Cardiac glucose utilization in mice with mutated α- and β-thyroid hormone receptors

2004 ◽  
Vol 287 (6) ◽  
pp. E1149-E1153 ◽  
Author(s):  
Takanori Esaki ◽  
Hideyo Suzuki ◽  
Michelle Cook ◽  
Kazuaki Shimoji ◽  
Sheue-Yann Cheng ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Thyroid Hormone ◽  
Cardiac Function ◽  
Hormone Receptors ◽  
Glucose Utilization ◽  
Wild Type ◽  
Binding Region ◽  
Binding Ability ◽  
Β Receptor ◽  
Thyroid Hormone Resistance Syndrome

Abnormal thyroid function is usually associated with altered cardiac function. Mutations in the thyroid hormone (TH)-binding region of the TH β-receptor (TRβ) that eliminate its TH-binding ability lead to the thyroid hormone resistance syndrome (RTH) in humans, which is characterized by high blood TH levels, goiter, hyperactivity, and tachycardia. Mice with “knock-in” mutations in the TH α-receptor (TRα) or TRβ that remove their TH-binding ability have been developed, and those with the mutated TRβ (TRβ PV/PV) appear to provide a model for RTH. These two types of mutants show different effects on cerebral energy metabolism, e.g., negligible change in glucose utilization (CMRGlc) in TRβ PV/PV mice and markedly reduced CMRGlc, like that found in cretinous rats, in the mice (TRα PV/+) with the knock-in mutation of the TRα gene. Studies in knockout mice have indicated that the TRα may also influence heart rate. Because mutations in both receptor genes appear to affect some parameters of cardiac function and because cardiac functional activity and energy metabolism are linked, we measured heart glucose utilization (HMRGlc) in both the TRβ PV/PV and TRα PV/+ mutants. Compared with values in normal wild-type mice, HMRGlc was reduced (−77 to −95%) in TRα PV/+ mutants and increased (87 to 340%) in TRβ PV/PV mutants, the degree depending on the region of the heart. Thus the TRα PV/+ and TRβ PV/PV mutations lead, respectively, to opposite effects on energy metabolism in the heart that are consistent with the bradycardia seen in hypothyroidism and the tachycardia associated with hyperthyroidism and RTH.

scholarly journals The Impact of a Non-Functional Thyroid Receptor Beta upon Triiodotironine-Induced Cardiac Hypertrophy in Mice

2015 ◽  
Vol 37 (2) ◽  
pp. 477-490 ◽  
Author(s):  
Güínever Eustáquio do Império ◽  
Isalira Peroba Ramos ◽  
Letícia Aragão Santiago ◽  
Guilherme Faria Pereira ◽  
Norma Aparecida dos Santos Almeida ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Hormone Receptors ◽  
Heart Function ◽  
Hypertrophic Growth ◽  
Regulation Mechanisms ◽  
Heart Functions ◽  
The Impact

Background/Aims: Thyroid hormone (TH) signalling is critical for heart function. The heart expresses thyroid hormone receptors (THRs); THRα1 and THRβ1. We aimed to investigate the regulation mechanisms of the THRβ isoform, its association with gene expression changes and implications for cardiac function. Methods: The experiments were performed using adult male mice expressing TRβΔ337T, which contains the Δ337T mutation of the human THRB gene and impairs ligand binding. Cardiac function and RNA expression were studied after hypo-or hyperthyroidism inductions. T3-induced cardiac hypertrophy was not observed in TRβΔ337T mice, showing the fundamental role of THRβ in cardiac hypertrophy. Results: We identified a group of independently regulated THRβ genes, which includes Adrb2, Myh7 and Hcn2 that were normally regulated by T3 in the TRβΔ337T group. However, Adrb1, Myh6 and Atp2a2 were regulated via THRβ. The TRβΔ337T mice exhibited a contractile deficit, decreased ejection fraction and stroke volume, as assessed by echocardiography. In our model, miR-208a and miR-199a may contribute to THRβ-mediated cardiac hypertrophy, as indicated by the absence of T3-regulated ventricular expression in TRβΔ337T mice. Conclusion: THRβ has important role in the regulation of specific mRNA and miRNA in T3-induced cardiac hypertrophic growth and in the alteration of heart functions.

