PON3::LCN1 and HTN3::MSANTD3 Gene Fusions With NR4A3/NR4A2 Expression in Salivary Acinic Cell Carcinoma.

Acinic cell carcinoma of the salivary gland (AciCC) is a low-grade carcinoma characterized by the overexpression of the transcription factor nuclear receptor subfamily 4 group A member 3 (NR4A3). AciCC has been the subject of a few molecular research projects. This study delves into AciCC's molecular landscape to identify additional alterations and explore their clinical implications. RNA sequencing and immunohistochemical staining for markers NR4A3/NR4A2, DOG-1, S100, and mammaglobin were utilized on 41 AciCCs and 11 secretory carcinoma (SC) samples. NR4A3 was evident in 35 AciCCs, while the residual 6 were NR4A3-negative and NR4A2-positive; SC samples were consistently NR4A3-negative. A novel fusion, PON3 exon 1- LCN1 exon 5, was detected in 9/41 (21.9%) AciCCs, exhibiting a classical histologic pattern with serous cell components growing in solid sheets alongside the intercalated duct-like component. Clinical follow-up of 39 patients over a median of 59 months revealed diverse prognostic outcomes: 34 patients exhibited no disease evidence, whereas the remaining 5 experienced poorer prognosis, involving local recurrence, lymph node, and distant metastasis, and disease-associated death, 4 of which harbored the PON3::LCN1 fusion. In addition, the HTN3::MSANTD3 fusion was recurrently identified in 7/41 AciCC cases. SC patients lacked both fusions. Immunohistochemistry uncovered differential expression of DOG-1, S100, and mammaglobin across samples, providing nuanced insights into their roles in AciCC. This study accentuates PON3::LCN1 and HTN3::MSANTD3 fusions as recurrent molecular events in AciCC, offering potential diagnostic and prognostic utility and propelling further research into targeted therapeutic strategies.

How the Xenopus eleutheroembryonic thyroid assay compares to the amphibian metamorphosis assay for detecting thyroid active chemicals.

The Xenopus Eleutheroembryonic Thyroid Assay (XETA) was recently published as an OECD Test Guideline for detecting chemicals acting on the thyroid axis. However, the OECD validation did not cover all mechanisms that can potentially be detected by the XETA. This study was therefore initiated to investigate and consolidate the applicability domain of the XETA regarding the following mechanisms: thyroid hormone receptor (THR) agonism, sodium-iodide symporter (NIS) inhibition, thyroperoxidase (TPO) inhibition, deiodinase (DIO) inhibition, glucocorticoid receptor (GR) agonism, and uridine 5'-diphospho-glucuronosyltransferase (UDPGT) induction. In total, 22 chemicals identified as thyroid-active or -inactive in Amphibian Metamorphosis Assays (AMAs) were tested using the XETA OECD Test Guideline. The comparison showed that both assays are highly concordant in identifying chemicals with mechanisms of action related to THR agonism, DIO inhibition, and GR agonism. They also consistently identified the UDPGT inducers as thyroid inactive. NIS inhibition, investigated using sodium perchlorate, was not detected in the XETA. TPO inhibition requires further mechanistic investigations as the reference chemicals tested resulted in opposing response directions in the XETA and AMA. This study contributes refining the applicability domain of the XETA, thereby helping to clarify the conditions where it can be used as an ethical alternative to the AMA.

Cadmium exposure activates mitophagy through downregulating thyroid hormone receptor/PGC1α signal in preeclampsia.

