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PubMed2002

In vivo regulation of human skeletal muscle gene expression by thyroid hormone.

Thyroid hormones are key regulators of metabolism that modulate transcription via nuclear receptors. Hyperthyroidism is associated with increased metabolic rate, protein breakdown, and weight loss. Although the molecular actions of thyroid hormones have been studied thoroughly, their pleiotropic effects are mediated by complex changes in expression of an unknown number of target genes. Here, we measured patterns of skeletal muscle gene expression in five healthy men treated for 14 days with 75 microg of triiodothyronine, using 24,000 cDNA element microarrays. To analyze the data, we used a new statistical method that identifies significant changes in expression and estimates the false discovery rate. The 381 up-regulated genes were involved in a wide range of cellular functions including transcriptional control, mRNA maturation, protein turnover, signal transduction, cellular trafficking, and energy metabolism. Only two genes were down-regulated. Most of the genes are novel targets of thyroid hormone. Cluster analysis of triiodothyronine-regulated gene expression among 19 different human tissues or cell lines revealed sets of coregulated genes that serve similar biologic functions. These results define molecular signatures that help to understand the physiology and pathophysiology of thyroid hormone action.

Administration, Oral↗

PubMed2006

Amphibian metamorphosis as a model for the developmental actions of thyroid hormone.

Thyroid hormone (TH) elicits multiple physiological actions in vertebrates from fish to man. These actions can be divided into two broad categories: those where the hormone regulates developmental processes and those that involve actions in the adult organism. Amphibian metamorphosis is a most dramatic example of extensive morphological, biochemical and cellular changes occurring during post-embryonic development, which is obligatorily initiated and sustained by TH. It is, therefore, an ideal model system to understand the action of the hormone. Each tissue of the frog tadpole responds differently to TH, ranging from altered gene expression, morphogenesis, tissue re-structuring and extensive cell death, according to a developmental programme set in place before the thyroid gland begins to secrete the hormone. The key element determining the response to the hormone is the nuclear thyroid hormone receptor (TR). As in most vertebrates, there are two thyroid hormone receptors, TRalpha and TRbeta, which repress transcription in the absence of the ligand and whose concentration in the tissues is directly modulated by the hormone itself. In Xenopus, biochemical and in situ techniques have shown that the amount of TRbeta mRNA and protein are elevated 50-100 times during TH-induced metamorphic climax. This phenomenon of "autoinduction" of receptor is also seen with developmental or inductive processes regulated by other hormones acting through nuclear receptors. It is possible that receptor upregulation may be a pre-requisite for hormonal response. Recent molecular and cell biological studies have suggested that TRs function as multimeric complexes with other nuclear or chromatin proteins, such as co-repressors and co-activators, to regulate the structure of the chromatin, and thereby determine the transcription of the receptor-specified target gene. There is evidence that this may also be so for thyroid hormone regulated transcription during amphibian metamorphosis.

Amphibians↗

PubMed1999

The human fetal retinal pigment epithelium: A target tissue for thyroid hormones.

Thyroid hormone (T(3)) has previously been shown to regulate visual function in experimental animals and humans. To determine if T(3) exerts direct effects on retinal function, cultured human fetal retinal pigment epithelial (RPE) cells were tested for the presence of thyroid hormone receptors (TRs) and T(3) responses. Using TR-isoform-specific reverse-transcriptase polymerase chain reaction techniques, mRNA was detected for alpha1, alpha2 and beta1 TR isoforms. Immunohistochemistry using a polyclonal antibody that simultaneously recognizes alpha1, alpha2 and beta1 TRs showed nuclear staining of the fetal RPE. Specific binding of (125)I-T(3) to RPE cell nuclear extracts was detected, and Scatchard analysis revealed a K(d) of 110 pM. To determine if RPE cells can respond to T(3), hyaluronic acid (HA) levels in cell culture media were measured after 2, 4 or 6 days of growth in medium containing 10(-7) M T(3). T(3) inhibited accumulation of HA in the cell culture medium of RPE cells. This effect was not evident at 2 days, but at 4 days there was 42.8% less HA in cell culture medium of RPE cells grown in 10(-7) M T(3) (p < 0.01, t test). The effect persisted through 6 days, when there was 46.3% less HA in cell culture medium of RPE cells grown in 10(-7) M T(3) (p < 0.001, t test). The data indicate that human fetal RPE cells are a direct target for thyroid hormones.

