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At least 667 records · Page 37Linked to original sources

PubMed2003

Modulation by steroid receptor coactivator-1 of target-tissue responsiveness in resistance to thyroid hormone.

Mutations in the thyroid hormone receptor-beta gene (TR beta) cause resistance to thyroid hormone. How the action of mutant thyroid hormone nuclear receptors (TRs) is regulated in vivo is not clear. We examined the effect of a TR coactivator, steroid receptor coactivator-1 (SRC-1), on target-tissue responsiveness by using a mouse model of resistance to thyroid hormone, TR beta PV knockin mice, in the SRC-1 null background. Lack of SRC-1 intensified the dysfunction of the pituitary-thyroid axis and impaired growth in TR beta(PV/+) mice but not in TR beta(PV/PV) mice. In TR beta(PV/PV) mice, however, lack of SRC-1 intensified the pathological progression of thyroid follicular cells to papillary hyperplasia, reminiscent of papillary neoplasia. In contrast, lack of SRC-1 did not affect responsiveness in the liver in regulating serum cholesterol in either TR beta(PV/+) or TR beta(PV/PV) mice. Lack of SRC-1 led to changes in the abnormal expression patterns of several T(3) target genes in the pituitary and liver. Thus, the present studies show that a coactivator such as SRC-1 could modulate the in vivo action of TR beta mutants in a tissue-dependent manner.

Animals↗

PubMed1977

Changes in the circulating thyroid hormones during anaesthesia and thyroid surgery.

The circulating thyroid hormones were found to respond to general anaesthesia and surgery of the thyroid gland in a similar manner to that reported with general surgery. When compared with the preoperative plasma concentration, the post-operative thyroxine levels showed a significant rise, whereas the triiodothyronine level fell.

Adolescent↗

PubMed1989

Effect of thyroidectomy of immature male chickens on circulating thyroid hormones and on response to thyroid-stimulating hormone and chronic cold exposure.

Previous studies in the author's laboratory established that thyroidectomized (Tx) immature male chickens had significant levels of circulating thyroid hormones, and it was proposed that extrathyroidal tissue might be present. Three experiments were conducted to further investigate this possibility. In all experiments, thyroid glands were removed surgically at 3 wk of age. In the first experiment, birds were kept until 20 wk of age. It was found that only triidothyronine levels were reduced significantly in the Tx birds. In the second experiment, Tx as well as sham-operated control groups received a single iv injection of bovine thyroid-stimulating hormone (TSH) to determine if extrathyroidal tissue in Tx birds would respond to exogenous TSH. It was found that circulating thyroxine (T4) concentrations in sham-operated control birds, but not Tx birds, were increased following TSH injection. In the third experiment, Tx and sham-operated birds were exposed chronically to cold (7 C), and only circulating T4 was found to be elevated in both groups. It was concluded that extrathyroidal tissue in Tx birds does not respond to TSH.

Aging↗

PubMed1991

Thyroid hormone: half-sites and insights. Molecular Approaches to the Study of Thyroid hormone Action: a Keystone Symposium, Tamarron, CO, USA, March 8-14, 1991.

As is evident from the range of topics addressed in this review, T3 has important and interesting effects on virtually every biological system in higher organisms. Many of these effects are beginning to be understood at the molecular level, while others are not far behind. It is striking that the diversity of biological activities of T3 is reflected in a broad spectrum of molecular mechanisms. Even within the relatively circumscribed paradigm of receptor activation by hormone binding, a surprisingly large number of possible interactions and complications has been discovered. This richness of alternative interactions leads directly to complex and unanticipated regulatory possibilities. A major strength of this meeting was that it encompassed the broad range of T3 effects and thereby was able to provide something new for every attendee. From this perspective, it is easy to predict that study of T3 will continue to provide new and surprising insights into major biological questions for years to come.

Animals↗

PubMed1994

Thyroid hormone autoantibodies in patients with Graves' disease: effect of anti-thyroid drug treatment.