Gestational cadmium exposure increases the risk of preeclampsia. Placenta mitophagy was activated in preeclampsia. The aim of present study was to explore the mechanism of cadmium-induced mitophagy activation and its association with preeclampsia. Mitophagy markers expression levels were detected by quantitative real-time PCR, Western blot, immunofluorescence and immunochemistry in preeclampsia placenta. JEG3 cells were treated with CdCl2, iopanoic acid (IOP), 3-methyladenine and PGC1α SiRNA to verify mechanism of cadmium-induced mitophagy. Mitophagy marker LC3BII/I and P62 expression were increased and mitochondrial membrane receptor protein TOM20 and FUNDC1 expression were decreased in preeclampsia placenta as compared with that in normotension control. Mitophagy marker LC3BII/I and P62 expression were increased and TOM20 and FUNDC1 expression was decreased in CdCl2-treated JEG3 cells. Meanwhile, mitochondrial biogenesis regulator, PGC1α expression was decreased in preeclampsia and CdCl2-treated JEG3 cells. The expressions of LC3B and P62 were increased and the expressions of TOM20, FUNDC1 and PGC1α were decreased in IOP-treated cell. PGC1α SiRNA transfection led to increased expression of LC3BII/I and P62 and decreased expression of TOM20 and FUNDC1. The expression of sFlt1 was increased in preeclampsia placenta, CdCl2-treated cells, in IOP-treated cells and in PGC1α SiRNA transfected cells. 3-methyladenine treatment protected the increased expression of sFlt1 in CdCl2-treated cells, in IOP-treated cells and in PGC1α SiRNA transfected cells. Meanwhile, co-treatment of cadmium and IOP or PGC1αSiRNA led to a reduce expressions of OPA1, MFN1, MFN2 and FUNDC1 as compared to cadmium-treated, IOP-treated and PGC1α SiRNA-treated cells. These results elucidated that maternal cadmium exposure activated placenta mitophagy through downregulation of thyroid hormone receptor signal mediated decreased expression of PGC1α and was associated with the occurrence of preeclampsia.

Metabolic Messengers: Thyroid Hormones.

Thyroid hormones (THs) are key hormones that regulate development and metabolism in mammals. In man, the major target tissues for TH action are the brain, liver, muscle, heart, and adipose tissue. Defects in TH synthesis, transport, metabolism, and nuclear action have been associated with genetic and endocrine diseases in man. Over the past few years, there has been renewed interest in TH action and the therapeutic potential of THs and thyromimetics to treat several metabolic disorders such as hypercholesterolemia, dyslipidaemia, non-alcoholic fatty liver disease (NAFLD), and TH transporter defects. Recent advances in the development of tissue and TH receptor isoform-targeted thyromimetics have kindled new hope for translating our fundamental understanding of TH action into an effective therapy. This review provides a concise overview of the historical development of our understanding of TH action, its physiological and pathophysiological effects on metabolism, and future therapeutic applications to treat metabolic dysfunction.

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

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

Regulation of hypothalamic reactive oxygen species and feeding behavior by phosphorylation of the beta 2 thyroid hormone receptor isoform.

Unlike other thyroid hormone receptors (THRs), the beta 2 isoform (THRB2) has a restricted expression pattern and is uniquely and abundantly phosphorylated at a conserved serine residue S101 (S102 in humans). Using tagged and or phosphorylation-defective (S101A) THRB2 mutant mice, we show that THRB2 is present in a large subset of POMC neurons and mitigates ROS accumulation during ROS-triggering events, such as fasting/refeeding or high fat diet (HFD). Excessive ROS accumulation in mutant POMC neurons was accompanied by a skewed production of orexigenic/anorexigenic hormones, resulting in elevated food intake. The prolonged exposure to pathogenic hypothalamic ROS levels during HFD feeding lead to a significant loss of POMC neurons in mutant versus wild-type (WT) mice. In cultured cells, the presence of WT THRB2 isoform, but not other THRs, or THRB2S101A, reduced ROS accumulation upon exogenous induction of oxidative stress by tert-butyl hydroperoxide. The protective function of phospho-THRB2 (pTHRB2) did not require thyroid hormone (TH), suggesting a TH-independent role of the THRB2 isoform, and phospho-S101 in particular, in regulating oxidative stress. We propose that pTHRB2 has a fundamental role in neuronal protection against ROS cellular damage, and mitigates hypothalamic pathological changes found in diet-induced obesity.

The ecological function of thyroid hormones.

Thyroid hormones (TH) are central hormonal regulators, orchestrating gene expression and complex biological processes vital for growth and reproduction in variable environments by triggering specific developmental processes in response to external cues. TH serve distinct roles in different species: inducing metamorphosis in amphibians or teleost fishes, governing metabolic processes in mammals, and acting as effectors of seasonality. These multifaceted roles raise questions about the underlying mechanisms of TH action. Recent evidence suggests a shared ecological role of TH across vertebrates, potentially extending to a significant portion of bilaterian species. According to this model, TH ensure that ontogenetic transitions align with environmental conditions, particularly in terms of energy expenditure, helping animals to match their ontogenetic transition with available resources. This alignment spans post-embryonic developmental transitions common to all vertebrates and more subtle adjustments during seasonal changes. The underlying logic of TH function is to synchronize transitions with the environment. This review briefly outlines the fundamental mechanisms of thyroid signalling and shows various ways in which animals use this hormonal system in natural environments. Lastly, we propose a model linking TH signalling, environmental conditions, ontogenetic trajectory and metabolism. This article is part of the theme issue 'Endocrine responses to environmental variation: conceptual approaches and recent developments'.

