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At least 613 records · Page 34Linked to original sources
PubMed1984

Determinants of thyroid hormone and thyroid-lipid interrelationships in Jerusalem.

In a study of 652 boys and 556 girls, aged 17, and 1,020 men and 575 women from the Jerusalem Lipid Research Clinic, serum thyroxine was higher in females than in males and higher in 17-year-old boys than in men. In most age- and sex groups, thyroxine was highest in Israelis originating from Asian and other Middle Eastern countries and lowest in immigrants or children of immigrants from Western countries. As in other population-based studies, we found a statistically significant negative correlation between thyroxine and triglyceride in adult males and negative correlations between thyroxine and high-density lipoprotein-cholesterol in all age- and sex groups. No associations between thyroxine and low-density lipoprotein-cholesterol or very low-density lipoprotein-cholesterol were observed.

Adolescent↗
PubMed2006

Thyroid hormone mediated changes in gene expression can be initiated by cytosolic action of the thyroid hormone receptor beta through the phosphatidylinositol 3-kinase pathway.

Thyroid hormone (TH) action is mediated principally through binding of the hormone ligand, 3,3,5-triiodothyronine (T3), to TH receptors (TRs). This hormone-receptor interaction recruits other proteins to form complexes that regulate gene expression by binding to DNA sequences in the promoter of target genes. We recently described an extranuclear mechanism of TH action that consists of the association of TH-liganded TRbeta with p85alpha [regulatory subunit of phosphatidylinositol 3-kinase (PI3K)] in the cytosol and subsequent activation of the PI3K, generating phosphatidylinositol 3,4,5-triphosphate [PtdIns(3,4,5)P3]. This initiates the activation of a signaling cascade by phosphorylation of Akt, mammalian target of rapamycin (mTOR) and its substrate p70(S6K), leading to the stimulation of ZAKI-4alpha synthesis, a calcineurin inhibitor. Furthermore, we found that this same mechanism leads to induction of the transcription factor hypoxia-inducible factor (HIF-1alpha), and its target genes, glucose transporter (GLUT)1, platelet-type phosphofructokinase (PFKP), and monocarboxylate transporter (MCT) 4. These genes are of special interest, because their products have important roles in cellular glucose metabolism, from glucose uptake (GLUT1) to glycolysis (PFKP) and lactate export (MCT4). These results demonstrate that the TH-TRbeta complex can exert a non-genomic action in the cytosol leading to changes in gene expression by direct (HIF-1alpha) and indirect (ZAKI-4alpha, GLUT1, PFKP) means.

Journal Article↗
PubMed1992

Feedback regulation of thyrotropin-releasing hormone gene expression by thyroid hormone in the hypothalamic paraventricular nucleus.

Hypothyroidism caused by chemical or surgical thyroidectomy or hypophysectomy causes a substantial increase in the content of thyrotropin-releasing hormone (TRH) mRNA and proTRH exclusively in cells of the medial and periventricular paravocellular subdivisions of the hypothalamic paraventricular nucleus (PVN). This response may be important to raise the anterior pituitary thyrostat to promote increased secretion of thyroid-stimulating hormone (TSH) and to induce the secretion of a more biologically active TSH. The increase in TRH mRNA can be obliterated by stereotaxic implants of hormonally active L-triiodothyronine (T3) placed into the anterior hypothalamus but not by implants of the hormonally inactive 3,5'-diiodo-L-thyronine (T2); we therefore suggested that T3 has a direct action on TRH-containing cells of the PVN. Ablation of brainstem catecholaminergic projection fields to the PVN (known to stimulate TRH secretion) has no effect on TRH mRNA expression; beta 1 thyroid hormone receptor mRNA is present in extracts of the PVN. Euthyroid levels of serum T3 in hypothyroid animals achieved via intraperitoneally implanted osmotic minipumps are not associated with a return of PVN levels of TRH mRNA to normal unless circulating T3 levels are raised into the hyperthyroid range (1.7 times normal). This requirement is similar to that needed to normalize nuclear thyroid hormone receptor levels in the anterior pituitary of hypothyroid animals, suggesting that in addition to circulating T3 monodeiodination of T4 to T3 within the brain must also contribute to feedback inhibition of TRH mRNA. As Type II deiodinase activity is absent or very low in the PVN and does not rise with hypothyroidism, we propose that an alternative source for T4 monodeiodination exists within the central nervous system.

