Truncated variants of thyroid hormone receptor beta display disease-inflicting malfunctioning at cellular level.

Thyroid hormone receptor ß (THRß) is a member of the nuclear receptor superfamily of ligand-modulated transcription factors. Upon ligand binding, THRß sequentially recruits the components of transcriptional machinery to modulate target gene expression. In addition to regulating diverse physiological processes, THRß plays a crucial role in hypothalamus-pituitary-thyroid axis feedback regulation. Anomalies in THRß gene/protein structure are associated with onset of diverse disease states. In this study, we investigated disease-inflicting truncated variants of THRß using in-silico analysis and cell-based assays. We examined the THRß truncated variants on multiple test parameters, including subcellular localization, ligand-receptor interactions, transcriptional functions, interaction with heterodimeric partner RXR, and receptor-chromatin interactions. Moreover, molecular dynamic simulation approaches predicted that shortened THRß-LBD due to point mutations contributes proportionally to the loss of structural integrity and receptor stability. Deviant subcellular localization and compromised transcriptional function were apparent with these truncated variants. Present study shows that 'mitotic bookmarking' property of some THRß variants is also affected. The study highlights that structural and conformational attributes of THRß are necessary for normal receptor functioning, and any deviations may contribute to the underlying cause of the inflicted diseases. We anticipate that insights derived herein may contribute to improved mechanistic understanding to assess disease predisposition.

Selective thyroid hormone receptor beta agonist, GC-1, is capable to reduce growth of colorectal tumor in syngeneic mouse models.

OBJECTIVE: The effect of thyroid hormone (TH) on cancers was proposed more than 100 years ago; however, conclusions are conflicting. THs are precisely regulated at tissue and cellular levels. It seems that this regulation is altered in cancers. Thyroid hormone receptor beta (TRß) has anti-proliferative and tumor-suppressive effects in many cancer cells. Therefore, we decided to investigate thyroid hormone receptor beta (THRB) expression and activation by the selective agonist, GC-1, on tumor growth in a syngeneic mouse model of colorectal cancer (CRC) and colon cell lines. METHODS: In vitro cell viability assay using MTT analysis, cell cycle analysis by PI staining, and FACS analysis were performed. In vivo tumor growth measurements were carried out by caliper and [18F] Fluoro-2-deoxy-2-D-glucose (FDG) - PET imaging. Gene expressions were determined using quantitative-PCR. RESULTS: Some concentrations of GC-1 had a marked negative effect on the cell viability of colorectal cell lines. Cell cycle analysis showed that the anti-proliferative effect of GC-1 may not result from cell cycle arrest or apoptosis. Tumor growth analysis in mice harboring colorectal tumor showed that GC-1 treatment for 8 d profoundly inhibited tumor growth and 18FDG uptake. THRB expression was decreased in mice tumor; however, it was upregulated following GC-1 administration. CONCLUSIONS: Our results showed that specific activation of TRß by GC-1 had negative effect on tumor growth and restored its gene expression in tumors of CRC mice model.

Subcellular Distribution of Thyroid Hormone Receptor Beta in Ovarian Cancer.

Background: Since the most well-known function of thyroid hormone receptors (TRs) relies on their ability to act as ligand-activated transcription factors, their subcellular localization has been recognized to be relevant for their biological meaning. The current study aimed to determine the prevalence and subcellular distribution of TR beta and TR beta-1 in ovarian cancer (OC). Methods: Tissue was collected from 153 patients that had undergone surgery due to OC at the Department of Obstetrics and Gynaecology of the Ludwig-Maximilians-University Munich. Immunohistochemistry detecting TR beta and TR beta-1 was performed. Staining signals were quantified and tested for association with clinico-pathological parameters including overall survival (OS). Results: The subcellular distribution of TR beta and TR beta-1 differed among histologic subtypes, grade and FIGO stage. TR beta positivity was strongly linked to shortened overall survival (p < 0.001). Strikingly, this shortened OS was mainly attributed to those cases showing complete (p = 0.005) or incomplete shift of TR beta to the cytoplasm (p < 0.001). Significance was lost in multivariate testing. Conclusions: Cytoplasmatic localization of TR beta was associated with reduced OS, at least in univariate analysis. Since TRs have long been supposed to mainly function via the regulation of gene transcription in the nucleus, cytoplasmatic shifting might be interpreted as a regulator of their activity.