Factors and Mechanisms of Thyroid Hormone Activity in the Brain: Possible Role in Recovery and Protection.

Thyroid hormones (THs) are essential in normal brain development, and cognitive and emotional functions. THs act through a cascade of events including uptake by the target cells by specific cell membrane transporters, activation or inactivation by deiodinase enzymes, and interaction with nuclear thyroid hormone receptors. Several thyroid responsive genes have been described in the developing and in the adult brain and many studies have demonstrated a systemic or local reduction in TH availability in neurologic disease and after brain injury. In this review, the main factors and mechanisms associated with the THs in the normal and damaged brain will be evaluated in different regions and cellular contexts. Furthermore, the most common animal models used to study the role of THs in brain damage and cognitive impairment will be described and the use of THs as a potential recovery strategy from neuropathological conditions will be evaluated. Finally, particular attention will be given to the link observed between TH alterations and increased risk of Alzheimer's Disease (AD), the most prevalent neurodegenerative and dementing condition worldwide.

RP11-495P10.1 promotes HCC cell proliferation by regulating reprogramming of glucose metabolism and acetylation of the NR4A3 promoter via the PDK1/PDH axis.

The incidence and related death of hepatocellular carcinoma (HCC) have increased over the past decades. However, the molecular mechanisms underlying HCC pathogenesis are not fully understood. Long noncoding RNA (lncRNA) RP11-495P10.1 has been proven to be closely associated with the progression of prostate cancer, but its role and specific mechanism in HCC are still unknown. Here, we identify that RP11-495P10.1 is highly expressed in HCC tissues and cells and contributes to the proliferation of HCC cells. Moreover, this study demonstrates that RP11-495P10.1 affects the proliferation of HCC by negatively regulating the expression of nuclear receptor subfamily 4 group a member 3 (NR4A3). Glycometabolism reprogramming is one of the main characteristics of tumor cells. In this study, we discover that RP11-495P10.1 regulates glycometabolism reprogramming by changing the expression of pyruvate dehydrogenase kinase 1 (PDK1) and pyruvate dehydrogenase (PDH), thus contributing to the proliferation of HCC cells. Furthermore, knockdown of RP11-495P10.1 increases enrichment of H3K27Ac in the promoter of NR4A3 by promoting the activity of PDH and the production of acetyl-CoA, which leads to the increased transcription of NR4A3. Altogether, RP11-495P10.1 promotes HCC cell proliferation by regulating the reprogramming of glucose metabolism and acetylation of the NR4A3 promoter via the PDK1/PDH axis, which provides an lncRNA-oriented therapeutic strategy for the diagnosis and treatment of HCC.

Natural products and synthetic analogs as selective orphan nuclear receptor 4A (NR4A) modulators.

Although endogenous ligands for the orphan nuclear receptor 4A1 (NR4A1, Nur77), NR4A2 (Nurr1), and NR4A3 (Nor-1) have not been identified, several natural products and synthetic analogs bind NR4A members. These studies are becoming increasingly important since members of the NR4A subfamily of 3 receptors are potential drug targets for treating cancer and non-cancer endpoints and particularly those conditions associated with inflammatory diseases. Ligands that bind NR4A1, NR4A2, and NR4A3 including Cytosporone B, celastrol, bis-indole derived (CDIM) compounds, tryptophan/indolic, metabolites, prostaglandins, resveratrol, piperlongumine, fatty acids, flavonoids, alkaloids, peptides, and drug families including statins and antimalarial drugs. The structural diversity of NR4A ligands and their overlapping and unique effects on NR4A1, NR4A2, and NR4A3 suggest that NR4A ligands are selective NR4A modulators (SNR4AMs) that exhibit tissue-, structure-, and response-specific activities. The SNR4AM activities of NR4A ligands are exemplified among the Cytosporone B analogs where n-pentyl-2-[3,5-dihydroxy-2-(nonanoyl)]phenyl acetate (PDNPA) binds NR4A1, NR4A2 and NR4A3 but activates only NR4A1 and exhibits significant functional differences with other Cytosporone B analogs. The number of potential clinical applications of agents targeting NR4A is increasing and this should spur future development of SNR4AMs as therapeutics that act through NR4A1, NR4A2 and NR4A3.