Cells, Cultured↗

PubMed1985

Mechanism of action of thyroid hormones.

Thyroid hormones have ubiquitous effects and influence the function of most organs. The influences that thyroid hormones have on these diverse functions are primarily mediated through binding of T3 and T4 to specific nuclear receptor sites. The nuclear action of T3 results in organ-specific increases and decreases of specific mRNAs, leading to alteration in the level of the corresponding proteins. In addition to the well established nuclear action of T3, effects of thyroid hormone on other sites including cell membranes and mitochondria have been documented.

Animals↗

PubMed1989

Control of mitochondrial transcription by thyroid hormone.

Thyroid hormone regulation of rat liver mitochondrial transcription was investigated. Steady-state levels of mitochondrial transcripts were measured by Northern blot analysis using cloned fragments of rat mtDNA. Thyroid hormone increased the steady-state concentrations of all mitochondrial mRNAs by 2-8 fold after 1-3 days of hormone treatment, whereas no significant change in the mitochondrial rRNA was observed. Analysis of transcript synthesis in isolated mitochondria shows that part or all of this increase is accounted for by elevated synthesis. Mechanisms by which thyroid hormone regulates transcription of the mitochondrial genome are discussed.

Animals↗

PubMed2006

Regulation of nuclear coactivator and corepressor expression in mouse cerebellum by thyroid hormone.

Thyroid hormone (TH) has an important role in central nervous system development. TH action is mediated by a number of transcription factors including thyroid hormone receptors (TRs) in combination with a group of coregulators that can either activate (coactivators) or repress (corepressors) transcription in the presence of TH. The aims of this report were to determine if regulation of the corepressor Hairless (Hr) by TH was TR-isoform- mediated in neonatal cerebellum and to determine if other cerebellar corepressors (SMRT and NCoR) and coactivators (SRC family) are also regulated by TH. In order to study this we examined 14-day-old and adult knockout mice that lack expression of the TRbeta or TRalpha isoforms and measured mRNA expression in untreated, hypothyroid and TH-treated young mouse pups. TH-treated wild-type and TRbeta-deficient mice demonstrated upregulation of Hr by 22.8- +/- 8.6- and 11.8- +/- 3.6-fold respectively, which was not upregulated in TRalpha-deficient mice. In wild-type mice, TH treatment results in a reciprocal decrease (61%) in the coactivator SRC-1. These changes were not observed in adult mouse cerebellum. No effect was seen with NCoR and SRC-3 expression. SMRT was 3-fold increased in TH treatment of only wild-type mouse pups. We conclude that (1) TRalpha is the major TR regulating Hr expression in the cerebellum of young mouse pups; (2) TH upregulates Hr and SMRT and downregulates SRC-1; (3) NcoR and SRC-3 may not be regulated by TH in the cerebellum at the transcriptional level; and (4) autoregulation of TH action may be mediated through TH-dependent expression of the cofactors necessary for TH action in the cerebellum and may be developmentally specific.

Animals↗

PubMed1986

Serum thyroid hormones and thyroid hormone binding proteins in patients with completed stroke.

Thirty euthyroid patients hospitalized for completed stroke had serum thyroxine, triiodothyronine, thyroxine-binding globulin and thyroxine-binding prealbumin levels significantly decreased (p less than 0.01 to p less than 0.001) compared with 70 age- and sex-matched healthy controls. Admission serum thyroxine levels gave the best correlation with mortality (T4 less than 65 nmol/l = 100% mortality; 65-77 nmol/l = 38%; 78-90 nmol/l = 9%; greater than 90 nmol/l = 0%). In general, during hospitalization a progressive decrease in serum concentrations of these parameters was observed in the 11 patients who subsequently died, while there was a progressive increase in the 19 survivors. However, the most sensitive index of clinical recovery appeared to be prealbumin, since a decrease in prealbumin levels was observed in all subjects who died, and an increase in prealbumin was found in all survivors.