Resistance to thyroid hormone due to a novel THRB p.Val349Ala mutation in a Taiwanese boy.

Resistance to thyroid hormone (RTH) is a rare congenital disorder characterized by impaired sensitivity of target tissues to thyroid hormone. The disease is mostly caused by heterozygous mutations of thyroid hormone receptor ß (THRB) gene. We present a ten-year-old Taiwanese boy with goiter, mood disturbances and attention deficit hyperactivity disorder (ADHD). Blood tests showed elevated serum thyroxine (T4) and triiodothyronine (T3) levels with nonsuppressed thyrotropin (TSH) levels. Sella MRI failed to detect any pituitary adenoma. Initial treatment with anti-thyroid drugs resulted in increased TSH levels and goiter size. His medication was discontinued after his visit to our hospital for a second opinion. A thyrotropin-releasing hormone (TRH) stimulation test showed a normal TSH response to TRH stimulation. Molecular analysis identified a novel heterozygous THRB p.Val349Ala mutation. The patient attained normal growth and a paucity of symptoms without any medication during the follow-up period. We hope that the presentation of this case can make the early diagnosis of RTH possible so that inappropriate management of these patients can be avoided in the future.

Cytoplasmic and Nuclear Forms of Thyroid Hormone Receptor ß1 Are Inversely Associated with Survival in Primary Breast Cancer.

The aim of this study was to investigate the expression of thyroid hormone receptor ß1 (THRß1) by immunohistochemistry in breast cancer (BC) tissues and to correlate the results with clinico-biological parameters. In a well-characterized cohort of 274 primary BC patients, THRß1 was widely expressed with a predominant nuclear location, although cytoplasmic staining was also frequently observed. Both nuclear and cytoplasmic THRß1 were correlated with high-risk BC markers such as human epidermal growth factor receptor 2 (HER2), Ki67 (also known as MKI67), prominin-1 (CD133), and N-cadherin. Overall survival analysis demonstrated that cytoplasmic THRß1 was correlated with favourable survival (p = 0.015), whereas nuclear THRß1 had a statistically significant correlation with poor outcome (p = 0.038). Interestingly, in our cohort, nuclear and cytoplasmic THRß1 appeared to be independent markers either for poor (p = 0.0004) or for good (p = 0.048) prognosis, respectively. Altogether, these data indicate that the subcellular expression of THRß1 may play an important role in oncogenesis. Moreover, the expression of nuclear THRß1 is a negative outcome marker, which may help to identify high-risk BC subgroups.

MicroRNA 200a inhibits erythroid differentiation by targeting PDCD4 and THRB.

Previous studies on erythropoiesis revealed that microRNAs (miRNAs) play a critical role in erythroid differentiation. Given the abundance of identified miRNAs and the limited understanding of erythroid miRNAs, additional examination is required. Here, two sets of erythroid differentiation miRNome data were analysed to screen for novel erythroid-inhibiting miRNAs. MIR200A was selected based on its pattern of downregulated expression in the miRNome datasets during induction of erythroid differentiation. Overexpression of MIR200A in K562 and TF-1 cells confirmed its inhibitory role in erythroid differentiation. Further in vivo study indicated that overexpression of mir200a inhibited primitive erythropoiesis of zebrafish. Transcriptome analyses after MIR200A overexpression in TF-1 cells indicated a significant role in regulating erythroid function and revealed potential regulation networks. Additionally, bioinformatics and experimental analyses confirmed that PDCD4 (programmed cell death 4) and THRB (thyroid hormone receptor, beta) are both targets of MIR200A-3p. Gain- and loss-of-function studies of PDCD4 and THRB revealed that the two targets were capable of promoting erythroid gene expression. Overall, our results revealed that microRNA 200a inhibits erythroid differentiation by targeting PDCD4 and THRB.

Overexpression of thyroid hormone receptor ß1 altered thyroid hormone-mediated regulation of herpes simplex virus-1 replication in differentiated cells.