Animals↗
PubMed2004

Cardiac glucose utilization in mice with mutated alpha- and beta-thyroid hormone receptors.

Abnormal thyroid function is usually associated with altered cardiac function. Mutations in the thyroid hormone (TH)-binding region of the TH beta-receptor (TRbeta) 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 alpha-receptor (TRalpha) or TRbeta that remove their TH-binding ability have been developed, and those with the mutated TRbeta (TRbeta(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 (CMR(Glc)) in TRbeta(PV/PV) mice and markedly reduced CMR(Glc), like that found in cretinous rats, in the mice (TRalpha(PV/+)) with the knock-in mutation of the TRalpha gene. Studies in knockout mice have indicated that the TRalpha 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 (HMR(Glc)) in both the TRbeta(PV/PV) and TRalpha(PV/+) mutants. Compared with values in normal wild-type mice, HMR(Glc) was reduced (-77 to -95%) in TRalpha(PV/+) mutants and increased (87 to 340%) in TRbeta(PV/PV) mutants, the degree depending on the region of the heart. Thus the TRalpha(PV/+) and TRbeta(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.

Animals↗
PubMed1994

[Resistance to thyroid hormone].

Resistance to thyroid hormone (RTH), Refetoff's syndrome, is a syndrome of reduced responsiveness of target tissue to thyroid hormone (TH). Inheritance is usually autosomal dominant except in one family, being recessive. Since a point mutation was first discovered in the thyroid hormone receptor (TR) beta gene of a subject with RTH, approximately 93 unrelated families with RTH have been found to have mutations on TR beta gene. Clinically they presented either generalized (GRTH) or dominantly pituitary (PRTH) resistance to TH. In one family, affected consanguineous individuals lacked the entire protein coding region of both hTR beta alleles. In this family with recessively inherited RTH, the obligate heterozygous parents exhibited no clinical and laboratory abnormalities. Thus, manifestation of RTH in heterozygous individuals required the expression of a mutant receptor that interferes with the function of normal allele ("dominant negative effect"). The formation of mutant TR/TRAP (RXR etc.) heterodimer or mutant TR homodimer having the capability to bind the DNA for this dominant negative suppression of mutant TR beta, and the variation of TRE types, receptor isoforms and auxiliary proteins depending on the target tissue may play an important role in the manifestation of TH resistance. This may explain in part the intra- and inter-individual differences in organ resistance in patients with RTH. Studying the errors of nature would contribute to understand the molecular mechanism of TH action.

Genes, Dominant↗
PubMed1987

[Studies on cytosol thyroid hormone binding proteins in the rat liver: Part I. Stability and binding characteristics of thyroid hormone binding proteins].