We examined the effects of anti-thyroid drug treatment on serum autoantibodies against thyroid hormones (thyroid hormone autoantibodies, THAA), thyroglobulin (Tg) and thyroid peroxidase (TPO) in patients with Graves' disease by measuring each autoantibody level before and after treatment. Six patients among 40 untreated patients with Graves' disease had anti-thyroxine (T4) antibodies. One patient had both anti-T4 and anti-triiodothyronine (T3) antibodies. Thus the prevalence of THAA in untreated Graves' disease was 7 out of 40 (17.5%). Changes in T4-Ab levels after treatment varied. In five cases (cases 3-7) levels decreased 4-7 months after treatment. However, in the other two cases levels fluctuated 1, 3, 6 and 12 months after treatment. None of the previously THAA-negative patients became positive after treatment. Anti-Tg antibody (Tg-Ab) was positive in 34 out of 40 (85%) untreated cases and its level decreased in both THAA positive and negative patients after treatment. Anti-thyroid peroxidase antibody (TPO-Ab) was positive in 32 of the 40 (80%) untreated Graves' patients and its level significantly decreased after treatment. Our findings suggest that treatment with anti-thyroid drugs does not produce THAA in Graves' disease.

Adult↗

PubMed2005

Peripheral metabolism of thyroid hormone and glucose homeostasis.

Thyroid hormone action has long been recognized as an important determinant of glucose homeostasis. Recent advances in the knowledge of the physiology of the deiodinases indicate that through tissue-specific regulation of thyroid hormone metabolism, leading to local specificity of thyroid hormone action and target gene transcription patterns, they may have an important function in the modulation of carbohydrate metabolism. This review briefly addresses the role of thyroid hormone action on glucose homeostasis with a specific focus on the significance of the peripheral metabolism of thyroid hormone in the regulation of glucose homeostasis and insulin sensitivity.

Alleles↗

PubMed1998

Thyroid hormone and cardiovascular disease.

Thyroid hormone directly affects the heart and peripheral vascular system. The hormone can increase myocardial inotropy and heart rate and dilate peripheral arteries to increase cardiac output. An excessive deficiency of thyroid hormone can cause cardiovascular disease and aggravate many preexisting conditions. In severe systemic illness and after major surgical procedures changes in thyroid function can occur, leading to the "euthyroid sick syndrome." Patients will have normal or decreased levels of T4, decreased free and total T3, and usually normal levels of thyroid stimulating hormone. This syndrome may be an adaptive response to systemic illness that usually will revert to normal without hormone supplementation as the illness subsides. Recently, however, many investigators have explored the benefits of thyroid hormone supplementation in those diseases associated with euthyroid sick syndrome. Thyroid hormone's effects on the cardiovascular system make it an attractive therapy for those patients with impaired hemodynamics and low T3. Thyroid hormone has also been considered a treatment for patients with congestive heart failure, for patients undergoing cardiopulmonary bypass and heart transplantation, and for patients with hyperlipidemia. At present there is no evidence suggesting a favorable treatment outcome using thyroid hormone supplementation for any systemic condition except in those patients with documented hypothyroidism.

Cardiopulmonary Bypass↗

PubMed1981

Prealbumin and the thyroid hormone nuclear receptor.

The thyroid hormones exhibit a wide range of biological activities, which are now thought to be mediated by a specific receptor molecule in the nucleus of the target cells. This receptor appears to promote the production of new mRNA molecules, leading to the synthesis of proteins, but the precise mode of action of the receptor and the nature of the gene products are not known at present. Thyroid hormone binding proteins are also present in the blood plasma; in humans there are two distinct binding proteins, thyroxine binding globulin (TBG) and prealbumin (PA), sometimes known as thyroxine binding (TBPA). In addition to its hormone binding function PA is also involved in vitamin A transport through a protein-protein interaction with the specific vitamin A binding protein in plasma, retinol-binding protein (RBP). Prealbumin has been subjected to an extensive X-ray analysis of its molecular structure and interactions with the thyroid hormones. The PA molecule is a tetramer of 55 000 relative molecular mass, composed of identical subunits. The structure of the subunit is essentially an eight-stranded beta-barrel. The subunits are organized in the tetramer by extensive hydrogen-bond and hydrophobic contacts, giving rise to a prealbumin molecule with a channel running right through its centre, and two deep cylindrical-helical depressions in its outer surface. The central channel contains two identical binding sites for the thyroid hormones, which closely match the shape and chemistry of the iodothyronine nucleus of the hormones. The two deep surface depressions have found to be structurally complementary to the DNA double helix. This structural information on prealbumin may be appropriate to the nuclear receptor in the light of recent studies that suggest a considerable degree of functional similarity between the two molecules. In particular, the receptor appears to be composed of two units: a thyroid hormone binding unit, or core receptor, and a regulatory unit that modulates the hormone binding; this latter protein may be a histone. Separating the hormone binding unit from the holoreceptor radically changes the binding affinity for the thyroid hormones and their analogues, with the pattern of binding in the core receptor showing a striking similarity to the pattern in prealbumin. These and other similarities between the two proteins are examined, and possible relationships are considered.