scholarly journals Differences between the silencing-related properties of the extreme carboxyl-terminal regions of thyroid hormone receptors alpha 1 and beta 1

2000 ◽  
Vol 167 (2) ◽  
pp. 219-227 ◽  
Author(s):  
K Nishiyama ◽  
A Matsushita ◽  
H Natsume ◽  
T Mikami ◽  
R Genma ◽  
...  
Keyword(s):  
Amino Acid ◽  
Thyroid Hormone ◽  
Hormone Receptors ◽  
Target Genes ◽  
Thyroid Hormone Receptor ◽  
Thyroid Hormone Receptors ◽  
Human Thyroid ◽  
Wild Type ◽  
Amino Acid Deletion ◽  
The Difference

Human thyroid hormone receptor (TR) is encoded by two distinct genes, TR alpha and TR beta. TR heterodimerizes with retinoid X receptor (RXR) and binds efficiently to the thyroid hormone (T(3)) response element (TRE) of target genes. In the absence of T(3), unliganded TR suppresses the basal promoter activity of positively regulated genes (silencing). Silencing mediator for retinoid and thyroid hormone receptors (SMRT) and nuclear receptor co-repressor (N-CoR) interact with unliganded TR and function as corepressor proteins. Previously, we found beta F451X with carboxyl (C)-terminal 11-amino acid deletion had stronger silencing potency than wild-type TR beta 1 and beta E449X with C-terminal 13-amino acid deletion on a subset of TREs. In the present study, to assess the isoform-specific effects of the C-terminal truncations on TR silencing, we constructed two mutant TR alpha 1s (alpha F397X and alpha E395X) with the same respective C-terminal truncations as beta F451X and beta E449X and analysed their silencing activities. Unlike beta F451X and beta E449X, alpha F397X and alpha E395X showed similarly stronger silencing potency than wild-type TR alpha 1. We further studied the abilities of wild-type and the mutant TR beta 1s and alpha 1s on RXR and co-repressor binding by a two-hybrid interference assay. beta F451X had significantly stronger abilities to bind to RXR and SMRT than did wild-type TR beta 1 and beta E449X. In contrast, wild-type TR alpha 1, alpha F397X and alpha E395X showed similar abilities to bind to RXR and SMRT. beta E449X and alpha E395X, which have identical C-terminal truncation, showed less ability to bind to N-CoR than did wild-type TR beta 1 and beta F451X and wild-type TR alpha 1 and alpha F397X respectively. These results indicate that an identical C-terminal truncation gives rise to different effects on TR beta 1 and alpha1 with respect to silencing potency, RXR binding and SMRT binding. The difference in the silencing potency among wild-type TR beta 1, beta F451X and beta E449X correlated well with the difference in the ability to bind co-repressor SMRT.

scholarly journals Thyroid hormone-stimulated differentiation of primary rib chondrocytes in vitro requires thyroid hormone receptor β

2006 ◽  
Vol 191 (1) ◽  
pp. 221-228 ◽  
Author(s):  
Bénédicte Rabier ◽  
Allan J Williams ◽  
Frederic Mallein-Gerin ◽  
Graham R Williams ◽  
O Chassande
Keyword(s):  
Thyroid Hormone ◽  
Growth Plate ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptor ◽  
Primary Cultures ◽  
Wild Type ◽  
Proliferation And Differentiation ◽  
Thyroid Hormone Receptor Β