Many studies demonstrated the presence of cytosolic thyroid hormone binding proteins (CTHBPs) in various tissues, but the physiologic significance of these CTHBPs is not clear, partially because of the lack of information about the physicochemical properties of CTHBPs as purified forms. Since the difficulty in isolating these CTHBPs is considered to be due to instability during the various procedures for their isolation, studies on the stability of CTHBPs of rat liver were performed using a charcoal binding method to separate bound and free hormones. Binding characteristics of CTHBPs of rat liver were also determined. Specific triiodothyronine (T3) binding sites of cytosolic T3 binding protein (CT3BP) of rat liver were destroyed as the time progressed in homogenate at 0 degrees C, and Aprotinin (500 U/ml) had little effect in protecting these binding sites. T3 binding sites were stable in the form of cytosol at -20 degrees C up to 10 weeks. Dithiothreitol (DTT) had no effect on T3 binding to cytosol. T3 binding to CT3BP was pH-dependent with maximum specific binding at pH 7.4. T3 binding to CT3BP was stable at 4 degrees C overnight but was destroyed rapidly at 37 degrees C. Interestingly, specific T3 binding sites of CT3BP were completely abolished by dialysis, and Ca2+ or Mg2+ had no effect on retaining the specific binding sites. Thus, CT3BP was supposed to require some dialysable small molecule(s) to maintain specific T3 binding sites. Scatchard plot of T3 binding to crude cytosol revealed a high affinity, limited capacity T3 binding site with affinity constant (Ka) of 5.9 X 10(7) M-1 and maximum binding capacity (MBC) of 118 ng/g. liver. Relative affinities of T3 analogues for CT3BP were determined by comparing the molar concentrations of T3 analogues required for 50% inhibition of tracer 125I-T3 binding. If the affinity of L-T3 was assigned 100, D-T3 would have a value of 66.1; L-T4, 22.3; D-T4, 16.5; Triac, 6.2; and both Tetrac and reverse T3 were less than 1. Thus, the binding characteristics of CT3BP were fundamentally different from those of nuclear T3 receptor. Cytosolic thyroxine (T4) binding protein (CT4BP) of rat liver was relatively stable compared with CT3BP in homogenate at 0 degrees C. CT4BP was also stable in the form of cytosol at -20 degrees C for 10 weeks. CT4BP was pH-dependent with maximum specific binding at pH 7.4. It was stable at 4 degrees C overnight but destroyed rapidly at 37 degrees C. Specific T4 binding was decreased by dialysis but not abolished completely.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2003

Hormone-dependent repression of the E2F-1 gene by thyroid hormone receptors.

Thyroid hormone induces differentiation of many different tissues in mammals, birds, and amphibians. The different tissues all differentiate from proliferating precursor cells, and the normal cell cycle is suspended while cells undergo differentiation. We have investigated how thyroid hormone affects the expression of the E2F-1 protein, a key transcription factor that controls G1- to S-phase transition. We show that during thyroid hormone-induced differentiation of embryonic carcinoma cells and of oligodendrocyte precursor cells, the levels of E2F-1 mRNA and E2F-1 protein decrease. This is caused by the thyroid hormone receptor (TR) regulating the transcription of the E2F-1 gene. The TR binds directly to a negative thyroid hormone response element, called the Z-element, in the E2F-1 promoter. When bound, the TR activates transcription in the absence of ligand but represses transcription in the presence of ligand. In addition, liganded TR represses transcription of the S-phase-specific DNA polymerase alpha, thymidine kinase, and dihydropholate reductase genes. These results suggest that thyroid hormone-induced withdrawal from the cell cycle takes place through the repression of S-phase genes. We suggest that this is an initial and crucial step in thyroid hormone-induced differentiation of precursor cells.

Animals↗
PubMed1998

A role for helix 3 of the TRbeta ligand-binding domain in coactivator recruitment identified by characterization of a third cluster of mutations in resistance to thyroid hormone.

