Thyroid Hormone Receptor Research Articles

Structural insights into thyroid hormone receptors.

Thyroid hormone receptors (TRs) are essential components of the endocrine system, mediating the cellular effects of thyroid hormones. The two TR genes, THRA and THRB, encode four isoforms, with TRα1 and TRβ1 being the most prevalent. TRs are ligand-dependent transcription factors and members of the nuclear receptor superfamily, indispensable for human growth, development and metabolism. Dysfunctional TR signaling can lead to conditions like resistance to thyroid hormone (RTH) syndrome, thyroid cancer, and metabolic disorders. Structurally, TRs comprise several domains: a variable N-terminal domain, a conserved DNA-binding domain, and a ligand-binding domain that mediates interaction with hormones and transcriptional coregulators. TRs predominantly function as heterodimers with the retinoid X receptor (RXR), binding to thyroid hormone response elements (TREs) in target genes to regulate their transcription. This review examines the structural studies on TRs, primarily performed through X-ray crystallography, that have provided detailed insights into TR functions, including DNA recognition, ligand binding, and coregulator interactions. We also discuss how these findings have deepened our understanding of TR mechanisms and contributed to the interpretation of pathogenic mutations.

EXTH-50. THYROID HORMONE-INDUCED DIFFERENTIATION: A PROMISING THERAPEUTIC STRATEGY FOR MEDULLOBLASTOMA

Abstract Medulloblastoma (MB) is the most common malignant brain tumor in children, consisting of four major subgroups (WNT, SHH, Group 3, and Group 4) that differ in genetic/epigenetic profiles and prognoses. Despite current therapy, a significant proportion of patients still succumb to MB. Moreover, survivors often suffer severe side effects from aggressive treatments. Therefore, improved strategies to treat MB are urgently needed. MB tumor cells retain the capacity for differentiation and can undergo terminal differentiation, after which they lose their proliferative and tumorigenic capacity. This suggests that MB can potentially be treated by inducing tumor cell differentiation. However, the mechanisms underlying MB tumor cell differentiation remain unclear. Our recent studies reveal that thyroid hormone (TH) plays a critical role in promoting tumor cell differentiation in MB. Reduced TH levels free the TH receptor, TRα1, to bind to EZH2 and repress the expression of NeuroD1, a transcription factor that drives tumor cell differentiation. Increased TH levels reverse the EZH2-mediated repression of NeuroD1 by disrupting the binding between EZH2 and TRα1, thereby stimulating tumor cell differentiation and reducing MB growth. Importantly, triiodothyronine (T3, active form of TH) inhibits the growth of both SHH- and Group 3 tumors, suggesting that the tumor-inhibitory effect of T3 is not restricted by MB subgroups. Additionally, this effect is significantly enhanced by concurrent chemotherapy. These findings establish an unprecedented association between TH signaling and MB pathogenicity, providing solid evidence for TH as a promising therapeutic modality for MB treatment.

Neurodevelopment delay as the initial presentation of thyroid hormone resistance syndrome

Thyroid hormone (TH) resistance syndrome is a genetic disorder usually caused by a defect in TH receptors. Moreover, transport and intracellular metabolism alterations have also been described. This case report presents a child with Allan–Herndon–Dudley syndrome characterized by a mutation on the X-linked monocarboxylate transporter 8 gene, a condition that affects the transport of THs across the cell membrane, leading to hypothyroidism in the central nervous system and hyperthyroidism in peripheral tissues, causing severe neurodevelopmental delay manifesting as generalized hypotonia from birth. The utility of monitoring thyroid functions, genetic testing, and triiodothyroacetic acid in the management is highlighted.

Breast cancer cells utilize T3 to trigger proliferation through cellular Ca2+ modulation