Aged↗

PubMed2003

Plasma protein regulation by thyroid hormone.

Thyroid hormones (THs) regulate growth, development, differentiation and metabolic processes by interacting and activating thyroid hormone receptors (TRs). Although much progress has been made in our understanding of the transcriptional regulation of many TR target genes, little is known of the regulation of plasma protein gene expression by TRs. To investigate the role of TRs in plasma protein expression we used human hepatocellular carcinoma cell lines and carried out cDNA microarray analysis. Our results indicate that several plasma proteins including transferrin, prothrombin, angiotensinogen, haptoglobin, alpha-2-HS-glycoprotein alpha and beta chain, complement, lipoproteins and fibrinogen are up-regulated by THs. Furthermore, clusterin, alpha-2-macroglobulin precursor, prothymosin alpha and alpha-fetoprotein were found to be down-regulated by THs.Transferrin, an iron-binding protein expressed in all mammals, and mainly synthesized in the liver, was investigated further. Immunoblot and Northern blot analyses revealed that exposure of HepG2-TRalpha1 sub-lines and HepG2-Neo cells to tri-iodothyronine (T(3)) induced time- and dose-dependent increases in the abundance of transferrin mRNA and protein, with the extent of these effects correlating with the level of expression of TRalpha1. Nuclear run-on experiments indicate that this induction is functioning at the transcriptional level. Moreover, cyclohexamide treatment did not eliminate the induction of transferrin by TH. Thus, our results suggest that the induction of transferrin by TH is direct and may in fact be mediated by an as yet unidentified response element in the promoter region.

Blood Proteins↗

PubMed1988

Steady-state levels of G-proteins and beta-adrenergic receptors in rat fat cells. Permissive effects of thyroid hormones.

Thyroid hormones exert a permissive influence on the ability of cells to respond to other hormones. In hypothyroidism, stimulation of adenylate cyclase by beta-adrenergic agonists is impaired in rat fat cells, whereas inhibition by adenosine is potentiated. The effects of thyroid status on steady-state levels of the G-protein subunits alpha-Go, alpha-Gi, and beta-G35/36 were investigated using specific antibodies and quantitative immunoblotting of rat fat cell membranes. The amount of alpha-Go (Mr 39,000, alpha-G39) detected in fat cell membranes of euthyroid rats was 44 +/- 5 pmol/mg of membrane protein (n = 5). In the hypothyroid state, the amount of the alpha-subunits of Gi (Mr 41,000, alpha-G41) and Go were found to be markedly increased in comparison to the control. The steady-state level of alpha-G41 and alpha-G39 increased more than 50 and 70%, respectively, in the hypothyroid state. The beta-subunit of G-proteins of rat fat cells appears as a doublet of proteins with Mr = 35,000/36,000 on sodium dodecyl sulfate-polyacrylamide gels. The amount of beta-G35/36 detected in fat cell membranes of euthyroid rats was 0.20 +/- 0.03 nmol/mg of protein (n = 5) and was found to increase by about 60% in the hypothyroid state. Administration of triiodothyronine in vivo (short term hyperthyroidism) resulted in a decrease in the amounts of alpha-G41 and alpha-G39 subunits (25 and 20%, respectively). In contrast to these effects of thyroid hormones on Go and Gi, the steady-state level of beta-adrenergic receptors was not significantly altered by changes in thyroid status. Thus, thyroid status in vivo can modulate the steady-state levels of specific G-proteins.

Adipose Tissue↗

PubMed2006

Indirect regulation of human dehydroepiandrosterone sulfotransferase family 1A member 2 by thyroid hormones.