The active thyroid hormone, triiodothyronine (T3), binds to thyroid hormone receptors (TR) and plays an essential role in the control of chondrocyte proliferation and differentiation. Hypo- and hyperthyroidism alter the structure of growth plate cartilage and modify chondrocyte gene expression in vivo, whilst TR mutations or deletions in mice result in altered growth plate architecture. Nevertheless, the particular roles of individual TR isoforms in mediating T3 action in chondrocytes have not been studied and are difficult to determine in vivo because of complex cellular and molecular interactions that regulate growth plate maturation. Therefore, we studied the effects of TRα and TRβ on chondrocyte growth and differentiation in primary cultures of neonatal rib chondrocytes isolated from TRα- and TRβ-deficient mice. T3 decreased proliferation but accelerated differentiation of rib chondrocytes from wild-type mice. T3 treatment resulted in similar effects in TRα-deficient chondrocytes, but in TRβ-deficient chondrocytes, all T3 responses were abrogated. Furthermore, T3 increased TRβ1 expression in wild-type and TRα-deficient chondrocytes. These data indicate that T3-stimulated differentiation of primary rib chondrocytes in vitro requires TRβ and suggest that the TRβ1 isoform mediates important T3 actions in mouse rib chondrocytes.

scholarly journals Thyroid function and effect of aging in combined hetero/homozygous mice deficient in thyroid hormone receptors alpha and beta genes

2002 ◽  
Vol 172 (1) ◽  
pp. 177-185 ◽  
Author(s):  
RE Weiss ◽  
O Chassande ◽  
EK Koo ◽  
PE Macchia ◽  
K Cua ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Function ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptors ◽  
Thyroid Function Tests ◽  
Wild Type ◽  
Heterozygous Mouse ◽  
Tsh Secretion ◽  
Homozygous Deletions ◽  
Serum Tsh

The maintenance of thyroid hormone (TH) homeostasis is dependent on the synthesis and secretion of TH regulated by TSH. This is achieved, in turn, by the negative feedback of TH on TSH secretion and synthesis, which requires the interaction with TH receptors (TRs). Derived by alternative splicing of two gene transcription products, three TRs (TRbeta1, TRbeta2 and TRalpha1) interact with TH while another, TRalpha2, binds to DNA but not to TH. In this study we compare the results of thyroid function tests in mice with deletions of the TRalpha and TRbeta genes alone and present novel data on mice that are double homozygous and combined heterozygous. Homozygous deletions of both the TRalpha and TRbeta in the same mouse (TRalphao/o; TRbeta-/-) resulted in serum TSH values only slightly lower than those in athyreotic, Pax8 knockout mice. Whereas the absence of TRalpha alone does not cause resistance to TH, the absence of TRbeta in the presence of TRalpha results in a 205, 169, 544% increase in serum thyroxine (T(4)), triiodothyronine (T(3)) and TSH concentrations respectively. However, in the absence of TRbeta, loss of one TRalpha allele can worsen the resistance to TH with a 243 and 307% increase in T(4) and T(3) respectively. Similarly, while the heterozygous mouse with a single TRbeta allele shows no alteration in thyroid function, the concomitant deletion of TRalpha brings about mild but significant resistance to TH. Furthermore, the severity of the resistance to TH was noted to decrease with age in parallel with the decrease in serum free T(4) values also seen in wild-type mice. These results demonstrate that (1) unliganded TRalpha or TRbeta are not absolutely necessary for the upregulation of TSH; (2) TRbeta but not TRalpha is sufficient for TH-mediated downregulation of TSH; and (3) TRalpha may partially substitute for TRbeta in mediating a partial TH-dependent TSH suppression.

scholarly journals Impaired Interaction of Mutant Thyroid Hormone Receptors Associated with Human Hepatocellular Carcinoma with Transcriptional Coregulators**This work was supported by grants from Chang-Gung University (CMRP 737, CMRP893, NMRP 407) and the National Science Council of the Republic of China (NSC 87-2316-B-182002).