Thyroid hormone (T3) has been suggested to play a role in herpes simplex virus 1 (HSV-1) replication. It was previously reported that HSV-1 replication was suppressed by T3 in mouse neuroblastoma cells overexpressing thyroid hormone receptor ß1 (TRß1). Using a human neuro-endocrine cells LNCaP differentiated by androgen deprivation, HSV-1 replication was active but decreased by T3 at very low moi, probably due to low copy of TRß1. In this study, a recombinant HSV-1 was constructed expressing TRß1 (HSV-1/TRß1). Infection of Vero cells (very little TRß1 expression) with HSV-1/TRß1 exhibited increased replication in the presence of T3 compared to the counterpart without TRß1 overexpression. Interestingly, HSV-1/TRß1 infection of differentiated LNCaP cells showed strong suppression of viral replication by T3 and the removal of hormone did not fully reversed the suppression as was observed in parent virus. Quantitative analyses indicated that ICP0 expression was blocked using HSV-1/TRß1 for infection during T3 washout, suggesting that overexpression of TRß1 is likely to delay its inhibitory effect on viral gene expression. Together these results emphasized the importance of TRß1 in the regulation of HSV-1 replication in differentiated environment with neuronal phenotype.

The molecular mechanisms of TRß receptor interaction with polychlorinated biphenyls: A multispectral and computational exploration.

The thyroid hormone (TH) system is susceptible to the toxic effects of polychlorinated biphenyls (PCBs). Pollutants may disrupt the TH system by binding to serum TH transport proteins or interacting with thyroid hormone receptors (TRs) in target cells. However, the molecular mechanism of interaction with the Thyroid Hormone Receptor Beta (TRß) is not fully understood. This study employed fluorescence, UV-visible absorption, three-dimensional fluorescence, and Fourier-transform infrared spectroscopy, along with molecular docking and molecular dynamics simulations, to investigate the interaction between TRß and PCBs. Moreover, molecular docking and fluorescence resonance energy transfer (FRET) findings suggest that TRß and PCBs underwent resonance energy transfer consistent with Förster's theory. The root mean square deviation (RMSD) and docking outcomes indicate that the TRß-PCB29 complex exhibited optimal structural stability. Thus, the study concludes that integrating spectroscopic data with molecular docking is essential for a comprehensive analysis. Further analysis of intermolecular interactions using quantum chemistry and reduced density gradient analysis (RDG) analysis revealed that van der Waals forces are the primary drivers of PCBs to TRß.

Resmetirom's approval: Highlighting the need for comprehensive approaches in NASH therapeutics.

The recent FDA approval of Rezdiffra (resmetirom), an oral partial agonist of the thyroid hormone receptor-beta (THR-beta), for the treatment of noncirrhotic non-alcoholic steatohepatitis (NASH) with moderate to advanced fibrosis, has challenged conventional approaches to NASH drug development. Despite extensive efforts targeting typical pathways involved in NASH progression, such as lipogenesis, oxidative stress, and inflammation, these approaches have yet to yield any approved therapies. The success of resmetirom highlights the potential advantages of targeting THR-beta, which exerts pleiotropic effects on multiple pathways involved in NASH pathogenesis, including lipid metabolism, glucose homeostasis, and inflammation. In the phase 3 MAESTRONASH trial, resmetirom significantly improved NASH resolution, fibrosis, and LDL cholesterol levels compared to placebo, with a favorable safety profile. The tissue-specific action of resmetirom may also contribute to its efficacy and safety. The approval of resmetirom has opened new avenues for NASH drug development, emphasizing the importance of exploring novel mechanisms of action, developing targeted therapies, and embracing a more comprehensive approach to treatment. As the global burden of NASH continues to grow, the lessons learned from the success of resmetirom should inform future drug development strategies, offering hope to the millions of patients affected by this disease worldwide.

Resistance to Thyroid Hormone Beta Due to THRB Mutation in a Patient Misdiagnosed With TSH-Secreting Pituitary Adenoma.