Thyroid hormone, T(3), regulates cell metabolism, differentiation, and development. cDNA microarrays were performed to study the mechanism of target gene regulation after T(3) treatment in a thyroid hormone receptor-alpha (TRalpha)-overexpressing hepatoma cell line (HepG2-TRalpha). The differentially expressed target genes are several metabolic enzymes, including dehydroepiandrosterone-sulfotransferase family 1A member 2 (SULT2A1). Enzyme SULT2A1 was elevated roughly 5-fold at the protein level and 9-fold increase at the mRNA level after 48 h T(3) treatment in HepG2-TRalpha cells. Cycloheximide inhibited T(3)-induced SULT2A1 expression, suggesting that regulation was indirect. SULT2A1 has been reported to be regulated by the two transcription factors, steroidogenic factor 1 (SF1) and GATA, in the human adrenal gland. T(3) induced a 2.5- to 3.5-fold elevation of SF1 at the protein level and a 6.2-fold increase at the RNA level in HepG2-TRalpha cells. About seven SF1 binding sites exist on the SULT2A1 gene. To identify and localize the critical SF1 binding site, series of deletion mutants of SULT2A1 promoter fragments in pGL2 plasmid were constructed. The promoter activity of the SULT2A1 gene was enhanced about 2.8- to 7.1-fold by T(3). The -228 SF1 binding site was identified as the most critical site because deleting this region reduced T(3)-induced expression. Transcription factor SF1 application enhanced the -228 but not -117 reporter plasmid activities. SULT2A1 and SF1 up-regulation at protein and RNA levels in thyroidectomized rats occurred after T(3) application. In summary, this work demonstrated that the SULT2A1 gene was mediated by SF1 and indirectly regulated by T(3). Further study is required to elucidate the physiological importance of SULT2A1 induction mediated by T(3).

Animals↗

PubMed2005

Developmental changes of plasma inhibin, gonadotropins, steroid hormones, and thyroid hormones in male and female Shao ducks.

Plasma samples from developing male and female Shao ducks were assayed for immunoreactive (ir-) inhibin, follicle-stimulating hormone (FSH), luteinizing hormone (LH), steroid hormones, and thyroid hormones. In the male, plasma ir-inhibin significantly increased between 75 and 155 days posthatch, and then decreased slightly at day 165. Plasma FSH of male ducks decreased from day 35 to day 55, followed by progressive elevation until day 95. Plasma FSH of male ducks fell significantly at days 135 and 165, while plasma ir-inhibin rose to high level. In female ducks, plasma ir-inhibin remained low until the start of lay, and thereafter significantly increased at day 135. Plasma FSH fluctuated before day 95 and significantly rose at day 115, and decreased thereafter. In males, plasma LH did not vary significantly before day 135, however, plasma testosterone significantly increased from day 95 onwards. No changes in plasma LH were observed during development of female ducks. Plasma estradiol-17beta gradually increased reaching a peak level at day 135. Plasma progesterone did not vary significantly before day 135 and thereafter significantly increased. Both sexes showed a similar pattern in changes of plasma thyroid hormones during sexual development. There was a significant increase in plasma thyroxine (T4) at day 95, thereafter decreased. Plasma triiodothyronine (T3) was at high level at the earlier stage of development and significantly decreased at day 55. Significant increase in plasma T3 in male and female ducks was observed at 135 and 115 days, respectively. In conclusion, these results demonstrated that the rise in inhibin is correlated with age of sexual maturity in the female while the rise in inhibin significantly precedes sexual maturity in the male. There was a progressive increase in plasma steroid hormones towards sexual maturity, and there was no sex difference in the time course of thyroid hormones.

Animals↗

PubMed1977

The action of thyroid hormone.

Thyroid hormone affects both developmental and metabolic processes. It has a relatively specific effect on the synthesis of a number of enzymes and other proteins. The fundamental cellular mechanism of action seems to be at the level of genetic regulation. It involves interaction with nuclear receptors, leading to an activation of the protein synthesizing machinery. How binding to receptors is coupled to genetic activation is completely unknown. At least part of the metabolic effects of thyroid hormone could be mediated through an interaction with mitochondria and cell membrane, and with some enzymatic systems such as adenylcyclase.

Animals↗

PubMed1991

Inhibition of Ca2+ accumulation in isolated sarcoplasmic reticulum by thyroid hormones.

