tyramine (p-Tyr) act as agonists at all tested orthologs, but EC50 values of T1AM at rat Taar1 differed significantly when compared to all other tested vertebrate Taar1. Conclusions: The high structural conservation of Taar1 throughout vertebrate evolution highlights the physiological relevance of Taar1 but species-specific differences in T1AM potency at Taar1 orthologs suggest a specialization of rat Taar1 for T1AM recognition. In contrast, β-PEA and p-Tyr potencies were rather conserved throughout all tested Taar1 orthologs. We provide evidence that the observed differences in potency are related to differences in constraint during Taar1 evolution.
      Eur Thyroid J
  • The Multi-Target Ligand 3-Iodothyronamine Modulates Beta-Adrenergic
           Receptor 2 Signaling
    • Abstract: Background: 3-iodothyronamine (3-T1AM), a signaling molecule with structural similarities to thyroid hormones (TH), induces numerous physiological responses including reversible body temperature decline. One target of 3-T1AM is the trace amine-associated receptor 1 (TAAR1), which is a member of the rhodopsin-like family of G protein-coupled receptors (GPCRs). Interestingly, effects of 3-T1AM remain detectable in TAAR1 knockout mice, suggesting further targets for 3-T1AM such as adrenergic receptors. Therefore, we evaluated whether beta-adrenergic receptor 1 (ADRB1) and 2 (ADRB2) signaling are affected by 3-T1AM in HEK293 cells and in human conjunctival epithelial cells (IOBA-NHC), where these receptors are highly expressed endogenously. Methods: A label-free EPIC system for pre-screening the 3-T1AM-induced effects on ADRB1 and ADRB2 in transfected HEK293 cells was used. In addition, ADRB1 and ADRB2 activation was analyzed using a cAMP-assay and a MAPK reporter gene assay. Finally, fluorescence Ca2+-imaging was utilized to delineate 3-T1AM-induced Ca2+ signaling. Results: 3-T1AM (10-5-10-10M) enhanced isoprenaline-induced ADRB2-mediated Gs signaling but not of ADRB1. MAPK signaling remained unaffected for both receptors. In IOBA-NHC cells, norepinephrine-induced Ca2+-influxes were blocked by the non-selective ADRB blocker timolol (10 µM), indicating that ADRBs are most likely linked with Ca2+-channels. Notably, timolol was also found to block 3-T1AM (10-5M)-induced Ca2+ influx. Conclusions: The presented data support that 3-T1AM directly modulates beta-adrenergic-receptor signaling. The relationship between 3-T1AM and beta-adrenergic signaling also reveals a potential therapeutic value for suppressing Ca2+ channel-mediated inflammation processes, occurring in eye diseases such as conjunctivitis.
      Eur Thyroid J
  • Quantitative Analysis of Thyroid Hormone Metabolites in Cell Culture
           Samples using LC-MS/MS
    • Abstract: A liquid-liquid extraction and liquid chromatography-electrospray ionization tandem mass spectrometry (LC-MS/MS) method to determine thyronines (TH) and thyronamines (TAM) from cell culture media was developed. TH are metabolised by sequential deiodination to eventually yield thyronine (T0) but can also be decarboxylated, resulting in TAM. The method presented here for extraction of DMEM/F12 cell culture media is a fundamental procedure for a precise determination of 9 TH and 6 TAM from a single LC run. Analytes and internal standards (IS) were extracted from DMEM/F12 (w/o phenol-red) by liquid-liquid extraction using isopropanol-TBME (30:70 v/v). Measurement of TH and TAM was performed during a 10 min run-time using 13C6-T4, 13C6-T3, 13C6-rT3, 13C6-3,3′T2, and 2H4-T1AM as IS. Calibration curves covered 11 calibrators measured as triplicates each for the analysis of the 9 TH, 6 TAM metabolites and the 5 IS were linear and reproducible in the range of 0.12-120 nM (R2: 0.991-0.999) for all calibrators. The lower limit of quantification was 0.078-0.234 nM. Method validation and robustness were demonstrated by analysis of precision, accuracy, process efficiency, matrix effects, recoveries as well as intra- and interassay stability. These parameters were investigated for high, middle and low concentrations of quality controls of all 9 TH and 6 TAM metabolites. This validated, sensitive and interaction-free LC-MS/MS method allows rapid analysis and accurate determination of TH and TAM from DMEM/F12 (w/o phenol red) conditioned media and seems to be easily transferable and applied to commonly used buffers and cell culture media.