Elevated concentrations of T3 and T4 concomitant with nonsuppressed TSH are found in both TSH-producing tumors and resistance to thyroid hormone beta (RTHß), posing a diagnostic challenge. We demonstrate here a 54-year-old female who presented with palpitations, goiter, and elevated free T4 with nonsuppressed TSH concentrations (TSH 2.2 mIU/L [normal range, NR 0.27-4.2 mIU/L] and FT4 59.08 pmol/L [NR 12.0-22.0 pmol/L]). Because magnetic resonance imaging revealed a pituitary microadenoma (4 mm), she was diagnosed with TSH-secreting pituitary adenoma and underwent transsphenoidal surgery. Pathological reports showed no tumor cells. Subsequent genetic testing revealed a pathogenic variant in the THRB gene resulting in a His435Arg amino acid substitution in the T3 receptor isoform beta 1 (TRß1), suggestive of RTHß. In vitro and ex vivo studies revealed that the His435Arg mutated TRß1 (TRß1-H435R) completely abolishes the T3-induced transcriptional activation, nuclear receptor corepressor 1 release, steroid receptor coactivator 1 recruitment, and T3-induced thyroid hormone target gene expression, confirming the pathogenicity of this variant. The identification of a pituitary microadenoma in a patient with RTHß led to a misdiagnosis of a TSH-producing tumor and unnecessary surgery. Genetic testing proved pivotal for an accurate diagnosis, suggesting earlier consideration in similar clinical scenarios.

Safety and efficacy of resmetirom in the treatment of patients with non-alcoholic steatohepatitis and liver fibrosis: a systematic review and meta-analysis.

Introduction: Non-alcoholic fatty liver disease (NAFLD), spanning from non-alcoholic steatohepatitis (NASH) to liver fibrosis, poses a global health challenge amid rising obesity and metabolic syndrome rates. Effective pharmacological treatments for NASH and liver fibrosis are limited. Objective: This study systematically reviews and meta-analyzes the safety and efficacy of resmetirom, a selective thyroid hormone receptor-ß agonist, in NASH and liver fibrosis treatment. By analyzing data from clinical trials, we aim to offer evidence-based recommendations for resmetirom's use in managing these conditions and identify avenues for future research. Methods: Electronic databases (PubMed, Scopus, Science Direct, Google Scholar, ClinicalTrials.gov, and Cochrane CENTRAL) were systematically searched, supplemented by manual screening of relevant sources. Only English-language randomized controlled trials were included. Data extraction, risk of bias assessment, pooled analyses, and meta-regression were performed. Results: Three randomized controlled trials involving 2231 participants were analyzed. Resmetirom demonstrated significant reductions in hepatic fat fraction [standardized mean difference (SMD) -4.61, 95% CI -6.77 to -2.44, P < 0.0001], NASH resolution without worsening fibrosis [risk ratio (RR) 2.51, 95% CI 1.74-3.64, P = 0.00001), and liver fibrosis improvement (RR 2.31, 95% CI 1.20-4.44, P = 0.01). Secondary outcomes showed significant improvements in lipid profiles, liver enzymes, and NASH biomarkers with resmetirom treatment. Meta-regression revealed associations between covariates and primary outcomes. Conclusion: Resmetirom exhibits promising efficacy in reducing hepatic fat, improving NASH resolution, and ameliorating liver fibrosis with a favorable safety profile. Further research is warranted to validate findings and optimize therapeutic strategies for NASH and liver fibrosis management.

Comparative efficacy of THR-ß agonists, FGF-21 analogues, GLP-1R agonists, GLP-1-based polyagonists, and Pan-PPAR agonists for MASLD: A systematic review and network meta-analysis.