High levels of thyroid hormones are linked to increased risk and advanced stages of breast cancer. Our previous work demonstrated that the biologically active triiodothyronine (T3) facilitates mitochondrial ATP production by upregulating Ca2+ handling proteins, thereby boosting mitochondrial Ca2+ uptake and Krebs cycle activity. In this study, different cell types were utilized to investigate whether T3 activates a Ca2+-induced signaling pathway to boost cancer cell proliferation. Using live-cell imaging, biochemical assays, and molecular profiling, differences in intracellular signaling among MCF7 and MDA-MB-468 breast cancer cells, non-cancerous breast cells hTERT-HME1, and PC3 prostate carcinoma cells, previously found to be insensitive to thyroid hormones in terms of proliferation, were investigated. Our findings revealed that T3 upregulates 1,4,5-trisphosphate receptor 3 via thyroid hormone receptor α. This boosts mitochondrial Ca2+ uptake, reduction equivalent yield, and mitochondrial ATP production, supporting the viability and proliferation of breast cancer cells without affecting non-cancerous hTERT-HME1 or PC3 prostate carcinoma cells. Understanding the interplay between T3 signaling, organellar interaction, and breast cancer metabolism could lead to targeted therapies that exploit cancer cell vulnerabilities. Our findings highlight T3 as a crucial regulator of cancer metabolism, reinforcing its potential as a therapeutic target in breast cancer.Graphical

Nonylphenol and Cetyl Alcohol Polyethoxylates Disrupt Thyroid Hormone Receptor Signaling to Disrupt Metabolic Health.

Surfactants are molecules with both hydrophobic and hydrophilic structural groups that adsorb at the air-water or oil-water interface and serve to decrease the surface tension. Surfactants combine to form micelles that surround and break down or remove oils, making them ideal for detergents and cleaners. Two of the most important classes of nonionic surfactants are alkylphenol ethoxylates (APEOs) and alcohol ethoxylates (AEOs). APEOs and AEOs are high production-volume chemicals that are used for many industrial and residential purposes, including laundry detergents, hard-surface cleaners, paints, and pesticide adjuvants. Commensurate with better appreciation of the toxicity of APEOs and the base alkylphenols, use of AEOs has increased, and both sets of compounds are now ubiquitous environmental contaminants. We recently demonstrated that diverse APEOs and AEOs induce triglyceride accumulation and/or pre-adipocyte proliferation in vitro. Both sets of contaminants have also been demonstrated as obesogenic and metabolism disrupting in a developmental exposure zebrafish model. While these metabolic health effects are consistent across models and species, the mechanisms underlying these effects are less clear. This study sought to evaluate causal mechanisms through reporter gene assay assessments, relative binding affinity assays, co-exposure experiments, and use of both human cell and zebrafish models. We report that antagonism of thyroid hormone receptor signaling appears to mediate at least a portion of the polyethoxylate-induced metabolic health effects. These results suggest further evaluation is needed, given the ubiquitous environmental presence of these thyroid disrupting contaminants and reproducible effects in human cell models and vertebrate animals.

Thyroid and growth hormone endocrine disruption and mechanisms of homosalate and octisalate using wild-type, thrαa-/-, and dre-miR-499-/- zebrafish embryo/larvae

Homosalate (HS) and octisalate (OS), which are used in sunscreen for the purpose of blocking ultraviolet rays, are frequently detected in water environment. Although effects on estrogens and androgens have been reported, studies on thyroid and growth hormone endocrine disruption are limited. In the present study, larval mortality was compared in wild-type and two knockout fish (thyroid hormone receptor alpha a knockout (thrαa-/-) and dre-miR-499 knockout (dre-miR-499-/-)) after 96 h of exposure to HS and OS (0, 0.003, 0.03, 0.3, 3, 30 and 300 µg/L). To investigate the mechanisms of thyroid and growth hormone endocrine disruption, we measured the levels of triiodothyronine (T3), thyroxine (T4), thyroid stimulating hormone (TSH), growth hormone (GH), and insulin-like growth factor-1 (IGF-1), and the regulation of representative genes related to the hypothalamus-pituitary-thyroid (HPT) and GH/IGF axis in wild-type zebrafish exposed to target chemicals. The significantly lower larval survival rate of thrαa-/- and dre-miR-499-/- fish exposed to 300 μg/L of HS and OS suggest that thyroid hormone receptors and dre-miR-499 play a crucial role in the toxic effects of HS and OS. The finding of a significant increase in T3 and T4 in zebrafish larvae exposed to HS and OS supports a significant decrease in the crh gene. The reduction of GH and IGF-1 in fish exposed to HS and OS is well supported by the regulation of genes involved in the GH/IGF axis. Our observations suggest that exposure to HS and OS affects not only thyroid hormone receptors and their associated miRNAs, but also the feedback routes of HPT and GH/IGF axes, ultimately leading to growth reduction.