      Eur Thyroid J
  • Effect of Experimental Thyrotoxicosis Onto Blood Coagulation - A
           Proteomics Study
    • Abstract: Background: Hyperthyroidism is known to induce a hypercoagulable state. It stimulates plasma levels of procoagulative factors and reduces fibrinolytic activity. So far most of the data have been derived from patients with endogenous hyperthyroidism with a wide variability in the underlying pathogenesis and severity of the disease. Objectives: In this study we experimentally induced thyrotoxicosis in healthy volunteers to explore the effects of thyroxine excess on the plasma proteome. Using a shotgun-proteomics approach the abundance of plasma proteins was monitored before, during and after thyrotoxicosis. Methods: 16 healthy male subjects were sampled at baseline, 4 and 8 weeks under 250 µg/d thyroxine p.o., as well as 4 and 8 weeks after stopping the application. Plasma proteins were analyzed after depletion of 6 high-abundant proteins (MARS6) by LC-ESI-MS/MS mass spectrometry. Mass spectrometric raw data were processed using a label free, intensity-based workflow. Subsequently, the linear dependence between protein abundances and FT4-levels were calculated using a Pearson correlation. Results: All subjects developed biochemical thyrotoxicosis and this effect was reversed within the first 4 weeks of follow-up. None of the volunteers noticed any subjective symptoms. Levels of 10 proteins involved in the coagulation cascade specifically correlated with FT4 supporting an influence of thyroid hormone levels on blood coagulation even at non-pathological levels. Conclusions: Results suggest that experimental thyrotoxicosis exerts selective and specific thyroxine induced effects on coagulation markers. Our study design allows assessment of thyroid hormone effects on plasma protein levels without secondary effects of other diseases or therapies.
      Eur Thyroid J
  • Involvement of the L-Type Amino Acid Transporter Lat2 in the Transport of
           3,3′-Diiodothyronine Across the Plasma Membrane
    • Abstract: Thyroid hormones are transported across cell membranes by transmembrane transporter proteins, e.g. by members of the monocarboxylate transporter (MCT) and the L-type amino acid transporter (LAT) families. LATs consist of a light chain (e.g. LAT2) and a heavy chain (CD98), which is essential for their cell surface expression and functionality. Until now the specificity of Lat2 for thyroid hormones and their metabolites and its role in their transport are not fully clear. This fact motivated us to establish a cell system to elucidate the uptake of thyroid hormones and their metabolites by mouse Lat2. The co-injection of cRNA coding for Lat2 and CD98 into Xenopus laevis oocytes resulted in a markedly increased 3,3′-Diiodo-L-Thyronine (3,3′-T2) and to some extent also enhanced T3 transport. To gain insight into properties of thyroid hormones and their metabolites transported by Lat2, we inhibited 3,3′-T2 uptake by various iodothyronine derivatives. T1 and T2 derivatives as well as 2-aminobicyclo-[2,2,1]-heptane-2-carboxylic acid (BCH) strongly competed with 3,3′-T2 uptake. In addition, we performed T2 uptake measurements with the thyroid hormone specific transporter MCT8. For both, Lat2 and MCT8, Km values in a low micromolar range were calculated. We demonstrated that oocytes are a suitable system for thyroid hormone transport studies mediated by Lat2. Our data indicates that Lat2 compared to other thyroid hormone transporters prefers 3,3′-T2 as substrate. Thus, Lat2 might contribute to availability of thyroid hormone by importing and/or exporting 3,3′-T2, which is generated either by T3 inactivation or by rapid deiodinase 1-mediated rT3 degradation.
      Eur Thyroid J
  • Urine Metabolomics by 1H-NMR Spectroscopy Indicates
           Associations between Serum 3,5-T2 Concentrations and Intermediary
           Metabolism in Euthyroid Humans
    • Abstract: Context: 3,5-diiodo-L-thyronine (3,5-T2) is a thyroid hormone metabolite which exhibited versatile effects in rodent models, including the prevention of insulin resistance or hepatic steatosis typically forced by high-fat-diet. With respect to euthyroid humans, we recently observed a putative link between serum 3,5-T2 and glucose but not lipid metabolism. Objective: The aim of the present study was to widely screen the urine metabolome for associations with serum 3,5-T2 concentrations in healthy individuals. Study Design and Methods: Urine Metabolites of 715 euthyroid participants of the population-based Study of Health in Pomerania (SHIP-TREND) were analyzed by 1H-NMR spectroscopy. Multinomial logistic and multivariate linear regression models were used to detect associations between urine metabolites and serum 3,5-T2 concentrations. Results: Serum 3,5-T2 concentrations were positively associated with urinary levels of trigonelline, pyroglutamate, acetone and hippurate. In detail, the odds for intermediate or suppressed serum 3,5-T2 concentrations doubled owing to a one standard deviation (SD) decrease in urine trigonelline levels or increased by 29-50% in relation to a one SD decrease in urine pyroglutamate, acetone and hippurate levels. Conclusion: Our findings in humans confirmed metabolic effects of circulating 3,5-T2 on glucose and lipid metabolism, oxidative stress and enhanced drug metabolism as postulated before based on interventional pharmacological studies in rodents. Of note, 3,5-T2 exhibited a unique urinary metabolic profile distinct from previously published results for the classical thyroid hormones.
