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Nonalcoholic fatty liver disease (NAFLD) is a worldwide rising challenge because of hepatic, but also extrahepatic, complications. Thyroid hormones are master regulators of energy and lipid homeostasis, and the presence of abnormal thyroid function in NAFLD suggests pathogenic relationships. Specifically, persons with hypothyroidism feature dyslipidemia and lower hepatic β-oxidation, which favors accumulation of triglycerides and lipotoxins, insulin resistance, and subsequently de novo lipogenesis. Recent studies indicate that liver-specific thyroid hormone receptor β agonists are effective for the treatment of NAFLD, likely due to improved lipid homeostasis and mitochondrial respiration, which, in turn, may contribute to a reduced risk of NAFLD progression. Taken together, the possible coexistence of thyroid disease and NAFLD calls for increased awareness and optimized strategies for mutual screening and management.

Long-term exposure of exogenous compounds to thyroid hormone receptors (TRs) may lead to thyroid dysfunction. Quantitative structure-activity relationship (QSAR) is expected to predicting the binding affinity of compounds to TR. In this work, two comprehensive and large datasets for TRα and TRβ were collected and investigated. Five machine learning models were established to predict the pIC50 of compounds. Meanwhile, the reliability of the models was ensured by a variety of evaluation parameters. The results showed that the support vector regression model exhibited the best robustness and external prediction ability (

We report a patient with congenital hypothyroidism due to athyreosis complicated by a heterozygous thyroid hormone receptor beta (THRβ) gene mutation (R320L), resulting in a severe resistance to thyroid hormone beta phenotype. The proband inherited the mutant allele from his father, presenting a very mild phenotype. While the precise reason for this discrepancy remains unknown, we postulate the possibility of de novo mutation and mosaicism in the father. Correlating thyrotropin (TSH) with free thyroxine (fT4) allowed us to predict the amount of fT4 required to normalize the proband's TSH, which supported the treatment with high dose of levothyroxine.

Resistance to thyroid hormone syndrome (RTHS) is defined as increased thyroxine and triiodothyronine associated with normal or increased thyrotropin. This is usually due to a pathogenic variant of the gene coding for thyroid hormone receptor B (THRB). THRB is a rare genetic disorder characterized by an altered response of target tissue to the thyroid hormone action. Retrospective cross-sectional observational study with diagnosis of RTHS evaluated in secondary and tertiary hospitals for 6 years, from 2014 to 2020, in order to describe variables including age, sex, anthropometric data, clinical and biochemical characteristics of patients, who were divided according to age, in a pediatric group from 0 to 14 years (index cases), and an adult group composed of adult relatives of index cases. A molecular analysis of the THRB gene was performed. The total retrospective cohort included 7 pediatric patients and 15 adults. We found 22 cases with a clear male predominance (14/22). Mean age is 24.8 years old (22 days-70 years). Patients were referred because of symptoms 18.2% (4/22), analysis results 22.7% (5/22), or familial study 59.1% (13/22). About 31.8% (7/22) cases show goiter, 31.8% (7/22) sympathetic symptoms and 13.6% (3/22) abnormalities in behavior. In most cases, 77.3%, (17/22) show familial background of thyroid abnormalities. It is important to remark that 18.2% (4/22) relatives received previous incorrect treatments such as thyroidectomy, because of wrong diagnosis. In conclusion, a better understanding of RTHS, its prompt molecular diagnosis and genetic counseling, could avoid unnecessary tests and inappropriate treatments.

Objective Resistance to thyroid hormone beta (RTHβ) is an inherited syndrome caused by mutations in the thyroid hormone receptor β (THRB) gene. Patients with RTHβ typically have elevated thyroid hormone levels with non-suppressed serum thyroid-stimulating hormone (TSH). We aimed to elucidate the clinical, laboratory, and imaging findings of RTHβ patients and further to explore their association with THRB gene mutations. Design and methods We retrospectively reviewed the clinical charts and compared the clinical findings of 68 RTHβ patients (45 probands and 23 relatives) and 30 unaffected relatives in Kuma Hospital. Results Genetic testing revealed 35 heterozygous THRB gene mutations. Among all RTHβ patients, autoimmune thyroid disease (AITD) was detected in 42.1% of men and 40.9% of women, showing that the prevalence of AITD in affected males was significantly higher than in unaffected relatives (P = 0.019). During the follow-up of 44 patients, 13 patients (29.5%; 8 (42.1%) with AITD and 5 (20%) without AITD) temporarily showed thyroid function test results inconsistent with RTHβ. Two patients with the R383H mutation, which has little dominant-negative effect, temporarily showed normal thyroid hormone and TSH levels without AITD. Conclusions The frequency of AITD in male RTHβ patients was significantly higher compared to unaffected relatives. More than 20% of RTHβ patients temporarily showed laboratory findings atypical of RTHβ during their follow-up, and patients with AITD and specific THRB mutations were prone to display such findings. Therefore, genetic testing should be performed even for patients with fluctuations in thyroid function test results to avoid misdiagnosis and inappropriate treatment.

Background: Pituitary resistance to thyroid hormone (PRTH) is often seen in congenital hypothyroidism (CH), presenting as elevated thyrotropin (TSH) values despite (high-)normal thyroid hormone (TH) values achieved by levothyroxine treatment. In this study, we describe a girl with CH who was referred because of difficulties interpreting thyroid function tests. She was thought to have PRTH associated with CH, but genetic studies discovered a pathogenic variant in THRB, causing resistance to TH (RTH-β). Methods: Clinical, genetic, and biochemical data of the proband's family were collected. Results: The 3-year-old girl was diagnosed with CH due to a homozygous pathogenic c.470del p.(Asn157Thrfs*3) SLC5A5 variant in the neonatal period. She needed a notably high levothyroxine dose to normalize TSH, leading to high free thyroxine levels. There were no signs of hyperthyroidism. Sequencing identified a heterozygous pathogenic c.947G>A p.(Arg316His) THRB variant. Conclusions: To our knowledge, this is the first report of concomitant SLC5A5 and THRB variants causing CH and RTH-β.