A comprehensive evaluation of the endocrine-disrupting effects of emerging organophosphate esters

The ubiquitous presence of organophosphate esters (OPEs) in the environment has prompted growing concerns about their potential health risks, particularly their endocrine-disrupting effects. This study comprehensively evaluated the endocrine-disrupting properties of six emerging OPEs: five aryl-OPEs (2-ethylhexyl diphenyl phosphate (EHDPP), tris (2-biphenylyl) phosphate (TBPP), resorcinol bis (diphenyl phosphate) (RDP), 4-hydroxyphenyl diphenyl phosphate (para-OH-TPHP), and 3-hydroxyphenyl diphenyl phosphate (meta-OH-TPHP)) and one alkyl-OPE, triallyl phosphate (TAP). Our findings revealed that all tested aryl-OPEs exhibited antagonistic effects on one or more hormone receptors. Importantly, para-OH-TPHP demonstrated the most potent antagonistic activity, inhibiting estrogen receptor α (ERα), thyroid hormone receptor β (TRβ), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR) with the concentration of test compounds showing 20 % relative inhibitory concentration (RIC20) value below 10−6 mol/L (M). RDP antagonized ERα and cortical receptors (GR and MR), TBPP affected TRβ and GR, while EHDPP and meta-OH-TPHP targeted MR. Regarding steroidogenesis, para-OH-TPHP significantly inhibited genes for estrogen (cyp19) and cortisol synthesis (cyp11b2), and along with meta-OH-TPHP, EHDPP, TAP, and RDP downregulated cyp11a1, a rate-limiting enzyme in hormone synthesis. All compounds caused malformations and swimming abnormalities in zebrafish embryos/larvae at concentrations of 10−7 M or higher, with para-OH-TPHP showing nearly 50 % peak induction. Furthermore, the six compounds tested influenced genes associated with the hypothalamic-pituitary–gonadal (HPG) axis in both zebrafish larvae and adult female zebrafish, in addition to affecting the reproductive behavior of zebrafish. A weighted scoring system was employed to rank the endocrine-disrupting potency of the OPEs, with para-OH-TPHP exhibiting the highest risk, followed by EHDPP, RDP, TBPP, meta-OH-TPHP, and TAP. Collectively, our results highlight the significant endocrine-disrupting effects of emerging OPEs, underscoring the urgent need for further research to assess their potential health implications.

The effect of diet-induced weight-loss on subcutaneous adipose tissue expression of genes associated with thyroid hormone action

Background & AimsWe have recently demonstrated that subcutaneous adipose tissue (SAT) expression of genes associated with thyroid hormone (TH) action is altered in obesity and insulin resistance. The aim of the present study was to examine the effect of diet-induced weight-loss on SAT expression of genes associated with TH action. MethodsThe study group comprised 38 individuals with overweight/obesity, which completed 12-week dietary intervention program. Hyperinsulinemic-euglycemic clamp and SAT biopsy were performed before and after the program. Fifteen normal-weight individuals were examined at baseline only. ResultsOverweight/obese individuals had lower free thyroxine (fT4) and higher free triiodothyronine (fT3)/fT4 ratio, lower SAT TH receptor isoforms (TRα and TRβ, encoded by THRA and THRB, respectively) and peroxisome proliferator-activated receptor γ coactivator 1α (PPARGC1A) mRNA expression and higher SAT type II and type III iodothyronine deiodinase (encoded by DIO2 and DIO3, respectively) and nuclear receptor corepressor (NCOR1) mRNA expression in comparison with normal-weight individuals. Diet-induced weight loss resulted in a decrease in fT3 and fT3/fT4 ratio and an increase in SAT THRA, THRB and PPARGC1A. SAT NCOR1 and forkhead box protein O1 (FOXO1) decreased only in individuals, who lost at least 10 kg (n=20). Higher increase in insulin sensitivity after weight loss was associated with a lower decrease in fT3/fT4 ratio. ConclusionsDiet-induced weight loss partly reverses alterations in SAT expression of genes associated with TH action. Responses of circulating TH and SAT expression of genes associated with TH action to diet-induced weight loss are related to body weight and insulin sensitivity.

GnRH-Gonadotropes Interactions Revealed by Pituitary Single-cell Transcriptomics in Zebrafish.