      Eur Thyroid J
  • Understanding the Healthy Thyroid State in 2015
    • Abstract: Thyroid hormones (TH) are of crucial importance for the physiological function of almost all organs. In cases of abnormal TH signaling, pathophysiological consequences may arise. The routine assessment of a healthy or diseased thyroid function state is currently based on the determination of serum concentrations of thyroid stimulating hormone (TSH), and the TH T3 and T4. However, definition of a ‘normal' TSH range and similarly ‘normal' T3 and T4 concentrations remains the subject of debates in different countries worldwide and has important implications on patients' treatment in clinic. Not surprisingly, a significant number of patients, whose thyroid function tests are biochemically determined to be within the normal range, complain of impaired well-being. The reasons for this are so far not fully understood, but it has been recognized that thyroid function status needs to be ‘individualized' and extended beyond simple TSH measurement. Thus, more precise and reliable parameters are required in order to optimally define the healthy thyroid status of an individual, and as a perspective to employ these in clinical routine. With the recent identification of new key players in TH action a more accurate assessment of patients' thyroid status may in the future become possible. Recently described distinct TH derivatives and metabolites, TH transporters, non-genomic TH effects, either through membrane-bound or cytosolic signaling, and classical nuclear TH action, allow for insights into molecular and cellular pre-conditions of a healthy thyroid state. This will be a prerequisite to improve management of thyroid dysfunction, and additionally, to prevent and target TH-related non-thyroid disease.
      Eur Thyroid J
  • Serum Thyrotropin Concentrations are Not Associated with the
           Ankle-Brachial Index - Results from Three Population-Based Studies
    • Abstract: Background: There is only limited data on the potential association between thyroid dysfunction and peripheral arterial disease (PAD). Objective: The aim of our study was to investigate the potential association of thyroid function, as defined by serum concentrations of the clinically used primary thyroid function marker thyrotropin (TSH) and 3,5-diiodothyronine (3,5-T2) with the ankle-brachial index (ABI) as marker of PAD. Methods: We used data from 5818 individuals from three cross-sectional population-based studies conducted in Northeast (SHIP-2 and SHIP-TREND) and Central Germany (CARLA). Measurement of serum TSH concentrations was conducted in one central laboratory for all three studies. In a randomly selected sub-population of 750 individuals of SHIP-TREND, serum 3,5-T2 concentrations were measured with a recently developed immunoassay. ABI was measured either by hand-held Doppler ultrasound by the Huntleigh Dopplex D900 or palpatory by the OMRON HEM-705CP device. Results: Serum TSH concentrations were not significantly associated with ABI values in any of the three studies. Likewise, groups of individuals with a TSH
  • Differences in Mouse Hepatic Thyroid Hormone Transporter Expression with
           Age and Hyperthyroidism
    • Abstract: Background: Clinical features of thyroid dysfunction vary with age and an oligosymptomatic presentation of hyperthyroidism is frequently observed in the elderly. This suggests age modulation of thyroid hormone (TH) action, which may occur by e.g. alterations in TH production, metabolism and/or TH action in target organs. Objectives: In this paper we address possible changes in TH transporter expression in liver tissues as a mechanism of age-dependent variation in TH action. Methods: Chronic hyperthyroidism was induced in male 4 and 20 months old C57BL6/NTac mice (n = 8-10) by intraperitoneal injections of 1µg/g body weight L-Thyroxine (T4) every 48 h over 7 weeks. Control animals were injected with PBS. Total RNA was isolated from livers for analysis of TH transporter and TH responsive gene expression. TH concentrations were determined in mice sera. Results: Baseline serum free T4 concentrations were significantly higher in euthyroid young compared to old mice. T4 treatment increased TT4, fT4 and fT3 to comparable values in young and old mice. In the euthyroid state, TH transporter expression was significantly higher in old than in young mice, except for Mct8 and Oatp1a1 expression levels. Hyperthyroidism resulted in upregulation of Mct10, Lat1 and Lat2 in liver tissue while Oatp1a1, Oatp1b2 and Oatp1a4 expression was downregulated. This effect was preserved in old animals. Conclusion: Here we show age-dependent differences in TH transporter mRNA expression in the eu- and hyperthyroid state of mice focusing on the liver as a classical TH target organ.
      Eur Thyroid J
  • Do Not Forget Nephrotic Syndrome as a Cause of Increased Requirement of
           Levothyroxine Replacement Therapy
    • Abstract: Nephrotic syndrome increases L-thyroxine requirements because of urinary loss of free and protein-bound thyroid hormones. We report 2 hypothyroid patients referred to us because of high serum TSH, even though the L-thyroxine daily dose was maintained at appropriate levels or was increased. The cause of nephrotic syndrome was multiple myeloma in one patient and diabetic glomerulosclerosis in the other patient. As part of the periodic controls for diabetes, urinalysis was requested only in the second patient so that proteinuria could be detected. However, as in the first patient, facial puffiness and body weight increase were initially attributed to hypothyroidism, which was poorly compensated by L-thyroxine therapy. In the first patient, the pitting nature of the pedal edema was missed at the initial examination. An endocrinologist consulted over the phone by the practitioner hypothesized some causes of intestinal malabsorption of L-thyroxine. This diagnosis would have been accepted had the patient continued taking a known sequestrant of L-thyroxine, i.e. calcium carbonate. The diagnostic workup of patients with increasing requirements of L-thyroxine replacement therapy should not be concentrated on the digestive system alone. Careful history taking and physical examination need to be thorough. Endocrinologists should not forget nephrotic syndrome that, in turn, can be secondary to serious diseases.
      Eur Thyroid J
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