AIMS: To compare the efficacy of thyroid hormone receptor beta (THR-ß) agonists, fibroblast growth factor 21 (FGF-21) analogues, glucagon-like peptide-1 receptor agonists (GLP-1RAs), GLP-1-based polyagonists, and pan-peroxisome proliferator-activated receptor (Pan-PPAR) agonists in the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS: A database search for relevant randomized double-blind controlled trials published until July 11, 2024, was conducted. Primary outcomes were the relative change in hepatic fat fraction (HFF) and liver stiffness assessed non-invasively by magnetic resonance imaging proton density fat fraction and elastography. Secondary outcomes included histology, liver injury index, lipid profile, glucose metabolism, blood pressure, and body weight. RESULTS: Twenty-seven trials (5357 patients with MASLD) were identified. For HFF reduction, GLP-1-based polyagonists were most potentially effective (mean difference [MD] -51.47; 95 % confidence interval [CI]: -68.25 to -34.68; surface under the cumulative ranking curve [SUCRA] 84.9) vs. placebo, followed by FGF-21 analogues (MD -47.08; 95 % CI: -58.83 to -35.34; SUCRA 75.5), GLP-1R agonists (MD -37.36; 95 % CI: -69.52 to -5.21; SUCRA 52.3) and THR-ß agonists (MD -33.20; 95 % CI: -43.90 to -22.51; SUCRA 36.9). For liver stiffness, FGF-21 analogues were most potentially effective (MD -9.65; 95 % CI: -19.28 to -0.01; SUCRA 82.2) vs. placebo, followed by THR-ß agonists (MD -5.79; 95 % CI: -9.50 to -2.09; SUCRA 58.2), and GLP-1RAs (MD -5.58; 95 % CI: -15.02 to 3.86; SUCRA 54.7). For fibrosis improvement in histology, GLP-1-based polyagonists were most potentially effective, followed by FGF-21 analogues, THR-ß agonists, Pan-PPAR agonists, and GLP-1R agonists; For MASH resolution in histology, GLP-1-based polyagonists were most potentially effective, followed by THR-ß agonists, GLP-1R agonists, FGF-21 analogues, and Pan-PPAR agonists. THR-ß agonists are well-balanced in liver steatosis and fibrosis, and excel at improving lipid profiles; FGF-21 analogues are effective at improving steatosis and particularly exhibit strong antifibrotic abilities. GLP-1R agonists showed significant benefits in improving liver steatosis, glucose metabolism, and body weight. GLP-1-based polyagonists have demonstrated the most potential efficacy overall in terms of comprehensive curative effect. Pan-PPAR agonists showed distinct advantages in improving liver function and glucose metabolism. CONCLUSION: These results illustrate the relative superiority of the five classes of therapy in the treatment of MASLD and may serve as guidance for the development of combination therapies.

Comparative Phenotyping of Mice Reveals Canonical and Noncanonical Physiological Functions of TRα and TRß.

Thyroid hormone (TH) effects are mediated through TH receptors (TRs), TRα1, TRß1, and TRß2. The TRs bind to the DNA and regulate expression of TH target genes (canonical signaling). In addition, they mediate activation of signaling pathways (noncanonical signaling). Whether noncanonical TR action contributes to the spectrum of TH effects is largely unknown. The aim of this study was to attribute physiological effects to the TR isoforms and their canonical and noncanonical signaling. We conducted multiparameter phenotyping in male and female TR knockout mice (TRαKO, TRßKO), mice with disrupted canonical signaling due to mutations in the TR DNA binding domain (TRαGS, TRßGS), and their wild-type littermates. Perturbations in senses, especially hearing (mainly TRß with a lesser impact of TRα), visual acuity, retinal thickness (TRα and TRß), and in muscle metabolism (TRα) highlighted the role of canonical TR action. Strikingly, selective abrogation of canonical TR action often had little phenotypic consequence, suggesting that noncanonical TR action sufficed to maintain the wild-type phenotype for specific effects. For instance, macrocytic anemia, reduced retinal vascularization, or increased anxiety-related behavior were only observed in TRαKO but not TRαGS mice. Noncanonical TRα action improved energy utilization and prevented hyperphagia observed in female TRαKO mice. In summary, by examining the phenotypes of TRα and TRß knockout models alongside their DNA binding-deficient mutants and wild-type counterparts, we could establish that the noncanonical actions of TRα and TRß play a crucial role in modulating sensory, behavioral, and metabolic functions and, thus, contribute to the spectrum of physiological TH effects.

Thyroid Hormone Receptor-ß Agonists in NAFLD Therapy: Possibilities and Challenges.

Nonalcoholic fatty liver disease (NAFLD) is a progressive metabolic liver disease with an unknown pathogenesis and no FDA-approved drug treatment to date. Hypothyroidism has been identified as a risk factor for NAFLD as thyroxine is required for regulating metabolism in adults. Thyroxine has been shown to reduce fat in the livers of murine models with experimentally induced NAFLD. The use of synthetic thyroxine has been shown to increase lipid metabolism leading to weight loss; however, thyroxine has also been shown to cause many side effects, especially in the heart. Overcoming these cardiac side effects involves designing agonists specific to one of the 2 gene subtypes for the thyroid hormone (TH) receptor (TR), TRß. While the other TH receptor subtype, TRα, is mainly expressed in the heart and is responsible for thyroxine's cardiac function, TRß is mainly expressed in the liver and is involved in liver function. Using TRß-specific agonists to treat NAFLD can prevent cardiac and other adverse side effects. Several TRß-specific agonists have shown positive therapeutic effects in NAFLD animal models and have entered clinical trials. We seek to provide a comprehensive updated reference of TRß-specific agonists in this review and explore the future therapeutic potential of TRß-specific activation in the treatment of NAFLD.