GnRH governs reproduction by regulating pituitary gonadotropins. Unlike most vertebrates, gnrh-/- zebrafish are fertile. To elucidate the role of the hypophysiotropic-Gnrh3 and other mechanisms regulating pituitary gonadotropes, we profiled the gene expression of all individual pituitary cells of wild-type and gnrh3-/- adult female zebrafish. The single-cell RNA sequencing showed that LH and FSH gonadotropes express the 2 gonadotropin beta subunits with a ratio of 140:1 (lhb:fshb) and 4:1 (fshb:lhb), respectively. Lh gonadotropes predominantly express genes encoding receptors for GnRH (gnrhr2), thyroid hormone, estrogen, and steroidogenic factor 1. No GnRH receptor transcript was enriched in FSH gonadotropes. Instead, cholecystokinin receptor-b and galanin receptor-1b transcripts were enriched in these cells. The loss of the Gnrh3 gene in gnrh3-/- zebrafish resulted in downregulation of fshb in LH gonadotropes and upregulation of pituitary hormones like TSH, GH, prolactin, and proopiomelanocortin-a. Likewise, targeted chemogenetic ablation of Gnrh3 neurons led to a decrease in the number of fshb+, lhb + and fshb+/lhb + cells. Our studies suggest that Gnrh3 directly acts on LH gonadotropes through Gnrhr2, but the outcome of this interaction is still unknown. Gnrh3 also regulates fshb expression in both gonadotropes, most likely via a non-GnRH receptor route. Altogether, while LH secretion and synthesis are likely regulated in a GnRH-independent manner, Gnrh3 seems to play a role in the cellular organization of the pituitary. Moreover, the coexpression of lhb and fshb in both gonadotropes provides a possible explanation as to why gnrh3-/- zebrafish are fertile.

Role of TRIP13 in human cancer development.

As an AAA + ATPase, thyroid hormone receptor interacting protein 13 (TRIP13) primarily functions in DNA double-strand break repair, chromosome recombination, and cell cycle checkpoint regulation; aberrant expression of TRIP13 can result in chromosomal instability (CIN). According to recent research, TRIP13 is aberrantly expressed in a variety of cancers, and a patient's poor prognosis and tumor stage are strongly correlated with high expression of TRIP13. Tumor cell and subcutaneous xenograft growth can be markedly inhibited by TRIP13 knockdown or TRIP13 inhibitor administration. In the initiation and advancement of human malignancies, TRIP13 seems to function as an oncogene. Based on available data, TRIP13 may function as a biological target and biomarker for cancer. The creation of inhibitors that specifically target TRIP13 may present novel approaches to treating cancer.

Actions of thyroid hormones and thyromimetics on the liver.

Thyroid hormones (triiodothyronine and thyroxine) are pivotal for metabolic balance in the liver and entire body. Dysregulation of the hypothalamus-pituitary-thyroid axis can contribute to hepatic metabolic disturbances, affecting lipid metabolism, glucose regulation and protein synthesis. In addition, reductions in circulating and intrahepatic thyroid hormone concentrations increase the risk of metabolic dysfunction-associated steatotic liver disease by inducing lipotoxicity, inflammation and fibrosis. Amelioration of hepatic metabolic disease by thyroid hormones in preclinical and clinical studies has spurred the development of thyromimetics that target THRB (the predominant thyroid hormone receptor isoform in the liver) and/or the liver itself to provide more selective activation of hepatic thyroid hormone-regulated metabolic pathways while reducing thyrotoxic side effects in tissues that predominantly express THRA such as the heart and bone. Resmetirom, a liver and THRB-selective thyromimetic, recently became the first FDA-approved drug for metabolic dysfunction-associated steatohepatitis (MASH). Thus, a better understanding of the metabolic actions of thyroid hormones and thyromimetics in the liver is timely and clinically relevant. Here, we describe the roles of thyroid hormones in normal liver function and pathogenesis of MASH, as well as some potential clinical issues that might arise when treating patients with MASH with thyroid hormone supplementation or thyromimetics.