Hypothalamic Thyroid Hormone Receptor α1 Signaling Controls Body Temperature.

Background: The importance of thyroid hormones (THs) for peripheral body temperature regulation has been long recognized, as medical conditions such as hyper- and hypothyroidism lead to alterations in body temperature and energy metabolism. In the past decade, the brain actions of THs and their respective nuclear receptors, thyroid hormone receptor α1 (TRα1) and thyroid hormone receptor beta (TRß), coordinating body temperature regulation have moved into focus. However, the exact roles of the individual TR isoforms and their precise neuroanatomical substrates remain poorly understood. Methods: Here we used mice expressing a mutant TRα1 (TRα1+m) as well as TRß knockouts to study body temperature regulation using radiotelemetry in conscious and freely moving animals at different ambient temperatures, including their response to oral 3,3',5-triiodothyronine (T3) treatment. Subsequently, we tested the effects of a dominant-negative TRα1 on body temperature after adeno-associated virus (AAV)-mediated expression in the hypothalamus, a region known to be involved in thermoregulation. Results: While TRß seems to play a negligible role in body temperature regulation, TRα1+m mice had lower body temperature, which was surprisingly not entirely normalized at 30°C, where defects in facultative thermogenesis or tail heat loss are eliminated as confounding factors. Only oral T3 treatment fully normalized the body temperature profile of TRα1+m mice, suggesting that the mutant TRα1 confers an altered central temperature set point in these mice. When we tested this hypothesis more directly by expressing the dominant-negative TRα1 selectively in the hypothalamus via AAV transfection, we observed a similarly reduced body temperature at room temperature and 30°C. Conclusion: Our data suggest that TRα1 signaling in the hypothalamus is important for maintaining body temperature. However, further studies are needed to dissect the precise neuroanatomical substrates and the downstream pathways mediating this effect.

Thyroid hormone receptor Thra and Thrb knockout differentially affects osteoblast biology and thyroid hormone responsiveness in vitro.

Thyroid hormones (TH) are important modulators of bone remodeling and thus, thyroid diseases, in particular hyperthyroidism, are able to compromise bone quality and fracture resistance. TH actions on bone are mediated by the thyroid hormone receptors (TR) TRα1 and TRß1, encoded by Thra and Thrb, respectively. Skeletal phenotypes of mice lacking Thra (Thra0/0 ) and Thrb (Thrb-/- ) are well-described and suggest that TRα1 is the predominant mediator of TH actions in bone. Considering that bone cells might be affected by systemic TH changes seen in these mutant mice, here we investigated the effects of TR knockout on osteoblasts exclusively at the cellular level. Primary osteoblasts obtained from Thra0/0 , Thrb-/- , and respective wildtype (WT) mice were analyzed regarding their differentiation potential, activity and TH responsiveness in vitro. Thra, but not Thrb knockout promoted differentiation and activity of early, mature and late osteoblasts as compared to respective WT cells. Interestingly, while mineralization capacity and expression of osteoblast marker genes and TH target gene Klf9 was increased by TH in WT and Thra-deficient osteoblasts, Thrb knockout mitigated the responsiveness of osteoblasts to short (48 h) and long term (10 d) TH treatment. Further, we found a low ratio of Rankl, a potent osteoclast stimulator, over osteoprotegerin, an osteoclast inhibitor, in Thrb-deficient osteoblasts and in line, supernatants obtained from Thrb-/- osteoblasts reduced numbers of primary osteoclasts in vitro. In accordance to the increased Rankl/Opg ratio in TH-treated WT osteoblasts only, supernatants from these cells, but not from TH-treated Thrb-/- osteoblasts increased the expression of Trap and Ctsk in osteoclasts, suggesting that osteoclasts are indirectly stimulated by TH via TRß1 in osteoblasts. In conclusion, our study shows that both Thra and Thrb differentially affect activity, differentiation and TH response of osteoblasts in vitro and emphasizes the importance of TRß1 to mediate TH actions in bone.

Thyroid hormone action during GABAergic neuron maturation: The quest for mechanisms.