The thyroid hormone receptor beta (TRβ) is a tumor suppressor in multiple types of solid tumors, most prominently in breast and thyroid cancer. An increased understanding of the molecular mechanisms by which TRβ abrogates tumorigenesis will aid in understanding the core tumor-suppressive functions of TRβ. Here, we restored TRβ expression in the MDA-MB-468 basal-like breast cancer cell line and perform RNA-sequencing to determine the TRβ-mediated changes in gene expression and associated signaling pathways. The TRβ expressing MDA-MB-468 cells exhibit a more epithelial character as determined by principle component analysis-based iterative PAM50 subtyping score and through reduced expression of mesenchymal cytokeratins. The epithelial to mesenchymal transition pathway is also significantly reduced. The MDA-MB-468 data set was further compared with RNA sequencing results from TRβ expressing thyroid cancer cell line SW1736 to determine which genes are TRβ correspondingly regulated across both cell types. Several pathways including lipid metabolism and chromatin remodeling processes were observed to be altered in the shared gene set. These data provide novel insights into the molecular mechanisms by which TRβ suppresses breast tumorigenesis.

Thyroid hormones (THs) and TH receptor-beta (TRβ) reduce hepatic triglycerides, indicating a therapeutic potential for TH analogs in liver steatosis. To avoid adverse extrahepatic, especially TRα-mediated effects such as tachycardia and bone loss, TH analogs with combined TRβ and hepatocyte specificity are desired. MGL-3196 is a new TH analog that supposedly meets these criteria. Here, we characterize the thyromimetic potential of MGL-3196 in cell-based assays and address its cellular uptake requirements. We studied the contribution of liver-specific organic anion transporters (OATP)1B1 and 1B3 to MGL-3196 action. The TR isoform-specific efficacy of MGL-3196 compared with 3,5,3′-triiodothyronine (T3) was determined with luciferase assays and gene expression analysis in OATP1B1 and OATP1B3 and TRα- or TRβ-expressing cells and in primary murine hepatocytes (PMHs) from wild-type and TRβ knockout mice. We measured the oxygen consumption rate to compare the effects of MGL-3196 and T3 on mitochondrial respiration. We identified OATP1B1 as the primary transporter for MGL-3196. MGL-3196 had a high efficacy (90% that of T3) in activating TRβ, while the activation of TRα was only 25%. The treatment of PMHs with T3 and MGL-3196 at EC50 resulted in a similar induction of Dio1 and repression of Serpina7. In HEK293 cells stably expressing OATP1B1, MGL-3196 had comparable effects on mitochondrial respiration as T3. These data indicate that MGL-3196’s hepatic thyromimetic action, the basis for its therapeutic use, results from a combination of hepatocyte-specific transport by OATP1B1 and the selective activation of TRβ over TRα.

Context Resistance to thyroid hormone β syndrome (RTHβ) is caused by pathogenic variants in the THRB gene, but such variants are found in only 85% of cases. We report the case of a patient with RTHβ phenotype but for whom we found a pathogenic variant of the THRB gene in a mosaic state. Case Description The patient is a 52-year-old woman with clinical and biological signs of RTHβ. Symptoms included asthenia, cardiac palpitations, and diarrhea. Repeated thyroid function tests showed an elevated serum TSH, elevated serum free T4, and variably normal or slightly elevated serum fT3. Pituitary magnetic resonance imaging was normal, and the thyrotropin-releasing hormone test result was compatible with the diagnosis of RTHβ syndrome. Initial Sanger sequencing on blood samples could not highlight the presence of a mosaic variant because of insufficient sensitivity. When next-generation sequencing became accessible, blood samples were retested and we found a known pathogenic variant: c.949G > A; p.(ala317Thr), with an allelic frequency of 12%. Other samples from tissues of different embryological origin were also tested and found an allelic frequency of 5.7%, 17.9%, 9.9%, 6.4%, and 0% on urine tests, oral swab, nasal mucosa swab, skin biopsy, and conjunctival swab, respectively. Cloning confirmed the allelic frequency observed. Conclusions We highlight that a pathogenic variant in a mosaic state in the THRB gene may be the cause of an authentic RTHβ syndrome. High-throughput sequencing of multiple tissues eases the detection of pathogenic variant in a mosaic state and allows the correct diagnosis of patients with true RTHβ, thus avoiding patient mismanagement.

Introduction Breast cancer co-occurred with thyroid cancer might be associated with thyroid hormone receptor (TR) and estrogen receptor (ER), but few have been reported. We aimed to investigate the expression and prognostic significance of ERs and TRs in such settings. Material and methods Tissue microarrays were constructed from 75 patients with breast and thyroid cancer (BC + TC) who were retrospectively recruited between 1999 and 2012 and 147 with breast cancer only (BC controls). The ERα, ERβ, TRα, and TRβ expression levels were analyzed by immunohistochemistry. Results TRα expression was more frequently observed in the BC + TC group than the BC control group both in the normal (51.5% vs 23.3%, respectively, p = 0.009) and cancer tissues (21.6% vs 6.8%, respectively, p = 0.001). The BC + TC group showed greater ERα-positivity in the cancer tissues (79.7% vs 58.7%, respectively, p = 0.002) than the BC control group. The degree of ERα- and TRα-positivity was unchanged by radioactive treatment or serum thyroid stimulating hormone levels. In the BC + TC group, ERα-positivity was associated with earlier disease stage I/IIA (81.0% vs 50.0%; p = 0.031) and lower recurrence rates (8.5% vs 40.0%; p = 0.002). TRα-positivity alone was not associated with any recurrence-free survival-related differences, and ERα- and TRα-negativity were associated with significantly shorter recurrence-free survival (p Conclusion Enhanced ERα and TRα expression in breast cancer is associated with thyroid cancer occurrence, and the observed association with prognosis suggests the possible role of ERs and TRs in the link between breast cancer and thyroid cancer.