TRIP13 is Critical for the Survival of B-cell Lymphomas and Myeloid Leukemias In Vitro

Hematologic malignancies represent a diverse group of blood tumors accounting for approximately 10% of all cancer cases in the US. Based on the site of manifestation, presumed cell of origin, genetic abnormalities, and clinical features, we recognize more than 100 clinically important subtypes of hematologic malignancies broadly categorized into three main groups: leukemia, lymphoma, and multiple myeloma. While the prognosis for patients with specific subtypes of hematologic malignancies, such as Hodgkin lymphomas or chronic lymphocytic leukemia has significantly improved over the last several years, other subtypes such as acute myeloid leukemia or non-Hodgkin lymphomas still present with significant treatment challenges. A better understanding of molecular drivers of tumor maintenance is needed to improve existing therapies. Thyroid hormone receptor interactor 13 (TRIP13) is an AAA + ATPase that plays an important yet poorly understood role in the regulation of the mammalian cell cycle. The TRIP13 gene is highly expressed in various human tumors including colorectal carcinoma and glioblastoma, and it seems to promote tumorigenesis. Recently, we identified TRIP13 as a gene overexpressed in Peripheral T-cell lymphomas where it plays a critical role in tumor maintenance by regulating the G2-M phase of the cell cycle. However, the biological activities of TRIP13 in non-T cell hematologic malignancies have not been investigated to date. Here we used shRNA-mediated knockdown and a small molecule inhibitor to downregulate TRIP13 in B-cell lymphoid and myeloid lineages. We found genetic downregulation inhibited the proliferation of both B-cell lymphomas and acute myeloid leukemia cell lines in vitro. The pharmacologic inhibition of TRIP13 effectively induced the G0/G1 cell cycle arrest and apoptosis of B-cell lymphomas. Altogether these data demonstrate that TRIP13 is critical for the maintenance of hematologic malignancies of B-cell and myeloid malignancies in vitro. Thus, TRIP13 might be a good target in the treatment of various types of hematologic malignancies.

Effects of Thyroid Hormones on Cellular Development in Human Ovarian Granulosa Tumor Cells (KGN).

Ovarian cancer is a common malignant tumor in the female reproductive system, and Granulosa cell tumor (GCT) of the ovary is a rare type of ovarian cancer, which significantly threatens women's reproductive health. It has been reported that dysregulation of thyroid hormones (THs) may be closely related to the progression and prognosis of ovarian cancer. Moreover, THs regulate phosphorylation of signal transducer and activator of transcription (STAT3) and Octamer-binding transcription factor 4 (OCT4) expression. It has been reported that STAT3 and OCT4 play important roles in cellular development and tumorigenesis. However, the mechanisms by which THs affect the development of GCT are still remained unclear. To evaluate the effect of THs on human ovarian granulosa tumor cells (KGN), cells were treated with 3,5,3' -triiodothyronine (T3). Oct4 small interfering (Oct4 siRNA) or STAT3 inhibitor C188-9 was also co-cultured with cells in some experiments, respectively. The cell viability, proliferation, and proteins content were detected by CCK-8, EdU, and Western Blotting, respectively. The results showed that T3 enhanced cell viability and proliferation. Moreover, T3 also increased the expression of thyroid hormone receptor (TR), p-STAT3, and OCT4 proteins. The effects of T3 on both p-STAT3 and OCT4 expression were blocked by TR antagonist 1-850. Meanwhile, C188-9, an inhibitor of STAT3, decreased T3-induced cellular viability, proliferation, and OCT4 expression, highlighting that p-STAT3 can regulate the expression of OCT4 and affect cellular viability, and proliferation. Furthermore, T3-induced cellular growth was reduced by Oct4 siRNA, which indicates that T3 regulates cellular development through OCT4. These findings suggest that T3 increases cellular development via OCT4, which is mediated by phosphorylation of STAT3, and TR is also involved in these processes.

TRIP13: A promising cancer immunotherapy target.

The tumor microenvironment (TME) facilitates tumor development through intricate intercellular signaling, thereby supporting tumor growth and suppressing the immune response. Thyroid hormone receptor interactor 13 (TRIP13), an AAA+ ATPase, modulates the conformation of client macromolecules, consequently influencing cellular signaling pathways. TRIP13 has been implicated in processes such as proliferation, invasion, migration, and metastasis during tumor progression. Recent studies have revealed that TRIP13 also plays a role in immune response suppression within the TME. Thus, inhibiting these functions of TRIP13 could potentially enhance immune responses and improve the efficacy of immune checkpoint inhibition. This review summarizes the recent research progress of TRIP13 and discusses the potential of targeting TRIP13 to improve immune-based therapies for patients with cancer.