Thyroid hormones inhibit Ca2+ accumulation and ATPase activity of isolated sarcoplasmic reticulum vesicles. Half-maximal inhibition was obtained by about 2.5 microM. The ATP hydrolysis activity of the purified (Ca2+ + Mg2+)-ATPase or of the SR vesicles, in the presence of the Ca2+ ionophore A23187, is not inhibited by T3 or T4. Modification of T3 or T4 in the ring portion, but not in the amino portion, of the molecules results in T4 and T3 analogues which are unable to inhibit Ca2+ accumulation. T3 and T4 have no significant effect on various partial reactions of the transport cycle such as: the binding of ATP and Ca2+, or ADP-ATP exchange and E-P formation from ATP, but they inhibit the E-P formation from inorganic phosphate (Pi) and ATP-Pi exchange. The inhibition of both Ca2+ accumulation and ATPase activity by T3 or T4 is increased in the presence of Pi. Binding sites for [125I]T3 and for [125I]T4 in SR proteins were demonstrated using either equilibrium dialysis or gel overlay techniques. The results suggest that the thyroid hormones inhibit the ATP-dependent Ca2+ accumulation, probably by inhibiting the transport of anions which act as the Ca2+ precipitating anion.

Animals↗

PubMed1979

Corticosteroids and thyroid function. Different effects on plasma volume, thyroid hormones and thyroid hormone-binding proteins after oral and intravenous administration.

The influence of glucocorticosteroids on plasma volume, thyroid hormones and thyroid hormone-binding proteins was studied in 17 patients. Plasma volume was not affected either by i.v. beta-methasone (6 mg daily) or by oral prednisolone (45--180 mg daily) given for 5 days. The serum T3 concentration decreased while rT3 increased independently of the route of administration of corticosteroids. Serum T4 concentration decreased after i.v. but not after oral administration of corticosteroids. Oral steroids as compared to i.v. increased the 125I-triiodothyronine uptake test value. The serum TBG concentration decreased independently of the route of administration, while the serum TBPA concentration increased after oral corticosteroids but was unchanged after i.v. treatment. The serum TSH concentration was slightly reduced. About half of the patients were given both corticosteroids and nutrition i.v. and the other half were given all treatment by mouth. The part played by the route of administration of corticosteroids and calories, respectively, cannot be evaluated at present but these factors seem to be of importance.

Administration, Oral↗

PubMed2003

Downregulation of vascular angiotensin II type 1 receptor by thyroid hormone.

Thyroid hormone has a broad effect on cardiovascular system. 3,3',5-triiodo-l-thyronine (T3), a biologically active form of thyroid hormone, increases cardiac contractility. T3 causes arterial relaxation and reduction of systemic vascular resistance, resulting in an increase in cardiac output. However, the molecular mechanisms of vascular relaxation by T3 are incompletely characterized. We studied the effect of T3 on the angiotensin (Ang) II type 1 receptor (AT1R) expression in vascular smooth muscle cells. T3 dose-dependently decreased expression levels of AT1R mRNA, with a peak at 6 hours of stimulation. Binding assay using [125I]Sar1-Ile8-Ang II revealed that AT1R number was decreased by stimulation with T3 without changing the affinity to Ang II. T3 reduced calcium response of vascular smooth muscle cells to Ang II by 26%. AT1R promoter activity measured by luciferase assay was reduced by 50% after 9 hours of T3 administration. mRNA stability was also decreased by T3. Real-time quantitative reverse transcription-polymerase chain reaction and Western blot analysis revealed that AT1R mRNA and protein were downregulated in the aorta of T3-treated rats. These results suggest that T3 downregulates AT1R expression both at transcriptional and posttranscriptional levels, and attenuates biological function of Ang II. Our results suggest that downregulation of AT1R gene expression may play an important role for T3-induced vascular relaxation.

Angiotensin II↗

PubMed2002

Regulation of human adipocyte gene expression by thyroid hormone.