AimsWe conducted this study with two aims: (1) whether TRβ could be damaged by NAFLD, thereby represent thyroid hormone resistance-like manifestation and (2) to analyze the potential role of SPP1 in TH signaling pathway on the process of NAFLD. This study is expected to provide a new perspective on the therapeutic mechanism in the pathological course of NAFLD.MethodsA total of 166 patients diagnosed with type 2 diabetes mellitus (T2DM) were enrolled in this study. All patients had a BMI above 24 kg/m2 and were stratified into two groups: NAFLD and Non-NAFLD groups. Ages, gender, BMI, duration of diabetes and biochemical markers were obtained from participants’ records. We downloaded the dataset GSE48452 from GEO. The Pathview library was used to make the thyroid hormone signaling pathway visualization. The CIBERSORT algorithm was applied to calculate the infiltrated immune cells in obese NAFLD patients. C57BL/6 mice were randomly selected to constitute the normal control (NC) group and were fed a normal chow diet; the rest of the mice were fed a high-fat diet (HFD). After 12 weeks HFD feeding, the mice were sacrificed by cervical dislocation, and blood samples were collected. Mouse livers were also collected; one part of each liver was fixed in 10% formalin for histological analysis, and the other part was snap-frozen for subsequent molecular analyses. To explore the relationship between SPP1, TRβ and lipid deposition in hepatocytes, HepG2 cells were treated with 50 μ M concentration of PA and/or 20 ng/ml concentration of rh-SPP1 for 48h. In addition, the PC3.1-TRβ plasmid was constructed for further validation in HepG2 cells. We used THP-1 cells to construct an M1 macrophage model in vitro. We then analyzed THP-1 cells treated with various concentrations of PA or TSH.Results(1) After adjusting for all factors that appeared P value less than 0.1 in the univariate analysis, BMI, TSH, and FT3 were significant independent risk factors of NAFLD (ORs were 1.218, 1.694, and 2.259, respectively); (2) A further analysis with BMI stratification indiacted that both FT3 and TSH had a significant change between individuals with NAFLD and Non-NAFLD in obesity subgroup; however, there was no statistic difference in over-weight group; (3) Bioinformatics analysis of GSE48452 had shown that several key molecular (including TRβ) of thyroid hormone pathway affected by NAFLD induced transcriptomic changes and the expression levels of SPP1, FABP4 and RPS4Y1 were significantly higher, while the expression levels of PZP and VIL1 were significantly decreased in NAFLD patients(adjusted p < 0.05, |logFC| > 1.0). The CIBERSORT algorithm showed increased M0 and M1, decreased M2 macrophage infiltration in NAFLD with comparison to healthy obese group; (4) After 12 weeks of HFD-feeding, the obesity mice had significantly higher serum TSH and In IHC-stained liver sections of obesity group, the intensity of SPP1 had a significantly increased, while TRβ reduced; (5) In vitro studies have shown SPP1 aggravated lipid deposition in hepatic cells dependent on down-regulating the expression of TRβ and TSH acts to promote secretion of SPP1 in M1 macrophage cells.ConclusionsSPP1 secretion induced by M1 macrophage polarization, which may down-regulates TRβ in hepatocytes via paracrine manner, on the one hand, the lipid deposition aggravating in liver, on the other hand, a compensatory increase of TSH in serum. The increased TSH can further lead to the following SPP1 secretion of M1 macrophage. The positive feedback crosstalk between thyroid and liver, may be plays an important role in maintaining and amplifying pathological process of NAFLD.

Bisphenol A (BPA) and its analogs are frequently detected in human daily necessities and environmental media. Placental thyroid hormone plays an important role in fetal development. Herein, we followed the adverse outcome pathway (AOP) to explore the toxic mechanisms of BPA and its analogs toward placental thyroid hormone receptor (TR). First, the TOX21 database was used, and the interactions between BPA analogs and the ligand-binding domains (LBDs) of two subtypes of TR (TRα and TRβ) were subjected to

Background and purpose Activation of hepatic thyroid hormone receptor β (THR-β) is associated with systemic lipid lowering, increased bile acid synthesis, and fat oxidation. In patients with non-alcoholic steatohepatitis (NASH), treatment with THR-β agonists decreased hepatic steatosis and circulating lipids, and induced resolution of NASH. We chose resmetirom (MGL-3196), a liver-directed, selective THR-β agonist, as a prototype to investigate the effects of THR-β activation in mice with diet-induced obesity (DIO) and biopsy-confirmed advanced NASH with fibrosis. Experimental approach C57Bl/6J mice were fed a diet high in fat, fructose, and cholesterol for 34 weeks, and only biopsy-confirmed DIO-NASH mice with fibrosis were included. Resmetirom was administered at a daily dose of 3 mg·kg-1 p.o., for 8 weeks. Systemic and hepatic metabolic parameters, histological non-alcoholic fatty liver disease (NAFLD) activity and fibrosis scores, and liver RNA expression profiles were determined to assess the effect of THR-β activation. Key results Treatment with resmetirom did not influence body weight but led to significant reduction in liver weight, hepatic steatosis, plasma alanine aminotransferase activity, liver and plasma cholesterol, and blood glucose. These metabolic effects translated into significant improvement in NAFLD activity score. Moreover, a lower content of α-smooth muscle actin and down-regulation of genes involved in fibrogenesis indicated a decrease in hepatic fibrosis. Conclusion and implications Our model robustly reflected clinical observations of body weight-independent improvements in systemic and hepatic metabolism including anti-steatotic activity.

Over the last decades, short-chain chlorinated paraffins (SCCPs), medium-chain chlorinated paraffins (MCCPs), and long-chain chlorinated paraffins (LCCPs) have become the most heavily produced monomeric organohalogen compound class of environmental concern. However, knowledge about their toxicology is still scarce, although SCCPs were shown to have effects on the thyroid hormone system. The lack of data in the case of MCCPs and LCCPs and the structural similarity with perfluoroalkyl substances (PFAS) prompted us to test CPs in the novel TTR-TR CALUX assay for their thyroid hormone transport disrupting potential. Four self-synthesized and additionally purified single chain length CP mixtures (C10-CPs, C11-CPs, C14-CPs and C16-CPs) and two each of industrial MCCP and LCCP products were tested in parallel with PFOA. All CP mixtures influenced the TTR binding of T4, giving activities of 1,300 to 17,000 µg/g PFOA equivalents and lowest observable effect concentrations (LOELs) of 0.95 to 0.029 mM/L incubate. Highest activities and lowest LOELs were observed for C16-CPs (48.3% Cl content, activity 17,000, LOEL 0.047 mM/L) and a LCCP mixture (71.7% Cl content; activity 10,000; LOEL 0.029 mM/L). A trend of higher activities and lower LOELs towards longer chains and higher chlorination degrees was implied, but could not be statistically confirmed. Irrespectively, the less well examined and current-use LCCPs showed the highest response in the TTR-TRβ CALUX assay.