TRβ activation confers AT2-to-AT1 cell differentiation and anti-fibrosis during lung repair via KLF2 and CEBPA

Aberrant repair underlies the pathogenesis of pulmonary fibrosis while effective strategies to convert fibrosis to normal regeneration are scarce. Here, we found that thyroid hormone is decreased in multiple models of lung injury but is essential for lung regeneration. Moreover, thyroid hormone receptor α (TRα) promotes cell proliferation, while TRβ fuels cell maturation in lung regeneration. Using a specific TRβ agonist, sobetirome, we demonstrate that the anti-fibrotic effects of thyroid hormone mainly rely on TRβ in mice. Cellularly, TRβ activation enhances alveolar type-2 (AT2) cell differentiation into AT1 cell and constrains AT2 cell hyperplasia. Molecularly, TRβ activation directly regulates the expression of KLF2 and CEBPA, both of which further synergistically drive the differentiation program of AT1 cells and benefit regeneration and anti-fibrosis. Our findings elucidate the modulation function of the TRβ-KLF2/CEBPA axis on AT2 cell fate and provide a potential treatment strategy to facilitate lung regeneration and anti-fibrosis.

The Thyroid Hormone Analog GC-1 Mitigates Acute Lung Injury by Inhibiting M1 Macrophage Polarization.

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a life-threatening condition with a high mortality rate of ≈40%. Thyroid hormones (THs) play crucial roles in maintaining homeostasis of the cellular microenvironment under stress. The previous studies confirmed that the clinical-stage TH analog GC-1 significantly alleviates pulmonary fibrosis by improving the function of mitochondria in epithelial cells. However, the effects of GC-1 on macrophages in lung injury and the related mechanisms remain unclear. This study evaluated the therapeutic effects of GC-1 in two murine models of lipopolysaccharide (LPS)- or hydrochloric acid (HCl)-induced ALI. Additionally, mouse alveolar macrophages (AMs) and human THP-1-derived macrophages are utilized to investigate the impact of GC-1 on macrophage polarization. GC-1 effectively reduces the inflammatory response and lung injury in ALI mice, as evidenced by neutrophil infiltration, cytokine levels, alveolar fluid clearance, and pulmonary pathology. Notably, GC-1 selectively inhibits M1 macrophage polarization, which may be achieved by impeding NF-κB signaling activation through the DNMT3b-PPARγ-NF-κB pathway in a TH receptor β1 (TRβ1)-dependent manner, consequently suppressing the polarization of macrophages toward the M1 phenotype and overproduction of inflammatory cytokines. Overall, these findings highlight the immunomodulatory property of GC-1 as an anti-inflammatory strategy for ALI/ARDS and inflammation-related diseases.

8747 A Rare Receptor Resistance with Paradoxical Outcomes!

Abstract Disclosure: I. Patoli: None. S. Batool: None. A.S. Gill: None. A. Makdissi: None. Introduction: Resistance to thyroid hormone receptor is an uncommon cause of abnormal TFTs. (1) We present an interesting case of THRB resistance with cardiac arrhythmia (CA). Clinical Case: 46-year-old man with history of atrial fibrillation (Afib) was referred to endocrinology for evaluation of abnormal TFTs and thyroid nodule. He had a recent hospital admission for Afib with rapid ventricular response; 3 years ago, he was treated with amiodarone for 2 months. TFTs revealed normal TSH of 1.375, elevated FT4 of 2.76 (normal ranges 0.55-4.78 and 0.89-1.76, respectively). Neck CT scan showed large peripherally enhancing centrally necrotic mass with calcification encompassing nearly the entirety of left thyroid lobe measuring 2.2 x 3.6 x 4.6 cm. A 0.8 cm hypodensity within right thyroid lobe also visualized. Thyroid ultrasound showed nodules bilaterally with the largest one in the lower pole of left lobe. FNA biopsy showed Bethesda category- II benign, benign appearing follicular cells and abundant colloid. Repeat labs showed similar results with persistently elevated free T4 (2.56) with equilibrium dialysis, normal alpha subunit, normal TSH (2.14) with human anti-mouse antibody (HAMA) antibody was negative. Alpha subunit:TSH ratio was <1. He remained clinically euthyroid over the course of 1.5 year but repeat labs at that time indicated that TSH had increased to 17 with elevated free T4 (2.6) . MRI brain ruled out TSH secreting adenoma. He reported thyroid abnormalities in son and brother but was unable to provide details. He was referred for genetic screening which showed THRB with pathogenic variant: c.9628> G (p.Y321C). Conclusion: THRB resistance is an uncommonly diagnosed modality in endocrinology. The genes encoding thyroid hormone receptors are THRα gene and THRβ gene (2). Patients with inherited THRB pathogenic variants present with resistance to thyroid hormone and often enlarged thyroid gland. Interestingly, despite having receptor resistance, patients may manifest with CA. This is hypothesized to be due to elevated T4 and T3 concentration in the heart which primarily has higher expression of THRA (3). The diagnosis of thyroid hormone resistance is important to avoid treating asymptomatic patients where treatment is not warranted.