Changes in brain structure in subjects with resistance to thyroid hormone due to THRB mutations.

BACKGROUND: Being critical for brain development and neurocognitive function thyroid hormones may have an effect on behaviour and brain structure. Our exploratory study aimed to delineate the influence of mutations in the thyroid hormone receptor (TR) ß gene on brain structure. METHODS: High-resolution 3D T1-weighted images were acquired in 21 patients with a resistance to thyroid hormone ß (RTHß) in comparison to 21 healthy matched-controls. Changes in grey and white matter, as well as cortical thickness were evaluated using voxel-based morphometry (VBM) and diffusion tensor imaging (DTI). RESULTS: RTHß patients showed elevated circulating fT4 & fT3 with normal TSH concentrations, whereas controls showed normal thyroid hormone levels. RTHß patients revealed significantly higher scores in a self-rating questionnaire for attention deficit hyperactivity disorder (ADHD). Imaging revealed alterations of the corticospinal tract, increased cortical thickness in bilateral superior parietal cortex and decreased grey matter volume in bilateral inferior temporal cortex and thalamus. CONCLUSION: RTHb patients exhibited structural changes in multiple brain areas. Whether these structural changes are causally linked to the abnormal behavioral profile of RTHß which is similar to ADHD, remains to be determined.

THRB genetic polymorphisms can predict severe myelotoxicity after definitive chemoradiotherapy in patients with esophageal squamous cell carcinoma.

OBJECTIVE: Chemotherapy-related toxicities are difficult to predict before treatment. In this study, we investigated whether thyroid hormone receptor beta (THRB) genetic polymorphisms can serve as a potential biomarker in patients with esophageal squamous cell carcinoma (ESCC). METHODS: Forty-nine Japanese patients with ESCC who received a definitive chemoradiotherapy (CRT) with 5-fluorouracil and cisplatin in conjunction with concurrent irradiation were retrospectively analyzed. Severe acute toxicities, including leukopenia, stomatitis, and cheilitis, were evaluated according to 6 single nucleotide polymorphisms (SNPs) in the gene; the intronic SNPs of rs7635707 G/T, rs6787255 A/C, rs9812034 G/T, and rs9310738 C/T and the SNPs in the 3'-untranslated region (3'-UTR) of rs844107 C/T and rs1349265 G/A. RESULTS: Distribution of the 4 intronic SNPs, but not the 2 SNPs in the 3'-UTR, showed a significant difference between patients with and without severe acute leukopenia. Stomatitis and cheilitis were not associated with any of the 6 analyzed SNPs. Frequency of haplotype of the 4 intronic SNPs reached approximately 97% with the 2 major haplotypes G-A-G-C (73.4%) and T-C-T-T (23.5%). CONCLUSIONS: THRB intronic SNPs can provide useful information on CRT-related severe myelotoxicity in patients with ESCC. Future studies will be needed to confirm these findings.

Suppression of Calcium Entry Modulates the Expression of TRß1 and Runx2 in Thyroid Cancer Cells, Two Transcription Factors That Regulate Invasion, Proliferation and Thyroid-Specific Protein Levels.

The thyroid hormone receptor beta 1 (TRß1) is downregulated in several human cancer cell types, which has been associated with development of an aggressive tumor phenotype and the upregulation of Runt-related transcription factor 2 (Runx2). In this study, we show that the expression of TRß1 protein is downregulated in human thyroid cancer tissues and cell lines compared with the normal thyroid tissues and primary cell line, whilst Runx2 is upregulated under the same conditions. In contrast, the expression of TRß1 is upregulated, whereas Runx2 is downregulated, in STIM1, Orai1 and TRPC1 knockdown cells, compared to mock transfected cells. To study the functional significance of Runx2 in follicular thyroid cancer ML-1 cells, we downregulated it by siRNA. This increased store-operated calcium entry (SOCE), but decreased cell proliferation and invasion. Moreover, restoring TRß1 expression in ML-1 cells decreased SOCE, basal and sphingosine 1-phosphate (S1P)-evoked invasion, the expression of the promigratory S1P3 receptor and pERK1/2, and at the same time increased the expression of the thyroid specific proteins thyroglobulin, thyroperoxidase, and thyroid transcription factor-1. In conclusion, we show that TRß1 is downregulated in thyroid cancer cells and that restoration of its expression can reverse the cancer cell phenotype towards a normal thyroid cell phenotype.