Purpose In resistance to thyroid hormone due to mutations in thyroid hormone receptor β, peripheral tissues are variably refractory to the action of circulating thyroid hormones. We evaluated parameters contributing to atherosclerotic risk in this disorder. Methods We measured low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), nonesterified fatty acids (NEFA), intrahepatic lipid (IHL) and intramyocellular lipid (IMCL), Homeostasis-model assessment of insulin resistance (HOMA-IR), augmentation index (AIx) and pulse wave velocity (PWV), flow-mediated dilatation, and carotid intima-media thickness (cIMT) in an unselected, genetically confirmed cohort of adult RTHβ patients (n = 27-77) and compared these with measurements in healthy subjects (up to n = 100) and thyrotoxic patients (n = 40). Results Resistance to thyroid hormone beta (RTHβ) patients exhibited higher LDL-C (P = 0.008) and TG (P = 0.002) and lower HDL-C concentrations (P = 0.015 × 10–2) than control subjects, with LDL-C being higher than in thyrotoxic patients with comparable hyperthyroxinemia. Proprotein convertase subtilisin/kexin 9 (P = 0.002) and apolipoprotein B (P = 0.0009) levels were reduced in thyrotoxic patients but not lower in RTHβ patients or control subjects. Intrahepatic lipid (P = 0.02 × 10–4), IMCL (P = 0.002), HOMA-IR (P = 0.01 × 10–2), and NEFA (P = 0.04 × 10–6) were significantly higher in RTHβ patients than control subjects. Flow-mediated dilatation was increased (P = 0.04) but cIMT (P = 0.71), PWV P = 0.81), and AIx (P = 0.95) were unaltered in RTHβ patients. Conclusions We have documented mixed dyslipidemia with hepatic and IMCL accumulation in RTHβ, suggesting that surveillance for these metabolic abnormalities is warranted. How they combine with enhanced endothelial function and unaltered vessel wall thickness and compliance to determine overall cardiometabolic risk in this disorder remains to be defined.

Thyroid hormone receptors (TRs) play a critical role in human development, growth, and metabolism. Antagonists of TRs offer an attractive strategy to treat hyperthyroidism without the disadvantage of a delayed onset of drug action. While it is challenging to examine the atomistic behavior of TRs in a laboratory setting, computational methods such as molecular dynamics (MD) simulations have proven their value to elucidate ligand-induced conformational changes in nuclear receptors. Here, we performed MD simulations of TRα and TRβ complexed to their native ligand triiodothyronine (T3) as well as several antagonists. Based on the examination of 27 μs MD trajectories, we showed how binding of these compounds influences various structural features of the receptors including the helicity of helices 3 and 10 as well as the location of helix-12. Helices 3 and 12 are known to mediate coactivator association required for downstream signaling, suggesting these changes to be the molecular basis for TR antagonism. A mechanistic analysis of the trajectories revealed an allosteric pathway between H3 and H12 to be responsible for the conformational adaptations. Even though a mechanistic understanding of conformational adaptations triggered by TR antagonists is important for the development of novel therapeutics, they have not been previously examined in detail as it was done here.

Resmetirom (MGL‐3196), a selective thyroid hormone receptor‐β agonist, was evaluated in a 36‐week paired liver biopsy study ({"type":"clinical-trial","attrs":{"text":"NCT02912260","term_id":"NCT02912260"}}NCT02912260) in adults with biopsy‐confirmed nonalcoholic steatohepatitis (NASH). The primary endpoint was relative liver fat reduction as assessed by MRI–proton density fat fraction (MRI‐PDFF), and secondary endpoints included histopathology. Subsequently, a 36‐week active treatment open‐label extension (OLE) study was conducted in 31 consenting patients (including 14 former placebo patients) with persistently mild to markedly elevated liver enzymes at the end of the main study. In patients treated with resmetirom (80 or 100 mg orally per day), MRI‐PDFF reduction at OLE week 36 was −11.1% (1.5%) mean reduction (standard error [SE]; P

Glioma is one of the most common types of primary intracranial tumors. The relationship between triiodothyronine (T3) and glioma is not clear. This study aimed to investigate the effect of T3 on the proliferation of glioma cells and its mechanism. Cell viability was analyzed by cell counting kit 8 assay. Flow cytometry analysis was used to detect cell apoptosis and cell cycle. Thyroid hormone receptor α (THRA) and thyroid hormone receptor β (THRB) were silenced by transfecting si-THRA and si-THRB plasmids into HS683 and A172 glioma cells. Western blot was performed to assess the protein expressions. The results indicated that triiodothyronine (T3) affected the viability, apoptosis and cell cycle of HS683 and A172 glioma cells. Cell apoptosis was significantly inhibited in si-THRA and si-THRB experimental groups. Moreover, knockdown of THRA and THRB reversed the G1 and G2 phase arrest led by T3 and induced an up-regulation of cyclin D1 expression. The phosphorylated extracellular signal-regulated kinase (p-ERK), p-AKT, and phosphorylated signal transducer and activator of transcription (p-STAT3) proteins were markedly increased by inhibiting THRA and THRB in HS683 and A172 glioma cells. T3 affected apoptosis and cell cycle of glioma cells through regulating THRA and THRB expressions. THRA and THRB may affect glioma development through regulating, at least partially, the mitogen-activated protein kinase (MAPK)/ERK and phosphoinositide 3-kinase (PI3K)/Akt signaling pathways.

Activation and/or modulation of the membrane-associated receptors plays a critical role in brain development. Thyroid hormone (TH) acts on both nuclear receptors (thyroid hormone receptor, TR) and membrane-associated receptors, particularly integrin αvβ3 in neurons and glia. Integrin αvβ3-mediated signal transduction mediates various cellular events during development including morphogenesis, migration, synaptogenesis, and intracellular metabolism. However, the involvement of integrin αvβ3-mediated TH action during brain development remains poorly understood. Thus, we examined the integrin αvβ3-mediated effects of TH (T3, T4, and rT3) in the neurons and astrocytes using primary cerebellar culture, astrocyte-enriched culture, Neuro-2A clonal cells, and co-culture of neurons and astrocytes. We found that TH augments dendrite arborization of cerebellar Purkinje cells. This augmentation was suppressed by knockdown of integrin αvβ3, as well as TRα and TRβ. A selective integrin αvβ3 antagonist, LM609, was also found to suppress TH-induced arborization. However, whether this effect was a direct action of TH on Purkinje cells or due to indirect actions of other cells subset such as astrocytes was not clarified. To further study neuron-specific molecular mechanisms, we used Neuro-2A clonal cells and found TH also induces neurite growth. TH-induced neurite growth was reduced by co-exposure with LM609 or knockdown of TRα, but not TRβ. Moreover, co-culture of Neuro-2A and astrocytes also increased TH-induced neurite growth, indicating astrocytes may be involved in neuritogenesis. TH increased the localization of synapsin-1 and F-actin in filopodia tips. TH exposure also increased phosphorylation of FAK, Akt, and ERK1/2. Phosphorylation was suppressed by co-exposure with LM609 and TRα knockdown. These results indicate that TRs and integrin αvβ3 play essential roles in TH-induced dendritogenesis and neuritogenesis. Furthermore, astrocytes-neuron communication via TR-dependent and TR-independent signaling through membrane receptors and F-actin are required for TH-induced neuritogenesis.