Endocrinology ◽  
2001 ◽  
Vol 142 (2) ◽  
pp. 653-662 ◽  
Author(s):  
Kwang-huei Lin ◽  
Yi-hsin Wu ◽  
shen-liang chen
Keyword(s):  
Hepatocellular Carcinoma ◽  
Thyroid Hormone ◽  
Reporter Gene ◽  
Hormone Receptors ◽  
Biological Activities ◽  
Human Hepatocellular Carcinoma ◽  
Dominant Negative ◽  
Wild Type ◽  
Transfected Cells ◽  
Transcriptional Coregulators

Abstract Thyroid hormone (T3) exerts its many biological activities through interaction with specific nuclear receptors (TRs) that function as ligand-dependent transcription factors at genes that contain a thyroid hormone response element (TRE). Mutant TRs have been detected in human hepatocellular carcinoma cell lines and tissue, but their contribution to carcinogenesis has remained unclear. The interaction of four such mutant TRs (J7-TRα1, J7-TRβ1, H-TRα1, and l-TRα1) with transcriptional coregulators has now been investigated. With the exception of J7-TRα1, which in the absence of T3 exhibited transcriptional silencing activity with a TRE-reporter gene construct in transfected cells, the mutant TRs had little effect (compared with that of wild-type receptors) on transcriptional activity of the reporter gene in the absence or presence of T3, of the transcriptional corepressors SMRT, NCoR or of the transcriptional coactivator SRC. Electrophoretic mobility-shift assays revealed that, in the presence of T3, the J7-TRβ1 mutant did not interact with SRC, whereas J7-TRα1 and H-TRα1 exhibited reduced abilities to associate with this coactivator and l-TRα1 showed an ability to interact with SRC similar to that of wild-type TRα1. The dominant negative activity of the mutant TRs in transfected cells appeared inversely related to the ability of the receptors to interact with SRC. Whereas J7-TRβ1, H-TRα1, and l-TRα1 did not interact with SMRT, and NCoR. J7-TRα1 bind to corepressors but failed to dissociate from them in the presence of T3. These aberrant interactions between the mutant TRs and transcriptional coregulators may contribute to the highly variable clinical characteristics of human hepatocellular carcinoma.

scholarly journals Constitutive activation of gene expression by thyroid hormone receptor results from reversal of p53-mediated repression.

1997 ◽  
Vol 17 (12) ◽  
pp. 7195-7207 ◽  
Author(s):  
J S Qi ◽  
V Desai-Yajnik ◽  
Y Yuan ◽  
H H Samuels
Keyword(s):  
Gene Expression ◽  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Promoter Activity ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptor ◽  
Gene Promoters ◽  
Wild Type ◽  
Constitutive Activation

Thyroid hormone receptor (T3R) is a member of the steroid hormone receptor gene family of nuclear hormone receptors. In most cells T3R activates gene expression only in the presence of its ligand, L-triiodothyronine (T3). However, in certain cell types (e.g., GH4C1 cells) expression of T3R leads to hormone-independent constitutive activation. This activation by unliganded T3R occurs with a variety of gene promoters and appears to be independent of the binding of T3R to specific thyroid hormone response elements (TREs). Previous studies indicate that this constitutive activation results from the titration of an inhibitor of transcription. Since the tumor suppresser p53 is capable of repressing a wide variety of gene promoters, we considered the possibility that the inhibitor is p53. Evidence to support this comes from studies indicating that expression of p53 blocks T3R-mediated constitutive activation in GH4C1 cells. In contrast with hormone-independent activation by T3R, p53 had little or no effect on T3-dependent stimulation which requires TREs. In addition, p53 mutants which oligomerize with wild-type p53 and interfere with its function also increase promoter activity. This enhancement is of similar magnitude to but is not additive with the stimulation mediated by unliganded T3R, suggesting that they target the same factor. Since p53 mutants are known to target wild-type p53 in the cell, this suggests that T3R also interacts with p53 in vivo and that endogenous levels of p53 act to suppress promoter activity. Evidence supporting both functional and physical interactions of T3R and p53 in the cell is presented. The DNA binding domain (DBD) of T3R is important in mediating constitutive activation, and the receptor DBD appears to functionally interact with the N terminus of p53 in the cell. In vitro binding studies indicate that the T3R DBD is important for interaction of T3R with p53 and that this interaction is reduced by T3. These findings are consistent with the in vivo studies indicating that p53 blocks constitutive activation but not ligand-dependent stimulation. These studies provide insight into mechanisms by which unliganded nuclear hormone receptors can modulate gene expression and may provide an explanation for the mechanism of action of the v-erbA oncoprotein, a retroviral homolog of chicken T3R alpha.