Animals↗

PubMed1998

[Non-thyroid indications of treatment with thyroid hormones].

INTRODUCTION: The use of thyroid hormone is currently strictly limited to thyroid diseases. Several recent papers have examined the effects of thyroid hormone in non-thyroidal diseases. These studies examined either the use of the pharmacological properties of thyroid hormone or the effect of the correction of the decrease in triiodothyronine (T3) associated with non-thyroid illnesses. CURRENT KNOWLEDGE AND KEY POINTS: Intravenous administration of T3 improves the cardiac index during ongoing cardiac surgery, with a paradoxical decrease in the incidence of atrial fibrillation. T3 administered by the oral route also improves the cardiac index in the medium term in dilated cardiomyopathy. No benefit on survival has been demonstrated in non-thyroidal diseases when using the pharmacological properties of thyroid hormone. Other situations, such as transplantation or neural rescue after cardiac arrest, are currently under study. In non-thyroidal diseases, administration of thyroxine (T4) has no effect because of the deeply disturbed metabolism of thyroid hormones. FUTURE PROSPECTS AND PROJECTS: Adverse metabolic effects of T4 and T3 therapy have probably been overestimated and may depend on the dose and on the time of administration in the course of the disease. Indications in cardiac surgery and cardiac diseases need to be clarified. To further understand the value of thyroid hormones in non-thyroidal diseases, placebo-controlled studies using small doses of T3 are required.

Animals↗

PubMed1997

The major transcription initiation site of the SV40 late promoter is a potent thyroid hormone response element.

Thyroid hormone receptors (TRs) are members of the nuclear hormone receptor superfamily, which act as transcription factors upon binding to specific DNA sequences called thyroid hormone (T3) response elements (TREs). Such elements are found in the upstream regulatory region of promoters as well as in intragenic sequences of T3-responsive genes. In this report, we demonstrate that SV40 late (SVL) promoter activity is strongly down-regulated by TR in the absence of ligand. Addition of T3 releases this repression, but does not further induce SVL promoter activity. Electrophoretic mobility shift analyses reveal a TR binding element that overlaps with the SV40 major late transcription initiation site. This element closely fits the consensus TRE, formed of two hexanucleotides organized in a tandem repeat separated by 4 nt, and is able to confer T3 responsiveness on a heterologous promoter. We further show that, although the presence of TR leads to quantitatively modified expression of an SVL-driven reporter gene, neither displacement of the site of transcription initiation nor modification of the splicing pattern of the primary transcripts occur.

3T3 Cells↗

PubMed2001

Cyclin D1 is an early target in hepatocyte proliferation induced by thyroid hormone (T3).