The design and development of agonists selectively targeting thyroid hormone receptor β (TRβ) and TRβ mutants remain challenging tasks. In this study, we first adopted the strategy of breaking the "His-Phe switch" to solve two problems, simultaneously. A structure-based design approach was successfully utilized to obtain compound

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 (TRβ) has anti-proliferative and tumor-suppressive effects in many cancer cells. Therefore, we decided to investigate thyroid hormone receptor beta (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 andOur results showed that specific activation of TRβ by GC-1 had negative effect on tumor growth and restored its gene expression in tumors of CRC mice model.

Background Colorectal cancer is common among obese individuals. The purpose of the current study was to determine changes in DNA methylation status and mRNA expression of thyroid hormone receptor beta (THRB), as a tumor suppressor, and thyroid hormone inactivating enzyme, type 3 deiodinase (DIO3) genes, in human epithelial colon tissues of healthy obese individuals. Methods Colon biopsies were analyzed by methylation sensitive-high resolution melting (MS-HRM) to investigate promoter methylation of DIO3 and THRB, and by quantitative real-time polymerase chain reaction to assay expression of DIO3 and THRB mRNA on eighteen obese and twenty-one normal-weight healthy men. Results There was no significant difference in mean methylation levels at the THRB promoter region between the two groups. Nevertheless, obesity decreased THRB expression levels, significantly (P P DIO3 (P Conclusions Our findings suggest that obesity may alter expression of THRB and DIO3 genes through epigenetic mechanism. Alterations of THRB and DIO3 expressions may predispose colon epithelium of obese patients to neoplastic transformation.

Cellular thyroid hormone homeostasis requires adequate function of: (1) thyroid hormone transporter proteins at the plasma membrane, (2) deiodinating enzymes and (3) nuclear thyroid hormone receptors (TRs). Defects in any of these processes give rise to distinct disease entities, collectively called thyroid hormone signaling disorders. Thyroid hormone analogues hold therapeutic potential in thyroid hormone signaling disorders by bypassing defective transporters or binding to mutant TRs. This review will focus on the application of analogues in thyroid hormone signaling disorders, particularly monocarboxylate transporter (MCT)8 deficiency, and resistance to thyroid hormone due to mutations in TRβ (RTHβ)

Thyroid hormones exert their action by binding to their thyroid hormone receptors among other mechanisms. They are involved in different cardiac functions, including contractility and rhythm. The mutation of thyroid hormone receptor β is the main cause of thyroid hormone resistance. The cardiac phenotype of mutated patients has been studied in several cohorts of patients with different mutations. Tachycardia, palpitation and cardiac arrhythmia frequently appear; atrial flutter/fibrillation is found in up to 20%. Cardiac systolic and diastolic functions are impaired compared to hyperthyroid or euthyroid subjects, but cases of heart failure have not been reported. No correlation between genotype and cardiac phenotype has been found. Patients with a mutation of thyroid hormone receptor α frequently present bradycardia and systolic and diastolic functions that are similar to those of hypothyroid subjects. Levothyroxine treatment partly improves these parameters.

We developed a thyroid testing panel to assess endocrine disrupting chemicals (EDCs) capacities to bind either the thyroid receptor β (TRβ) or the thyroid hormones transporter transthyretin (TTR). We first stably transfected a human U2OS cell line with TRβ and a luciferase reporter construct to develop the TRβ CALUX® reporter gene assay to assess chemicals’ potential to interact with TRβ. Secondly, we combined a TTR-binding assay with the TRβ CALUX (TTR-TRβ CALUX) and optimized the system to evaluate the competitive properties of EDCs towards T4 for TTR binding. Both systems were evaluated with a range of known thyroid-disrupting compounds. The agonistic/antagonistic TRβ CALUX successfully predicted 9/9 and 9/12 test compounds, respectively. The TTR-TRβ CALUX predicted 9/9 compounds and demonstrated competitive activities when analyzing waste water samples. We concluded that the proposed test battery is a promising screening method able to efficiently generate data on thyroid hormone interferences by chemicals.

Background: Thyroid hormone (TH) action is mediated by three major thyroid hormone receptor (THR) isoforms α1, β1, and β2 (THRA1, THRB1, and THRB2). These THRs and a fourth major but non-TH binding isoform, THRA2, are encoded by two genes Thra and Thrb. Reliable antibodies against all THR isoforms are not available, and THR isoform protein levels in mammalian tissues are often inferred from messenger RNA (mRNA) levels. Methods: We generated knock-in mouse models expressing endogenously and identically 2X hemagglutenin epitope (HA)-tagged THRs (THRA1/2, THRB1, and THRB2), which could then be detected by commercially available anti-HA antibodies. Using nuclear enrichment, immunoprecipitation, and Western blotting, we determined relative THR protein expression in 16 mouse organs. Results: In all peripheral organs tested except the liver, the predominant THR isoform was THRA1. Surprisingly, in metabolically active organs such as fat and muscle, THRB1 protein levels were up to 10 times lower than that of THRA1, while their mRNA levels appeared similar. In contrast to peripheral organs, the central nervous system (CNS) had a unique pattern with relatively low levels of both THRB1 and THRA1, and high levels of THRA2 expression. As expected, THRB2 was highly expressed in the pituitary, but a previously unknown sex-specific difference in THRB2 expression was found (female mice having higher pituitary expression than male mice). Higher THRB2 expression appears to make the central axis more sensitive to TH as both serum thyrotropin and Tshb mRNA levels were lower in female mice. Conclusions: Direct comparison of THR protein abundance in different organs using endogenously tagged HA-THR mouse lines shows that expression of THR isoforms is regulated at transcriptional and posttranscriptional levels, and in organ-specific manner. The prevalence of THRA1 and low abundance of THRB1 in majority of peripheral tissues suggest that peripheral actions of these isoforms should be revisited. A unique pattern of high THRA2 in CNS warrants further exploration of this non-TH binding isoform in brain development. Finally, THRB2, in addition to cell-specific control, is also regulated in a sex-specific manner, which may change the hypothalamus–pituitary–thyroid axis set point and perhaps metabolism in males and females.