Thyroid hormone and cardiac function in mice deficient in thyroid hormone receptor-α or -β: an echocardiograph study

2002 ◽  
Vol 283 (3) ◽  
pp. E428-E435 ◽  
Author(s):  
Roy E. Weiss ◽  
Claudia Korcarz ◽  
Olivier Chassande ◽  
Kevin Cua ◽  
Peter M. Sadow ◽  
...  
Keyword(s):  
Cardiac Output ◽  
Thyroid Hormone ◽  
Cardiac Index ◽  
Cardiac Function ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Wild Type ◽  
Lv Mass ◽  
Thyroid Hormone Receptor Α ◽  
Made In

We investigated the effect of thyroid hormone (TH) receptor (TR)α and -β isoforms in TH action in the heart. Noninvasive echocardiographic measurements were made in mice homozygous for disruption of TRα (TRα0/0) or TRβ (TRβ−/−). Mice were studied at baseline, 4 wk after TH deprivation (using a low-iodine diet containing propylthiouracil), and after 4-wk treatment with TH. Baseline heart rates (HR) were similar in wild-type (WT) and TRα0/0 mice but were greater in TRβ−/− mice. With TH deprivation, HR decreased 49% in WT and 37% in TRβ−/− mice and decreased only 5% in TRα0/0 mice from baseline, whereas HR increased in all genotypes with TH treatment. Cardiac output (CO) and cardiac index (CI) in WT mice decreased (−31 and −32%, respectively) with TH deprivation and increased (+69 and +35%, respectively) with TH treatment. The effects of CO and CI were blunted with TH withdrawal in both TRα0/0 (+8 and −2%, respectively) and TRβ−/− mice (−17 and −18%, respectively). Treatment with TH resulted in a 64% increase in LV mass in WT and a 44% increase in TRα0/0 mice but only a 6% increase in TRβ−/− mice (ANOVA P < 0.05). Taken together, these data suggest that TRα and TRβ play different roles in the physiology of TH action on the heart.

scholarly journals Analysis of the roles of mutations in thyroid hormone receptor-β by a bacterial biosensor system

2013 ◽  
Vol 52 (1) ◽  
pp. 55-66 ◽  
Author(s):  
Changhua Shi ◽  
Qing Meng ◽  
David W Wood
Keyword(s):  
Thyroid Hormone ◽  
Ligand Binding ◽  
Developmental Disorders ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptor ◽  
Binding Ability ◽  
Bacterial Biosensor ◽  
Bacterial System ◽  
Biosensor System ◽  
Thyroid Hormone Receptor Β

Mutations in thyroid hormone receptors (TRs) often lead to metabolic and developmental disorders, but patients with these mutations are difficult to treat with existing thyromimetic drugs. In this study, we analyzed six clinically observed mutations in the ligand-binding domain of the human TRβ using an engineered bacterial hormone biosensor. Six agonist compounds, including triiodothyronine (T3), thyroxine (T4), 3,5,3′-triiodothyroacetic acid (Triac), GC-1, KB-141, and CO-23, and the antagonist NH-3 were examined for their ability to bind to each of the TRβ mutants. The results indicate that some mutations lead to the loss of ability to bind to native ligands, ranging from several fold to several hundred fold, while other mutations completely abolish the ability to bind to any ligand. Notably, the effect of each ligand on each TRβ mutant in this bacterial system is highly dependent on both the mutation and the ligand; some ligands were bound well by a wide variety of mutants, while other ligands lost their affinity for all but the WT receptor. This study demonstrates the ability of our bacterial system to differentiate agonist compounds from antagonist compounds and shows that one of the TRβ mutations leads to an unexpected increase in antagonist ability relative to other mutations. These results indicate that this bacterial sensor can be used to rapidly determine ligand-binding ability and character for clinically relevant TRβ mutants.

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