Resistance to thyroid hormone (RTH) has hitherto been associated with thyroid hormone beta receptor (TRbeta) mutations which cluster in two regions (alphaalpha 310-353 and alphaalpha 429-461) of the hormone-binding domain and closely approximate the ligand-binding cavity. Here, we describe a third cluster of RTH mutations extending from alphaalpha 234-282 which constitute a third boundary of the ligand pocket. One mutant, T277A, exhibits impaired transactivation which is disproportionate to its mildly reduced ligand affinity (Ka). T3-dependent recruitment of coactivators (SRC-1, ACTR) by mutant receptor-RXR heterodimers was reduced in comparison with wild-type. Cotransfection of SRC-1 restored transactivation by T277A. In the TRbeta crystal structure this helix 3 residue is surface-exposed and is in close proximity to residues L454 and E457 in helix 12 which are known to be critical for coactivator interaction, suggesting that they all constitute part of a receptor-coactivator interface. The transcriptional function of other mutants (A234T, R243W/Q, A268D, Delta276I, A279V, R282S) in this cluster correlated with their reduced Ka and they inhibited wild-type TRbeta action in a dominant negative manner. DNA binding, heterodimerization and corepressor recruitment were preserved in all mutants, signifying the importance of these attributes for dominant negative activity and correlating with the absence of natural mutations in regions bordering the third cluster which mediate these functions.

Amino Acid Sequence↗
PubMed2006

Rapid nongenomic actions of thyroid hormone.

The binding of thyroid hormone to the thyroid hormone receptor (TR) mediates important physiological effects. However, the transcriptional effects of TR mediated by the thyroid response element (TRE) cannot explain many actions of thyroid hormone. We postulate that TR can initiate rapid, non-TRE-mediated effects in the cardiovascular system through cross-coupling to the phosphatidylinositol 3-kinase (PI3-kinase)/protein kinase Akt pathway. In vascular endothelial cells, the predominant TR isoform is TRalpha1. Treatment of endothelial cells with L-3,5,3'-triiodothyronine (T3) increased the association of TRalpha1 with the p85alpha subunit of PI3-kinase, leading to the phosphorylation and activation of Akt and endothelial nitric oxide synthase (eNOS). The activation of Akt and eNOS by T3 was abolished by the PI3-kinase inhibitors, LY294002 and wortmannin, but not by the transcriptional inhibitor, actinomycin D. To determine the physiological relevance of this PI3-kinase/Akt pathway, we administered T3 to mice undergoing transient focal cerebral ischemia. Compared with vehicle, a single bolus infusion of T3 rapidly increased Akt activity in the brain, decreased mean blood pressure, reduced cerebral infarct volume, and improved neurological deficit score. These neuroprotective effects of T3 were greatly attenuated or absent in eNOS-/- and TRalpha1-/-beta-/- mice and were completely abolished in WT mice pretreated with LY294002 or a T3 antagonist, NH-3. These findings indicate that the activation of PI3-kinase/Akt pathways can mediate some of the rapid, non-TRE effects of TR and suggest that the activation of Akt and eNOS contributes to some of the acute vasodilatory and neuroprotective effects of thyroid hormone.

Animals↗
PubMedDate not supplied

Selective modulation of thyroid hormone receptor action.

Thyroid hormones have some actions that might be useful therapeutically, but others that are deleterious. Potential therapeutically useful actions include those to induce weight loss and lower plasma cholesterol levels. Potential deleterious actions are those on the heart to induce tachycardia and arrhythmia, on bone to decrease mineral density, and on muscle to induce wasting. There have been successes in selectively modulating the actions of other classes of hormones through various means, including the use of pharmaceuticals that have enhanced affinities for certain receptor isoforms. Thus, there is reason to pursue selective modulation of thyroid hormone receptor (TR) function, and several agents have been shown to have some beta-selective, hepatic selective and/or cardiac sparring activities, although development of these was largely not based on detailed understanding of mechanisms for the specificity. The possibility of selectively targeting the TRbeta was suggested by the findings that there are alpha- and beta-TR forms and that the TRalpha-forms may preferentially regulate the heart rate, whereas many other actions of these hormones are mediated by the TRbeta. We determined X-ray crystal structures of the TRalpha and TRbeta ligand-binding domains (LBDs) complexed with the thyroid hormone analog 3,5,3'-triiodithyroacetic acid (Triac). The data suggested that a single amino acid difference in the ligand-binding cavities of the two receptors could affect hydrogen bonding in the receptor region, where the ligand's 1-position substituent fits and might be exploited to generate beta-selective ligands. The compound GC-1, with oxoacetate in the 1-position instead of acetate as in Triac, exhibited TRbeta-selective binding and actions in cultured cells. An X-ray crystal structure of the GC-1-TRbeta LBD complex suggests that the oxoacetate does participate in a network of hydrogen bonding in the TR LBD polar pocket. GC-1 displayed actions in tadpoles that were TRbeta-selective. When administered to mice, GC-1 was as effective in lowering plasma cholesterol levels as T(3), and was more effective than T(3) in lowering plasma triglyceride levels. At these doses, GC-1 did not increase the heart rate. GC-1 was also less active than T(3) in modulating activities of several other cardiac parameters, and especially a cardiac pacemaker channel such as HCN-2, which may participate in regulation of the heart rate. GC-1 showed intermediate activity in suppressing plasma thyroid stimulating hormone (TSH) levels. The tissue/plasma ratio for GC-1 in heart was also less than for the liver. These data suggest that compounds can be generated that are TR-selective and that compounds with this property and/or that exhibit selective uptake, might have clinical utility as selective TR modulators.