Thyroid hormone (TH) signaling plays a major role in mammalian brain development. Data obtained in the past years in animal models have pinpointed GABAergic neurons as a major target of TH signaling during development, which opens up new perspectives to further investigate the mechanisms by which TH affects brain development. The aim of the present review is to gather the available information about the involvement of TH in the maturation of GABAergic neurons. After giving an overview of the kinds of neurological disorders that may arise from disruption of TH signaling during brain development in humans, we will take a historical perspective to show how rodent models of hypothyroidism have gradually pointed to GABAergic neurons as a main target of TH signaling during brain development. The third part of this review underscores the challenges that are encountered when conducting gene expression studies to investigate the molecular mechanisms that are at play downstream of TH receptors during brain development. Unravelling the mechanisms of action of TH in the developing brain should help make progress in the prevention and treatment of several neurological disorders, including autism and epilepsy.

Analysis of an antioxidative defence system of hydrogen peroxide-treated pancreatic islet-derived 1.1B4 cells and siRNA targeting NR4A3-treated cells by microarray.

Pancreatic islet ß-cells weaken under oxidative stress. In this study, human pancreatic islet-derived 1.1B4 cells were exposed to H2O2 and analysed using a human microarray, which revealed that heme oxygenase 1 (HMOX1), glutamate-cysteine ligase, early growth response 1, nuclear receptor subfamily 4 group A member 3 (NR4A3) and jun B proto-oncogene were upregulated, whereas superoxide dismutase 1 and catalase were not. Expression of NR4A3 rapidly increased after H2O2 addition, and the 1.1B4 cells treated with siRNA targeting NR4A3 became sensitive to H2O2; further, HMOX1 expression was strongly inhibited, suggesting that NR4A3 is an oxidative stress-responsive transcription factor that functions through HMOX1 expression in pancreatic islet ß-cells. Expression of cyclin E1 and cyclin-dependent kinase 1 was also inhibited by siRNAs targeting NR4A3.

Local Thyroid Hormone Action in Brain Development.

Proper brain development essentially depends on the timed availability of sufficient amounts of thyroid hormone (TH). This, in turn, necessitates a tightly regulated expression of TH signaling components such as TH transporters, deiodinases, and TH receptors in a brain region- and cell-specific manner from early developmental stages onwards. Abnormal TH levels during critical stages, as well as mutations in TH signaling components that alter the global and/or local thyroidal state, result in detrimental consequences for brain development and neurological functions that involve alterations in central neurotransmitter systems. Thus, the question as to how TH signaling is implicated in the development and maturation of different neurotransmitter and neuromodulator systems has gained increasing attention. In this review, we first summarize the current knowledge on the regulation of TH signaling components during brain development. We then present recent advances in our understanding on how altered TH signaling compromises the development of cortical glutamatergic neurons, inhibitory GABAergic interneurons, cholinergic and dopaminergic neurons. Thereby, we highlight novel mechanistic insights and point out open questions in this evolving research field.

Development of binary classification models for grouping hydroxylated polychlorinated biphenyls into active and inactive thyroid hormone receptor agonists.

Some adverse effects of hydroxylated polychlorinated biphenyls (OH-PCBs) in humans are presumed to be initiated via thyroid hormone receptor (TR) binding. Due to the trial-and-error approach adopted for OH-PCB selection in previous studies, experiments designed to test the TR binding hypothesis mostly utilized inactive OH-PCBs, leading to considerable waste of time, effort and other material resources. In this paper, linear discriminant analysis (LDA) and binary logistic regression (LR) were used to develop classification models to group OH-PCBs into active and inactive TR agonists using radial distribution function (RDF) descriptors as predictor variables. The classifications made by both LDA and LR models on the training set compounds resulted in an accuracy of 84.3%, sensitivity of 72.2% and specificity of 90.9%. The areas under the ROC curves, constructed with the training set data, were found to be 0.872 and 0.880 for LDA and LR models, respectively. External validation of the models revealed that 76.5% of the test set compounds were correctly classified by both LDA and LR models. These findings suggest that the two models reported in this paper are good and reliable for classifying OH-PCB congeners into active and inactive TR agonists.

Diagnosis of acinic cell carcinoma of the salivary gland on cytology specimens: Role of NOR-1 (NR4A3) immunohistochemistry.