Thyroid hormones are key regulators of metabolism. In adipose tissue, changes in thyroid status result in alterations of lipolytic capacity. The effects of these hormones are mediated by thyroid hormone receptors that modulate gene transcription. Very few target genes have been identified in adipose tissue. To investigate the effect of T(3) on gene expression in human adipocytes, primary cultures of human sc adipose tissue explants were treated with T(3). (32)P-labeled cDNA probes prepared from isolated adipocyte total RNA were hybridized to cDNA arrays representing 1,176 genes. Among the statistically significant variations in mRNA levels with more than 1.3-fold difference, 13 and 6 genes were positively and negatively regulated, respectively (n = 3). The genes encoded proteins that were involved in signal transduction, lipid metabolism, apoptosis, and inflammatory response. Using RT-competitive PCR, we showed a down-regulation of phosphodiesterase 3B, alpha(2A)-adrenergic receptor, and G protein alpha(i2) subunit mRNAs, and an up-regulation of beta(2)-adrenergic receptor mRNA. These regulations may explain the T(3)-mediated increase in catecholamine-induced lipolysis. The down-regulation of sterol regulatory element binding protein-1c, a transcription factor controlling lipogenic gene expression, may constitute a link between thyrotoxicosis and insulin resistance. Thus, these data suggest that T(3) modulates expression of genes with a wide range of function in human adipose tissue.

Adipocytes↗

PubMed1993

Studies on the use of thyroid hormone and a thyroid hormone analogue in the treatment of congestive heart failure.

In heart failure, cardiac output is insufficient to meet the needs of the body for oxygen delivery. Available data suggest that alterations in thyroid hormone metabolism may contribute to defective myocardial performance. Accordingly, thyroid hormone or a thyroid hormone analogue that improves cardiac performance might be useful in the treatment of heart failure and has been studied. Experimental and theoretical results of these studies are reviewed and indicate that thyroid hormone increases cardiac output by a combination of effects on the heart and peripheral circulation, specifically by increasing myocardial contractile performance and decreasing venous compliance. In the rat postinfarction model of heart failure, treatment with low doses of thyroxine (1.5 micrograms/100 g) for 3 days produced a positive inotropic response, including an increase in rate of change of left ventricular pressure and a decrease in left ventricular end-diastolic pressure. These changes could be attributed to conversion to triiodothyronine, the active intracellular form of thyroid hormone. When treatment with thyroxine was continued at the same or higher doses (3 to 15 micrograms/100 g) for 10 to 12 days, heart rate increased and improvement in left ventricular end-diastolic pressure was not sustained. More favorable results were obtained with 3,5-diiodothyropropionic acid, a cardiotonic thyroid hormone analogue administered at doses of 375 microgram/100 g, given in combination with captopril. Thus, triiodothyronine or a thyroid hormone analogue may be a useful adjunct to other measures in the treatment of heart failure.

Animals↗

PubMed1983

Lack of refractoriness to stimulation with long acting thyroid stimulator of thyroid hormone synthesis and thyroid hormone secretion in mice in vivo.

The present study was undertaken to examine whether long acting thyroid stimulator (LATS) induces refractoriness of thyroid hormone synthesis and thyroid hormone secretion to the stimulator in vivo. Male DDY mice fed with a low iodine diet and given 5 micrograms/ml of triiodothyronine (T3) in drinking water and libitum for 4 days were injected with 0.025 ml of LATS positive serum (1000%/0.25 ml in rhe McKenzie bioassay) ip every 24 h for 9 days. Groups of 5 mice were sacrificed before and 1, 3, 5, 7 and 9 days after the first injection of LATS for the determinations of serum thyroxine (T4) concentrations, the 1 h thyroid 131I uptake and thyroid weight. Control mice were injected with LATS negative pooled normal sera. Serum T4 concentrations elevated significantly 24 h after the 3rd injection of LATS and remained elevated until the end of the experiment. One hour thyroid 131I uptake elevated about 3-fold 24 h after the first injection of LATS. It further increased 24 h after the 3rd injection of LATS to 10-fold of the value for control animals and stayed elevated at this same level for the remainder of the study. These results indicate that stimulating effects of LATS on thyroid hormone synthesis assessed by thyroid 131I uptake and thyroid hormone secretion assessed by serum T4 concentrations were not diminished by the prior administration of the stimulator. These findings suggest that LATS does not induce refractoriness of either thyroid hormone synthesis or thy roid hormone secretion to the stimulator in mide in vivo.

Animals↗