Background: Pathological conditions of the thyroid hormone (TH) system are routinely diagnosed by using serum concentrations of thyrotropin (TSH), which is sufficient in most cases. However, in certain conditions, such as resistance to TH due to mutations in THRB (RTHb) or TSH-releasing pituitary adenoma (TSHoma), TSH may be insufficient for a correct diagnosis, even in combination with serum TH concentrations. Likewise, under TH replacement therapy, these parameters can be misleading and do not always allow optimal treatment. Hence, additional biomarkers to assess challenging clinical conditions would be highly beneficial. Methods: Data from untargeted multi-omics analyses of plasma samples from experimental thyrotoxicosis in human and mouse were exploited to identify proteins that might represent possible biomarkers of TH function. Subsequent mouse studies were used to identify the tissue of origin and the involvement of the two different TH receptors (TR). For in-depth characterization of the underlying cellular mechanisms, primary mouse cells were used. Results: The analysis of the plasma proteome data sets revealed 16 plasma proteins that were concordantly differentially abundant under thyroxine treatment compared with euthyroid controls across the two species. These originated predominantly from liver, spleen, and bone. Independent studies in a clinical cohort and different mouse models identified CD5L as the most robust putative biomarker under different serum TH states and treatment periods. In vitro studies revealed that CD5L originates from proinflammatory M1 macrophages, which are similar to liver-residing Kupffer cells, and is regulated by an indirect mechanism requiring the secretion of a yet unknown factor from hepatocytes. In agreement with the role of TRα1 in immune cells and the TRβ-dependent hepatocyte-derived signaling, the in vivo regulation of Cd5l expression depended on both TR isoforms. Conclusion: Our results identify several novel targets of TH action in serum, with CD5L as the most robust marker. Although further studies will be needed to validate the specificity of these targets, CD5L seems to be a promising candidate to assess TH action in hepatocyte-macrophage crosstalk.

Among the inheritable forms of impaired sensitivity to thyroid hormone, resistance to thyroid hormone (RTH) due to mutations in the thyroid hormone receptor beta gene (THRB) is the first and best known described defect, revealing a wide phenotypic variability with an incompletely understood physiopathology. The objective of this study was to evaluate two novel mutations in THRB, N331H and L346R, in an attempt to provide a rational understanding of the harmful effects caused by them. The mutations of two patients with RTHβ were reproduced for analysis of gene transactivation by dual-luciferase reporter assay, and for molecular modeling for crystallography-based structural assessment. Serum measurements of TSH and FT4 were performed to compare the thyrotrophic resistance to thyroid hormone between RTHβ patients and controls. Both mutants showed impaired gene transactivation, with greater damage in L346R. Molecular modeling suggested that the damage occurring in N331H is primarily due to reduced strength of the hydrogen bonds that stabilize T3 in its ligand-binding cavity (LBC), whereas in L346R, the damage is more marked and is mainly due to changes in hydrophobicity and molecular volume inside the LBC. Hormonal dosages indicated that the L346R mutant exhibited greater thyrotrophic resistance than N331H. This study provides a rational understanding of the effects of mutations, indicating deleterious structural changes in the LBC in both THR, and discloses that not only the position of the mutation but, notably, the nature of the amino acid exchange, has a cardinal role in the functional damage of the receptor.

[Background]: A subpopulation of cancer stem cells (CSCs) with capacity for self-renewal is believed to drive initiation, progression, and relapse of breast tumors., [Methods]: Since the thyroid hormone receptor β (TRβ) appears to suppress breast tumor growth and metastasis, we have analyzed the possibility that TRβ could affect the CSC population using MCF-7 cells grown under adherent conditions or as mammospheres, as well as inoculation into immunodeficient mice., [Results]: Treatment of TRβ-expressing MCF-7 cells (MCF7-TRβ cells) with the thyroid hormone triiodothyronine (T3) decreased significantly CD44+/CD24− and ALDH+ cell subpopulations, the efficiency of mammosphere formation, the self-renewal capacity of CSCs in limiting dilution assays, the expression of the pluripotency factors in the mammospheres, and tumor initiating capacity in immunodeficient mice, indicating that the hormone reduces the CSC population present within the bulk MCF7-TRβ cultures. T3 also decreased migration and invasion, a hallmark of CSCs. Transcriptome analysis showed downregulation of the estrogen receptor alpha (ERα) and ER-responsive genes by T3. Furthermore, among the T3-repressed genes, there was an enrichment in genes containing binding sites for transcription factors that are key determinants of luminal-type breast cancers and are required for ER binding to chromatin., [Conclusion]: We demonstrate a novel role of TRβ in the biology of CSCs that may be related to its action as a tumor suppressor in breast cancer., We acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI)., This work was supported by grants BFU2014-53610-P (MINECO, AEI, FEDER, UE), CIBERONC CB/16/00228, and SAF2017-90604-REDT (Spanish Ministry of Economy and Competitiveness), and B2017/BMD-3724 (Comunidad de Madrid). The cost of this publication has been paid, in part, by FEDER funds.

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.