OBJECTIVES: Acinic cell carcinoma (AcCC) is often a challenging diagnosis on cytology. Recently, NOR-1 (NR4A3) has been demonstrated as a sensitive and specific marker for AcCC. Therefore, we conducted this study to evaluate NOR-1 expression in AcCC cytology specimens and to compare its reactivity in other salivary gland tumours (non-AcCC). METHODS: We retrospectively reviewed our database and selected cytology cases with available cell blocks, including 10 AcCC and 24 non-AcCC tumours (12 benign tumours and 12 malignant tumours). NOR-1 (1:50 dilution; SC393902 [H-7]; Santa Cruz Biotech) immunohistochemistry (IHC) was performed on all cases. RESULTS: All AcCC cases except two (2/10, 80%) showed positive nuclear staining of variable intensity for NOR-1, with the majority of cases (75%) demonstrating at least moderately intense nuclear expression. All non-AcCC cases were negative for NOR-1, demonstrating a specificity of 100%. CONCLUSION: We conclude that NOR-1 IHC is sensitive and very specific on cytology specimens and is able to distinguish AcCC from its mimickers reliably and classify them appropriately for further management.

Adipocyte Thyroid Hormone ß Receptor-Mediated Hormone Action Fine-tunes Intracellular Glucose and Lipid Metabolism and Systemic Homeostasis.

Thyroid hormone (TH) has a profound effect on energy metabolism and systemic homeostasis. Adipose tissues are crucial for maintaining whole-body homeostasis; however, whether TH regulates systemic metabolic homeostasis through its action on adipose tissues is unclear. Here, we demonstrate that systemic administration of triiodothyronine (T3), the active form of TH, affects both inguinal white adipose tissue (iWAT) and whole-body metabolism. Taking advantage of the mouse model lacking adipocyte TH receptor (TR) α or TRß, we show that TRß is the major TR isoform that mediates T3 action on the expression of genes involved in multiple metabolic pathways in iWAT, including glucose uptake and use, de novo fatty acid synthesis, and both UCP1-dependent and -independent thermogenesis. Moreover, our results indicate that glucose-responsive lipogenic transcription factor in iWAT is regulated by T3, thereby being critically involved in T3-regulated glucose and lipid metabolism and energy dissipation. Mice with adipocyte TRß deficiency are susceptible to diet-induced obesity and metabolic dysregulation, suggesting that TRß in adipocytes may be a potential target for metabolic diseases. ARTICLE HIGHLIGHTS: How thyroid hormone (TH) achieves its diverse biological activities in the regulation of metabolism is not fully understood. Whether TH regulates systemic metabolic homeostasis via its action on white adipose tissue is unclear. Adipocyte TH receptor (TR) ß mediates the triiodothyronine effect on multiple metabolic pathways by targeting glucose-responsive lipogenic transcription factor in white adipose tissue; mice lacking adipocyte TRß are susceptible to high-fat diet-induced metabolic abnormalities. TRß in white adipocytes controls intracellular and systemic metabolism and may be a potential target for metabolic diseases.

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

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

Noncoding Mutations in a Thyroid Hormone Receptor Gene That Impair Cone Photoreceptor Function.

The function of a hormone receptor requires mechanisms to control precisely where, when, and at what level the receptor gene is expressed. An intriguing case concerns the selective induction of thyroid hormone receptor ß2 (TRß2), encoded by Thrb, in the pituitary and also in cone photoreceptors, in which it critically regulates expression of the opsin photopigments that mediate color vision. Here, we investigate the physiological significance of a candidate enhancer for induction of TRß2 by mutagenesis of a conserved intron region in its natural context in the endogenous Thrb gene in mice. Mutation of e-box sites for bHLH (basic-helix-loop-helix) transcription factors preferentially impairs TRß2 expression in cones whereas mutation of nearby sequences preferentially impairs expression in pituitary. A deletion encompassing all sites impairs expression in both tissues, indicating bifunctional activity. In cones, the e-box mutations disrupt chromatin acetylation, blunt the developmental induction of TRß2, and ultimately impair cone opsin expression and sensitivity to longer wavelengths of light. These results demonstrate the necessity of studying an enhancer in its natural chromosomal context for defining biological relevance and reveal surprisingly critical nuances of level and timing of enhancer function. Our findings illustrate the influence of noncoding sequences over thyroid hormone functions.