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Tetsuya Tagami

Publications and source records attributed to Tetsuya Tagami.

13 recordsLinked to original sources
PubMed2006

Antithyroid drugs inhibit thyroid hormone receptor-mediated transcription.

CONTEXT: Methimazole (MMI) and propylthiouracil (PTU) are widely used as antithyroid drugs (ATDs) for the treatment of Graves' disease. Both MMI and PTU reduce thyroid hormone levels by several mechanisms, including inhibition of thyroid hormone synthesis and secretion. In addition, PTU decreases 5'-deiodination of T(4) in peripheral tissues. ATDs may also interfere with T(3) binding to nuclear thyroid hormone receptors (TRs). However, the effect of ATDs on the transcriptional activities of T(3) mediated by TRs has not been studied. OBJECTIVE: The present study was undertaken to determine whether ATDs have an effect on the gene transcription regulated by T(3) and TRs in vitro. METHODS: Transient gene expression experiments and GH secretion assays were performed. To elucidate possible mechanisms of the antagonistic action of ATDs, the interaction between TR and nuclear cofactors was examined. RESULTS: In the transient gene expression experiments, both MMI and PTU significantly suppressed transcriptional activities mediated by the TR and T(3) in a dose-dependent manner. In mammalian two-hybrid assays, both drugs recruited one of the nuclear corepressors, nuclear receptor corepressor, to the TR in the absence of T(3). In addition, PTU dissociated nuclear coactivators, such as steroid receptor coactivator-1 and glucocorticoid receptor interacting protein-1, from the TR in the presence of T(3). Finally, MMI decreased the GH release that was stimulated by T(3). CONCLUSIONS: ATDs inhibit T(3) action by recruitment of transcriptional corepressors and/or dissociation of coactivators. This is the first report to show that ATDs can modulate T(3) action at the transcriptional level.

Antithyroid Agents↗
PubMed2006

Molecular mechanism of the inhibitory effect of aldosterone on endothelial NO synthase activity.

Although the proinflammatory and profibrotic actions of aldosterone (Aldo) on the vasculature have been reported, the effects and molecular mechanisms of Aldo on endothelial function are yet to be determined. We investigated how Aldo regulates endothelial NO synthase (eNOS) function in human umbilical vein endothelial cells (HUVECs). HUVECs were incubated for 16 hours with Aldo 10(-7) mol/L. The concentration of reactive oxygen species was estimated by measuring 2',7'-dichlorodihydrofluorescein diacetate chemiluminescence. Signal transduction was estimated by Western immunoblots. Real-time RT-PCR was performed to measure expression of transcripts of endogenous GTP cyclohydrolase-1 and components of reduced nicotinamide-adenine dinucleotide phosphate oxidase. To eliminate the possible effect of the glucocorticoid receptor (GR) and to emphasize the role of mineralocorticoid receptor, we used GR small interfering RNA and knocked down GR expression in several experiments. NO output was estimated by intracellular cGMP concentration. Reactive oxygen species production increased significantly in Aldo-treated HUVECs but was abolished by pretreatment with eplerenone. Transcripts of p47(phox) were increased by Aldo treatment. Vascular endothelial growth factor-induced eNOS Ser 1177 but not Akt Ser 473 phosphorylation levels were reduced significantly by pretreatment with Aldo. Pretreatment with either eplerenone or okadaic acid restored phosphorylation levels of eNOS Ser 1177 in Aldo-treated cells, suggesting that protein phosphatase 2A was upregulated by Aldo via mineralocorticoid receptor. The decrease in NO output caused by Aldo pretreatment was reversed significantly by 5,6,7,8-tetrahydrobiopterin, GTP cyclohydrolase-1 overexpression, or p47(phox) knockdown. These results suggest that Aldo inhibits eNOS function through bimodal mechanisms of 5,6,7,8-tetrahydrobiopterin deficiency and protein phosphatase 2A activation.

Aldosterone↗
PubMed2005

Clinical and molecular features of a TSH-secreting pituitary microadenoma.