Context 3,5,3’-L-triiodothyronine (T3) is a potent inducer of hepatocyte proliferation via the Wnt/β-catenin signaling pathway. Previous studies suggested the involvement of rapid noncanonical thyroid hormone receptor (TR) β signaling, directly activating hepatic Wnt/β-catenin signaling independent from TRβ DNA binding. However, the mechanism by which T3 increases Wnt/β-catenin signaling in hepatocytes has not yet been determined. Objective We aimed to determine whether DNA binding of TRβ is required for stimulation of hepatocyte proliferation by T3. Methods Wild-type (WT) mice, TRβ knockout mice (TRβ KO), and TRβ mutant mice with either specifically abrogated DNA binding (TRβ GS) or abrogated direct phosphatidylinositol 3 kinase activation (TRβ 147F) were treated with T3 for 6 hours or 7 days. Hepatocyte proliferation was assessed by Kiel-67 (Ki67) staining and apoptosis by terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. Activation of β-catenin signaling was measured in primary murine hepatocytes. Gene expression was analyzed by microarray, gene set enrichment analysis (GSEA), and quantitative reverse transcription polymerase chain reaction. Results T3 induced hepatocyte proliferation with an increased number of Ki67-positive cells in WT and TRβ 147F mice (9.2% ± 6.5% and 10.1% ± 2.9%, respectively) compared to TRβ KO and TRβ GS mice (1.2% ± 1.1% and 1.5% ± 0.9%, respectively). Microarray analysis and GSEA showed that genes of the Wnt/β-catenin pathway—among them, Fzd8 (frizzled receptor 8) and Ctnnb1 (β-catenin)—were positively enriched only in T3-treated WT and TRβ 147F mice while B-cell translocation gene anti-proliferation factor 2 was repressed. Consequently, expression of Ccnd1 (CyclinD1) was induced. Conclusions Instead of directly activating Wnt signaling, T3 and TRβ induce key genes of the Wnt/β-catenin pathway, ultimately stimulating hepatocyte proliferation via CyclinD1. Thus, canonical transcriptional TRβ action is necessary for T3-mediated stimulation of hepatocyte proliferation.

Hydroxylated polybrominated diphenyl ethers (OH-PBDEs) have been identified as the strong endocrine disrupting chemicals to humans, which show structural similarity with endogenous thyroid hormones (THs) and thus disrupt the functioning of THs through competitive binding with TH receptors (TRs). Although previous studies have reported the hormone activities of some OH-PBDEs on TH receptor β (TRβ), the interaction mechanism remains unclear. Furthermore, hydroxyl dissociation of OH-PBDEs may alter their TR disrupting activities, which has not yet been investigated in depth. In this work, we selected 18 OH-PBDEs with neutral and anionic forms and performed molecular dynamics (MD) simulations to estimate their binding interactions with the ligand binding domain (LBD) of TRβ. The results demonstrate that most of OH-PBDEs have stronger binding affinities to TRβ-LBD than their anionic counterparts, and the hydroxyl dissociation of ligands differentiate the major driving force for their binding. More Br atoms in OH-PBDEs can result in stronger binding potential with TRβ-LBD. Moreover, 5 hydrophobic residues, including Met313, Leu330, Ile276, Leu346, and Phe272, are identified to have important contributions to bind OH-PBDEs. These results clarify the binding mechanism of OH(O

Transcriptional regulation in response to thyroid hormone (T3) is a dynamic and cell-type specific process that maintains cellular homeostasis and identity in all tissues. However, our understanding of the mechanisms of thyroid hormone receptor (TR) actions at the molecular level are actively being refined. We used an integrated genomics approach to profile and characterize the cistrome of TRβ, map changes in chromatin accessibility, and capture the transcriptomic changes in response to T3in normal thyroid cells. There are significant shifts in TRβ genomic occupancy in response to T3, which are associated with differential chromatin accessibility, and differential recruitment of SWI/SNF chromatin remodelers. We further demonstrate selective recruitment of BAF and PBAF SWI/SNF complexes to TRβ binding sites, revealing novel differential functions in regulating chromatin accessibility and gene expression. Our findings highlight three distinct modes of TRβ interaction with chromatin and coordination of coregulator activity.

The influence of temperature (25 and 32 °C) on the negative effects of the herbicide tebuthiuron (TBU, 0, 10, 50 and 200 ng.L-1, 16 days) on thyroid function and metamorphosis of Lithobates catesbeianus tadpoles was evaluated. Metamorphosis was accelerated by TBU exposure at 25 ºC, but delayed at 32 ºC with considerable losses of body mass. T3 and T4 levels were not altered. The highest TBU concentrarion at 25 ºC increased TR β and DIO3 transcript levels, which is consistent with development acceleration in tadpoles. At 32 ºC TR β transcript levels were lower than the values recorded at 25 ºC, and those tadpoles exposed to the highest TBU concentration presented increased diameter of thyroid follicles compared to controls at same temperature. This study evidences that TBU at environmentally realistic concentrations is able to disrupt thyroidogenesis in bullfrog tadpoles, impairing their development. These effects are influenced by temperature.

Background Over the last decade, per- and polyfluoroalkyl substances (PFASs) have become one of the most heavily investigated persistent organohalogen compound class of environmental concern. However, knowledge about their toxicology is still scarce, although PFASs as individual compounds and their industrial mixtures were shown to exert effects on the thyroid hormone system. Methods In vitro toxicity potency factors were established for thyroid hormone transport disruption potential using the novel TTR-TRβ CALUX® bioassay for major PFASs. We assessed technical PFASs mixtures, including aqueous film-forming foam (AFFF) surfactants and chromium mist suppressants (CMS) applications with and without total oxidizable precursor (TOP) by TTR-TRβ CALUX® assay for their thyroid hormone transport disrupting potential. Results All PFASs listed in the German guideline for drinking water (German Environment Agency, 2017) affected the T4 binding to TTR, an important plasma thyroid hormone transport protein. For all tested PFASs, potency factors based on PC80 values relative to PFOA could be obtained and ranged between PFBA (0.0018) and PFOS (2.0). Applying in vitro potency factors obtained from the present in vitro TTR-TRβ CALUX® assay study and recently reported in vivo potency factors (Zeilmaker et al., 2018; Bil et al., 2021) on the above-mentioned German guideline for PFAS in drinking water, showed that the cumulative effect-based trigger values (in vivo and in vitro) are comparable (3.0 vs. 2.9 to 4.6 μg PFOA-EQ/l). Additionally, AFFF surfactants and CMS with and without TOP assay were tested. Highest activities were found in the older AFFF surfactants (2013/2014) due to higher PFOS/PFOA levels, which were already substituted with 6:2 FTS in 2019, resulting in much lower PFOA-EQ levels. As expected also the PFOA-EQ levels increased in the samples with TOP treatment compared to the original AFFF surfactants and CMS as confirmed here by biological and chemical PFOA-equivalents (PFOA-EQ) analysis. Additionally, CMS (which have been used in the electroplating chromium industry since the 1950s) as well as PFOS-free, but not PFAS-free fume suppressants (such as Fumetrol® 21) have been tested in the TTR-TRβ CALUX® assay and showed much lower activity levels then the AFFFs, confirmed by the similar potency determination based on chemical PFASs analysis followed by transformation to PFOA-EQ for comparison. The potency factor of 6:2 FTS, which is the main substitute for PFOS in CMS, indicates that it is approximately 100-times less potent as a thyroid hormone disruptor as compared to PFOS. Conclusion Potency factors based on PC80 values from TTR-TRβ CALUX® relative to PFOA have been developed for major PFASs. In AFFF surfactants and CMS a trend of higher activities with higher amounts of PFOS and PFOA have been found. PFOA and PFOS showed high responses in the TTR-TRβ CALUX® assay and had the largest contributions to the PFOA-EQs in the AFFF surfactants and CMS applications. Using potency factors as determined in the TTR-TRβ CALUX® to convert PFASs assessed by chemical analysis to PFOA-EQ led to comparable results as compared to the results from PFASs measured directly by the TTR-TRβ CALUX® assay. This study supports the claim that semiquantitative effect- and group-based in vitro CALUX bioanalysis tools can be applied effectively to assess industrial products containing complex mixtures with PFAS compounds for which no instrumental analysis are established, and for many compounds where in vitro toxicity data are not yet available.