7308 A Case of Thyroid Hormone Resistance Associated With a Novel Mutation in the THRA Gene

Abstract Disclosure: J.A. Siddiqui: None. M. Barbosa: None. V. Fettig: None. C.J. Romero: None. Introduction: Thyroid hormone resistance (THR) is a syndrome leading to decreased response of target organs to thyroid hormone. Normal thyroid hormone action is mediated by thyroid hormone nuclear receptors and is essential for normal development and metabolism. Two isoforms are encoded by the thyroid hormone receptor α and β genes (THRA and THRB). Mutations in THRB are commonly reported with limited cases of THRA mutations. We report a 15-month-old and her mother with a pathogenic variant in the THRα receptor leading to thyroid hormone resistance. CASE: A 15-month-old ex-39-week gestation female was born small for gestational age (birth weight: 2450 grams,3rd %ile and birth length: 17 inches,1st %ile). The newborn screen was normal. She presented with macroglossia, low tone and global developmental delay. She had severe constipation complicated by rectal prolapse that required surgical correction. There are multiple relatives (mother, maternal half-brother and maternal grandparents) with neurodevelopmental issues. The mother’s previous genetic evaluation was non-diagnostic. Mother reports a thyroid condition but without treatment. The patient was initially referred to genetics and whole exome sequencing revealed a heterozygous c.1205 T>C p. (L402P) variant in the THRα gene, which was maternally inherited and reported as a variant of uncertain significance. On physical exam, Heart rate was 112 bpm; height <1%ile (Z-score -3.22 SD), weight 3%ile (Z-score -1.89 SD). Patient has a wide anterior fontanelle (4x3 cm), macroglossia and delayed teeth eruption. Other exam findings: non-palpable thyroid and postaxial polydactyly on the 5th digit of the right toe. Thyroid hormone testing: normal TSH 1.829 uIU/mL, low total T4 4.4 mcg/dL, low Free T4 of 0.58 ng/dL and high free T3 of 4.24 pg/mL. Levothyroxine treatment was initiated(25 mcg daily). After 1 month treatment, TSH level was 0.23 uIU/mL, total T4 was 6.1 mcg/dL and low reverse T3 of 5.8 ng/dL. DISCUSSION: Thyroid hormone resistance due to THRα mutations are rare and under-recognized. The main clinical phenotype includes growth retardation, delayed development, decreased muscle tone, delayed tooth eruption and constipation. Unlike patients with THRβ mutations, the hypothalamus-pituitary-thyroid axis in patients with THRα mutations is minimally affected with a normal TSH level. Total T3 levels are elevated with slightly low total T4 and free T4:T3 ratio is low. Treatment with levothyroxine leads to suppressions of TSH levels, therefore confirming intact central T3 feedback loop. Reports, however, show minor clinical improvements with treatment; therefore further research is needed in these patients to explore more effective therapeutic options. We present a case of a novel congenital THRA mutation leading to a clinical phenotype consistent with THR. She continues care in our clinic with hopes to further study her mutation. Presentation: 6/2/2024