Atypical Thyroid Function Tests and Thyroid Hormone Resistance.

Clinical interpretation of thyroid labs is usually straightforward. However, there are rare instances when the atypical profile of thyroid labs warrants systematic investigation to determine the underlying cause. We report the case of a 90-year-old Caucasian male with a chronic history of atrial fibrillation with chronic pacemaker dependence who presented with significantly elevated free thyroxine level (>7.77 ng/dL) but normal thyroid-stimulating hormone level (2.15 µIU/mL). After ruling out pituitary tumors and artifactual errors due to lab interference, the diagnosis of thyroid hormone resistance was made.

Acrylamide induces a thyroid allostasis-adaptive response in prepubertal exposed rats.

Some endocrine-disrupting chemicals (EDCs) can affect the endocrine system through covalent interactions with specific sites, leading to deregulation of physiological homeostasis. The acrylamide (AA) present in some fried or baked foods is an example of an electrophile molecule that is able to form adducts with nucleophilic regions of nervous system proteins leading to neurological defects. A positive correlation between increased urinary AA metabolite concentration and reduced levels of thyroid hormones (TH) was described in adolescents and young adults. Thus, this study aimed to evaluate whether AA affects the physiology of the hypothalamus-pituitary-thyroid (HPT) axis and the possible repercussions in peripheral TH-target systems. For this, male Wistar rats were exposed to doses of 2.5 or 5.0 mg AA/Kg/day, based on the LOAEL (Lowest Observed Adverse Effect Level) during prepubertal development. The expression of molecular markers of HPT functionality was investigated in the hypothalamus, pituitary, thyroid, heart and liver, as well as the hormonal and lipid profiles in blood samples. Herein, we showed that AA acts as EDCs for thyroid gland function, increasing the transcript expression of several proteins related to TH synthesis and altering hypothalamus-pituitary-thyroid axis homeostasis, an effect evidenced by the higher levels of THs in the serum. Compensatory mechanisms were observed in TH-target tissues, such as an increase in Dio3 mRNA expression in the liver and a reduction in Mct8 transcript content in the hearts of AA-treated rats. Together, these results pointed out an allostatic regulation of the HPT axis induced by AA and suggest that chronic exposure to it, mainly associated with food consumption, might be related to the higher prevalence of thyroid dysfunctions.

A Novel G385E Variant in the Cold Region of the T3-Binding Domain of Thyroid Hormone Receptor Beta Gene and Investigations to Assess Its Clinical Significance.

BACKGROUND: Resistance to thyroid hormone beta (RTHß) is characterized by elevated thyroid hormone and unsuppressed thyroid-stimulating hormone (TSH), caused by thyroid hormone receptor beta gene (THRB) defects. Most mutations producing RTHß phenotype are located in CG-rich regions of THRB, encoding the T3-binding and hinge domains of the receptor. However, a region encompassing codons 384-425 is virtually devoid of RTHß-causing mutations, termed "cold region." CASE: A 49-year-old woman was diagnosed with Hashimoto thyroiditis in her twenties, and levothyroxine (LT4) was initiated. During LT4 treatment she had slightly elevated free thyroxine and TSH levels, suggesting the possibility of RTHß. RESULTS: Sequencing of THRB identified a heterozygous missense variant c.1154G>A producing p.G385E in the proband. Since this variant of unknown significance (VUS) has not been reported in RTHß individuals and considering its location in the "cold region" of THRB, we questioned its relevance. In silico functional prediction algorithms showed conflicting results: PolyPhen-2 predicted this VUS to be probably damaging with a score of 1.000, while SIFT predicted it to be tolerated with a score of 0.07, thus making additional investigations necessary. Genotyping of family members revealed that the proband's mother and sister, without RTHß phenotype, also harbored the same variant. This indicates that the THRB G385E variant is unlikely to manifest RTHß phenotype and confirms its "cold" status. CONCLUSIONS: This study illustrates that assigning causality of a THRB VUS for RTHß based only on in silico prediction algorithms is not always fully reliable. Additional phenotype-genotype segregation in family members can assist in predicting functional consequences of missense mutations.