Background Post-translational modification (PTM) of proteins controls various cellular functions of transcriptional regulators and participates in diverse signal transduction pathways in cancer. The thyroid hormone (triiodothyronine, T3) plays a critical role in metabolic homeostasis via its direct interaction with the thyroid hormone receptor beta (TRβ). TRβ is involved in physiological processes, such as cell growth, differentiation, apoptosis, and maintenance of metabolic homeostasis through transcriptional regulation of target genes. Objective This study was performed to characterize the specific PTM of TRβ is an active control mechanism for the proteasomal degradation of TRβ in transcriptional signaling pathways in hepatocellular carcinoma cells. Methods Based on a previous study, we predicted that the lysine methyltransferase and methylation sites of TRβ by comparing the amino acid sequences of histone H3 and TRβ. Methyl-acceptor site of TRβ was confirmed by point mutation. TRβ protein stability was evaluated by ubiquitination assay with MG132. For glucose starvation, HepG2 cells were incubated in media without D-glucose. Proliferation-related proteins were detected by western blotting. MicroRNA level and autophagy marker were measured by real-time qPCR. Results The presence of enhancer of zeste homolog 2 (Ezh2), a methyltransferase of H3 lysine 27, as a methyltransferase of TRβ also revealed that direct lysine methylation and consequent stimulated protein degradation of TRβ underlies the negative correlation between Ezh2 and TRβ. Notably, glucose starvation significantly increased lysine methylation, and methylated TRβ showed further protein instability leading to an increase in the proliferation and growth of hepatocellular carcinoma cells. Conclusions TRβ functions as a tumor suppressor in various cancers; therefore, we evaluated the effect of TRβ degradation on oncogenesis during glucose starvation. These data clearly define a functional model and provide a link between metabolism and cancer by regulating methyl-dependent protein levels of tumor suppressors. Taken together, maintaining TRβ against methyl-dependent degradation is considered a possible therapeutic target for cancer progression.

Thyroid hormones (THs) are powerful regulators of metabolism with major effects on body weight, cholesterol, and liver fat that have been exploited pharmacologically for many years. Activation of gene expression by TH action is canonically ascribed to a hormone-dependent “switch” from corepressor to activator binding to thyroid hormone receptors (TRs), while the mechanism of TH-dependent repression is controversial. To address this, we generated a mouse line in which endogenous TRβ1 was epitope-tagged to allow precise chromatin immunoprecipitation at the low physiological levels of TR and defined high-confidence binding sites where TRs functioned at enhancers regulated in the same direction as the nearest gene in a TRβ-dependent manner. Remarkably, although positive and negative regulation by THs have been ascribed to different mechanisms, TR binding was highly enriched at canonical DR4 motifs irrespective of the transcriptional direction of the enhancer. The canonical NCoR1/HDAC3 corepressor complex was reduced but not completely dismissed by TH and, surprisingly, similar effects were seen at enhancers associated with negatively as well as positively regulated genes. Conversely, coactivator CBP was found at all TH-regulated enhancers, with transcriptional activity correlating with the ratio of CBP to NCoR rather than their presence or absence. These results demonstrate that, in contrast to the canonical “all or none” coregulator switch model, THs regulate gene expression by orchestrating a shift in the relative binding of corepressors and coactivators.

Progestin resistance is a major obstacle to conservative therapy in patients with endometrial cancer (EC) and endometrial atypical hyperplasia (EAH). However, the related inducing factor is yet unclear. In this study, thyroid hormone and its receptor α (TRα) and β (TRβ) of patients were assayed. THRB-silenced RL95-2 and KLE EC cells were cultured to investigate the response of progestins. Transcriptomics and Western blotting were performed to investigate the changes in signaling pathways. We found that THRB, rather than THRA, knockdown promoted the viability and motilities of RL95-2 cells but not KLE cells. The suppressive effect of progestins on cell growth and motility significantly decreased in THRB-silenced RL95-2 cells. Multiple proliferation-related signaling pathways were enriched, and the activities of mammalian targets of rapamycin (mTOR)/4e-binding protein 1 (4EBP1)/eukaryotic translation initiation factor 4G (eIF4G) rather than phosphorylated protein kinase B (Akt) were remarkably boosted. Progestin treatment enhanced the effects, and the augmentation was partially abated on supplementation with T3. In THRB-knockdown KLE cells, the progestins-activated partial signaling pathway expression (either mTOR or eIF4G), and supplementation with T3 did not induce noticeable alterations. The serum levels of triiodothyronine (T3) were significantly lower in patients with EC compared with healthy women. A strong expression of TRβ was observed in most patients with EC and EAH sensitive to progestin treatment. In contrast, TRα positive expression was detected in less than half of the patients sensitive to progestin therapy. In conclusion, THRB knockdown enhanced the viability and motility of type I EC cells and attenuated the suppressive effects of progestins by activating the mTOR-4EBP1/eIF4G pathway. Lower expression of THRB is likely correlated with progesterone resistance.