Animals↗
PubMed1984

Thyroid hormone secretion is more sensitive than thyroid cyclic AMP accumulation to stimulation with LATS in mice in vitro and in vivo.

The effects of LATS-immunoglobulin G (IgG) on thyroid hormone secretion and on thyroid cAMP concentrations were investigated in mice and compared to those of TSH. In the in vitro experiments, thyroid lobes were incubated in Krebs-Ringer bicarbonate buffer with LATS-IgG or TSH for 3 h or 2 h and T3 concentrations in buffer and thyroid cAMP were measured by RIA. T3 in the buffer was increased with 1.5 mg/ml of LATS-IgG (A) or 2.5 mg/ml of LATS-IgG (B) (1000%/5 mg or 400%/5 mg in the McKenzie bioassay, respectively), whereas thyroid cAMP was elevated only after incubation with two to four times higher doses of LATS-IgG (A) or LATS-IgG (B). 0.03 mU/ml of TSH increased T3 concentrations, while a two fold higher dose of TSH was required to increase thyroid cAMP. In the in vivo study, 5 mg of LATS-IgG (A) injected intravenously increased serum T4 concentrations but not thyroid cAMP. 2 mU of TSH increased serum T4, while 10 mU was needed to elevate thyroid cAMP. These results indicate that: i) thyroid hormone secretion is more sensitive than increases of thyroid cAMP to stimulation with LATS, which is similar to stimulation with TSH and that: ii) thyroid hormone secretion rather than increases of thyroid cAMP should be employed to detect serum thyroid stimulating activities when mouse thyroids are used.

Animals↗
PubMed1994

Nucleotide substitutions differentially affect direct repeat and palindromic thyroid hormone response elements.

Thyroid hormone receptors are transcription factors that bind to specific DNA sequences and regulate gene expression in a ligand-dependent manner. Thyroid hormone response elements can be composed of direct repeat or palindromic arrangements of half-sites. The traditional half-site has been considered to be the sequence 5'-AGGTCA, although we recently demonstrated that the optimal monomer-binding site is 2 base pairs larger, 5'-TAAGGTCA. It has generally been presumed that alterations in half-site sequence have commensurate effects on gene expression from direct repeat and palindromic response elements. However, in the present studies we demonstrate that palindromic elements are highly dependent on the presence of the two 5'-nucleotides (TA) for function, whereas this portion of the response element has minimal influence on hormone induction from direct repeat elements. Hormone induction correlates poorly with binding affinity for thyroid hormone receptor monomers, homodimers, or heterodimers with retinoid X receptors, either in the absence or presence of ligands. We speculate that the magnitude of hormone induction may reflect protein conformation differences induced by a combination of the presence of the appropriate 5'-nucleotides plus half-site orientation.

Animals↗