The thyroid hormone (T3) affects cell growth, differentiation, and regulates metabolic functions via its interaction with the thyroid hormone nuclear receptors (TRs). The mechanism by which TRs mediate cell growth is unknown. To investigate the mechanisms responsible for the mitogenic effect of T3, we have determined changes in activation of transcription factors, mRNA levels of immediate early genes, and levels of proteins involved in the progression from G1 to S phase of the cell cycle. We show that hepatocyte proliferation induced by a single administration of T3 to Wistar rats occurred in the absence of activation of AP-1, NF-kappa B, and STAT3 or changes in the mRNA levels of the immediate early genes c-fos, c-jun, and c-myc. These genes are considered to be essential for liver regeneration after partial hepatectomy (PH). On the other hand, T3 treatment caused an increase in cyclin D1 mRNA and protein levels that occurred much more rapidly compared to liver regeneration after 2/3 PH. The early increase in cyclin D1 expression was associated with accelerated onset of DNA synthesis, as demonstrated by a 20-fold increase of bromodeoxyuridine-positive hepatocytes at 12 h after T3 treatment and by a 20-fold increase in mitotic activity at 18 h. An early increase of cyclin D1 expression was also observed after treatment with nafenopin, a ligand of a nuclear receptor (peroxisome proliferator-activated receptor alpha) of the same superfamily of steroid/thyroid receptors. T3 treatment also resulted in increased expression of cyclin E, E2F, and p107 and enhanced phosphorylation of pRb, the ultimate substrate in the pathway leading to transition from G1 to S phase. The results demonstrate that cyclin D1 induction is one of the earlier events in hepatocyte proliferation induced by T3 and suggest that this cyclin might be a common target responsible for the mitogenic activity of ligands of nuclear receptors.

Animals↗

PubMed2003

Gene silencing by the thyroid hormone receptor.

The thyroid hormone receptors (TR) are able to bind DNA and to repress transcription in the absence of thyroid hormone. This repression function is an important feature of TRs as aberrant silencing can lead to severe diseases and developmental abnormalities. TR utilizes different mechanisms to achieve repression of target genes including the recruitment of cofactors called corepressors and interference with the basal transcriptional machinery. Recent studies have revealed an important role of chromatin in TR silencing involving different histone modifications and the responsible enzymes. Furthermore, the transcriptional properties of TR depend on the type of the TR DNA-binding elements. This review will focus on the molecular basis of gene silencing by TR and diseases caused by aberrant functioning.

Animals↗

PubMed2004

An RNA-binding domain in the thyroid hormone receptor enhances transcriptional activation.

Thyroid hormone plays important roles in development, differentiation, and metabolic homeostasis by binding to nuclear thyroid hormone receptors, which regulate target gene expression by interacting with DNA response elements and coregulatory proteins. We show that thyroid hormone receptors also are single-stranded RNA binding proteins and that this binding is functionally significant. By using a series of deletion mutants, a novel RNA-binding domain was localized to a 41-amino acid segment of thyroid hormone receptor alpha1 between the second zinc finger and the ligand-binding domain. This RNA-binding domain was necessary and sufficient for thyroid hormone receptor binding to the steroid receptor RNA activator (SRA). Although SRA does not bind directly to steroid receptors, it has been identified as a steroid receptor coactivator, and was thought not to be a coactivator for thyroid hormone receptors. However, transfection studies revealed that SRA enhances thyroid hormone induction of appropriate reporter genes and that the thyroid hormone receptor RNA-binding domain is important for this enhancement. We conclude that thyroid hormone receptors bind RNA through a novel domain and that the interaction of this domain with SRA, and perhaps other RNAs, enhances thyroid hormone receptor function.

Amino Acid Sequence↗

PubMed1996

Mutation in the thyroid hormone receptor (TR) beta gene (M313T) not previously reported in two unrelated families with resistance to thyroid hormone (RTH).

Two families expressing the RTH phenotype and harboring the same mutation in the TRbeta gene are described. Five and four affected members in each family were investigated as well as a total of 12 unaffected relatives. The mutation, a T to C transition of nucleotide 1223 in one allele of affected individuals, results in the replacement of the normal Met for a Thr. Haplotyping revealed that the same mutation developed in each family independently. Whereas attention deficit hyperactivity disorder was associated with RTH in 7 of the 9 affected individuals, it was also present in 2 family members without RTH.

Alleles↗

PubMed1980

[Normality of serum thyroid hormones, thyroxine binding globulin and thyroid stimulating hormone concentrations in normal adult men (author's transl)].