8780 The Role of Nuclear Receptor Corepressors 1 and 2 on Intestinal Carbohydrate Transport in Mice

Abstract Disclosure: M.J. Ritter: None. I. Amano: None. A.H. van der Spek: None. H.E. Daniel: None. A.N. Hollenberg: None. The nuclear receptor corepressors NCoR1 and NCoR2 are two critical regulators of metabolism that are required for maintaining metabolic homeostasis. Both NCoR1 and NCoR2 (also known as the silencing mediator of retinoic acid and thyroid hormone receptors; SMRT) recruit histone deacetylase 3 (HDAC3) to their deacetylase domain (DAD) to repress nuclear receptor (NR) target gene expression. Interruption of the DAD of NCoR1 in mice leads to lower body weight, decreased whole-body fat mass, insulin sensitization with altered oscillatory patterns of key metabolic genes (1). On the other hand, total body knock-out (KO) of SMRT leads to weight gain, insulin resistance, and hepatic steatosis with an increase in hepatic lipogenesis (2). Previously, we showed that the KO of NCoR1 and SMRT in tandem from adult mice led rapidly to weight loss, hypoglycemia, hypothermia and was lethal. Reductions in intestinal carbohydrate transporters were seen, including sodium-glucose linked transporter-1 (SGLT1), glucose transporter 2 (GLUT2), and glucose transporter 5 (GLUT5) (3). Thus, we hypothesized that NCoR1 and SMRT play unique roles in regulating intestinal carbohydrate metabolism, in turn controlling metabolic parameters including body mass and glucose levels. We then generated a novel model to enable KO of NCoR1 and SMRT throughout intestinal epithelial cells (IECs) in adult mice using a tamoxifen inducible cre under control of the villin 1 promoter. Mice were injected with tamoxifen and body weight and glucose were monitored daily. This was followed by both oral and intraperitoneal glucose tolerance testing (GTT) and metabolic phenotyping. Preliminary data showed that NCoR1 and SMRT KO leads to sustained weight loss and hypoglycemia with 50% survivability. Metabolic phenotyping confirmed reduction in body mass without concomitant reduction in food intake. Oral GTT showed a blunted peak in response to glucose gavage compared to intraperitoneal administration. Gene expression analysis showed reduction in SGLT1, GLUT2, and GLUT5 in addition to changes in metabolic pathways associated with fatty acid metabolism. Here, we show that NCoR1 and SMRT are critical regulators of body mass and glucose in part via their actions on carbohydrate transporters in the intestine. With the global burden of metabolic diseases, including obesity and diabetes, ever-rising, NCoR1 and SMRT represent an overlooked but important area of study to better our understanding of disease processes and identify new targets for treatment. We next aim to determine the functional mechanism by which weight loss and hypoglycemia develop in addition to identifying molecular targets and pathways regulated by NCoR1 and SMRT in IECs.

8398 Non-genomic Effects of Thyroid Hormones on the Breast Cancer Microenvironment

Abstract Disclosure: L. Drago: None. S. Shahrivari: None. N. Schwenk: None. P. Nelson: None. H. Hosseini: None. C. Spitzweg: None. Objective: Mesenchymal stem cells (MSCs) are central players in the genesis of the breast cancer tumor microenvironment and play a role in tumor initiation, progression, invasion, metastasis, angiogenesis as well as resistance to treatment. There is increasing evidence for an association between thyroid function and breast cancer risk. Thyroid hormone effects mediated through the αvβ3 integrin, a thyroid hormone receptor, are proposed as a pathophysiologic link to this observation. Methods: To evaluate the migratory behavior of MSCs in the presence or absence of thyroid hormone treatment in response to tumor-derived signals, a 3D migration assay was performed. MSCs pretreated with T3 (1nM) or T4 (1μM) with or without tetrac (100nM) (T4 analog, specific inhibitor of αvβ3 integrin-mediated thyroid hormone action) for 24 h were subjected to a gradient between serum-free medium and serum-free conditioned medium (CM) from five different breast cancer cell lines representative of different breast cancer subtypes including T47D as Luminal B, MCF7 as Luminal A, BT-474 and MDA-MB-453 as HER2, and MDA-MB-231 as Triple negative subtype. Results: MSCs subjected to a gradient between CM derived from each breast cancer cell line and serum-free medium showed directed chemotaxis towards tumor-CM with a significantly increased forward migration index (FMI) and center of mass (CoM). This migratory behavior was significantly enhanced upon treatment with T3 or T4. The cellular migration towards tumor-CM of MDA-MB-453, BT-474, and T47D was more effective upon MSC treatment with T3, but less so with T4. MSCs treated with T4 showed a better migratory performance towards the CM of MCF7 and MDA-MB-231. Except for T47D-CM, additional treatment with tetrac inhibited the enhanced effects of T3 and T4 on MSC migration demonstrating that this effect is mediated through αvβ3 integrin. Conclusion: Our preliminary in vitro data on the effects of thyroid hormones T3 and T4, and the thyroid hormone metabolite tetrac on MSC migration shows a distinct behaviour of MSCs in the presence of either T3 or T4 depending on the breast cancer cell subtype, suggesting a role of non-genomic, integrin αvβ3-mediated thyroid hormone action on MSC biology within the breast tumor microenvironment that warrants further investigation. Presentation: 6/3/2024