The normality of serum thyroxine (T4), triiodothyronine (T3), reverse T3, thyroxine binding globulin (TBG) and thyroid stimulating hormone (TSH) concentrations were investigated by using normal probability paper. 107 healthy adult men (age 35-48) were carefully selected; their healthiness was evaluated by physical, biochemical and roentogenologic examinations as well as by intensive interview on their past history. All assays were simultaneously carried out. When each cumulative distribution was plotted on normal probability paper, the straight line was obtained in T4, T3 and TBG but in rT3 and TSH, the lineality was seen only when logarithmic normal probability paper was used. The normal ranges by conventional statistical calculation, i.e., mean +/-2 S.D. was compared with those obtained on normal probability paper. The normal ranges of T4, T3 and TBG agreed well each other, whereas in rT3 and TSH, normal ranges obtained on the probability paper shifted toward higher levels than those by statistical calculations. Thus, it is suggested that the normal ranges of rT3 and TSH should be defined either by statistical calculation of each result after logarithmic transformation or by using logarithmic probability paper.

Adult↗

PubMed2007

Impaired adipogenesis caused by a mutated thyroid hormone alpha1 receptor.

Thyroid hormone (T3) is critical for growth, differentiation, and maintenance of metabolic homeostasis. Mice with a knock-in mutation in the thyroid hormone receptor alpha gene (TRalpha1PV) were created previously to explore the roles of mutated TRalpha1 in vivo. TRalpha1PV is a dominant negative mutant with a frameshift mutation in the carboxyl-terminal 14 amino acids that results in the loss of T3 binding and transcription capacity. Homozygous knock-in TRalpha1(PV/PV) mice are embryonic lethal, and heterozygous TRalpha1(PV/+) mice display the striking phenotype of dwarfism. These mutant mice provide a valuable tool for identifying the defects that contribute to dwarfism. Here we show that white adipose tissue (WAT) mass was markedly reduced in TRalpha1(PV/+) mice. The expression of peroxisome proliferator-activated receptor gamma (PPARgamma), the key regulator of adipogenesis, was repressed at both mRNA and protein levels in WAT of TRalpha1(PV/+) mice. Moreover, TRalpha1PV acted to inhibit the transcription activity of PPARgamma by competition with PPARgamma for binding to PPARgamma response elements and for heterodimerization with the retinoid X receptors. The expression of TRalpha1PV blocked the T3-dependent adipogenesis of 3T3-L1 cells and repressed the expression of PPARgamma. Thus, mutations of TRalpha1 severely affect adipogenesis via cross talk with PPARgamma signaling. The present study suggests that defects in adipogenesis could contribute to the phenotypic manifestation of reduced body weight in TRalpha1(PV/+) mice.

Adipocytes, White↗

PubMed1984

The effect of acute and chronic exercise on thyroid hormones in obesity.

Thyroid hormones were measured before, during and after acute exercise (60 min) or physical training (3 months) in obese women. Thyroid stimulating hormone concentration increased during acute work and decreased immediately after. No changes were seen during the two following days. An increase was seen after ten days as well as after three months of physical training. Thyroxine concentrations showed no changes. 3,5,3'-Triiodothyronine decreased slightly immediately after acute exercise, and after three months of physical training, 3,3',5'-triiodothyronine (reverse triiodothyronine) increased slowly during and after acute exercise. A negative correlation was found between changes in fasting insulin and thyroxine and a positive correlation between changes in blood pressure and triiodothyronine after training. Lack of agreement in previous reports is probably due to methodological differences such as methods more or less susceptible to fatty acid interference, and thyroid hormones changing differently during acute work and before and after physical training. The duration of the study may also be of importance, even 3 months possibly being too short for attaining equilibrium in thyroid homeostasis.

Exercise Test↗

PubMed1994

[Peripheral thyroid hormone resistance].

Peripheral thyroid hormone resistance (PTHR) was first described by Refetoff in 1967, and was characterized by raised serum hormone values of T4 and T3 and in appropriately elevated values of TSH. PTHR has been shown to be caused by a mutation in the TR beta gene resulting in impaired nuclear binding of thyroid hormones or an impaired post receptor hormone effect. The patients are often characterized phenotypically by impairment of bone, heart or cerebral function.

Humans↗