We describe a case of a thyroid stimulating hormone (TSH)-secreting pituitary microadenoma, and report the systematic gene expression profile of the surgically- removed tumor. A 50-year-old woman was referred to our hospital because she had high TSH, free-T4, and free-T3 levels, and a pituitary tumor that was visualized with magnetic resonance imaging. Her basal TSH level was high even after a high T3 loading dose, and increased following administration of thyroid releasing hormone (TRH) even after administration of a high dose of exogenous T3. Her clinical symptoms and peripheral markers for T3 were responsive to exogenous T3. There was no thyroid hormone receptor (TR) beta gene mutation. The patient was diagnosed with a TSH-secreting pituitary adenoma, and trans-sphenoid surgery was performed. The histologic features and immunophenotype were consistent with a TSH-secreting pituitary adenoma. Reverse transcription-polymerase chain reaction analysis of pituitary hormones, pituitary-specific transcription factors, receptors, and transcriptional cofactors of clinical significance was performed on the removed tumor. The tumor expressed TSH, growth hormone, prolactin, alpha-subunit, pituitary transcription factor-1 (pit-1) but not proopiomelanocortin (POMC), prophet of pit-1 (prop-1) and pituitary cell-restricted T box factor (Tpit). TRbeta and TRH-receptor gene expression was normal. Three steroid receptor coactivators (SRC)-1, SRC-2, and SRC-3 were expressed. Nuclear receptor corepressor (N-CoR)2 was absent in the tumor, whereas nuclear receptor corepressor (N-CoR1) was expressed. Somatostatin receptor type 1 expression was significantly decreased, whereas type 4 receptor was expressed, which are unusual characteristics for pituitary tumors. The gene expression pattern in the tumor might have a role in the clinical features of this case.

Adenoma↗
PubMed2004

Genomic structure and characterization of the 5'-flanking region of the human ghrelin gene.

Ghrelin, an endogenous ligand for the GH secretagogue receptor, induces GH secretion, food intake, and positive energy balance. Although ghrelin exhibits a variety of hormonal actions, the mechanisms regulating ghrelin expression and secretion remain unclear. To understand regulation of human ghrelin gene expression, we examined the genomic structure of approximately 5,000 bp of the 5'-flanking region of the human ghrelin gene. We performed rapid amplification of cDNA ends to estimate transcriptional start sites, indicating that there are two transcriptional initiation sites within the human ghrelin gene. Both transcripts were equally expressed in the human stomach, whereas the longer transcript was mainly expressed in a human medullary thyroid carcinoma (TT) cell line. Functional analysis using promoter-reporter constructs containing the 5'-flanking region of the gene indicated that the sequence residing within the -349 to -193 region is necessary for human ghrelin promoter function in TT cells. Within this region existed several consensus sequences for a number of transactivating regulatory proteins, including an E-box site. Destruction of this site decreased to 40% of the promoter activity. The upstream region of the promoter has two additional putative E-box sites, and site-directed mutagenesis suggested that these are also involved in promoter activation. Electrophoretic mobility shift assays demonstrated that the upstream stimulatory factor specifically bound to these E-box elements. These results suggest a potential role for upstream stimulatory factor transcription factors in the regulation of human ghrelin expression.

5' Flanking Region↗
PubMed2004

Adiponectin in anorexia nervosa and bulimia nervosa.

To study the role of adiponectin, a novel adipocyte-specific secreted protein, on the pathophysiology of eating disorders, circulating levels of fasting adiponectin, leptin, insulin, and glucose were measured in 31 female patients with anorexia nervosa (AN) and in 11 with bulimia nervosa. Hormone levels were compared with 16 age-matched, normal body weight controls, six healthy constitutionally thin subjects, and nine obese subjects. Moreover, changes in levels were reevaluated after nutritional treatment and weight gain in 13 patients with AN. Serum adiponectin concentrations in AN and bulimia nervosa were significantly lower than those in normal-weight controls. These results were unexpected because the levels were high in constitutionally thin subjects and low in obese subjects, which provide a negative correlation with body mass index (BMI) and body fat mass. In contrast, serum leptin levels correlated very well with BMI and fat mass among all the patients and controls. The insulin resistance was significantly low in AN and high in obese subjects. The concentrations of adiponectin after weight recovery increased to the normal level despite a relatively small increase in BMI. These findings suggest that abnormal feeding behavior in the patients with eating disorders may reduce circulating adiponectin level, and weight recovery can restore it.

Adiponectin↗
PubMed2003

Antiatherogenic effect of pioglitazone in type 2 diabetic patients irrespective of the responsiveness to its antidiabetic effect.

OBJECTIVE: Thiazolidinediones (TZDs), a class of insulin-sensitizing agents used clinically to treat type 2 diabetes, are also antiatherogenic. This study was designed to elucidate the relationship between the antiatherogenic and antidiabetic effects of pioglitazone, a TZD, in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: A total of 136 Japanese type 2 diabetic patients were included and divided into two groups: the pioglitazone-treated group (30 mg daily for 3 months) (n = 70) and the untreated control group (n = 66). The changes in glycolipid metabolism as well as plasma high-sensitivity C-reactive protein (CRP), leptin, adiponectin, and pulse wave velocity (PWV) were monitored to analyze the relationship between the antiatherogenic and antidiabetic effects of pioglitazone. RESULTS: The pioglitazone treatment significantly reduced hyperglycemia, hyperinsulinemia, and HbA(1c) levels and increased plasma adiponectin concentrations relative to the control group (P < 0.01). It also significantly decreased CRP and PWV (P < 0.01). The antiatherogenic effect was observed in both the nonresponders showing <1% of reduction in HbA(1c) (n = 30) and responders showing >1% of reduction (n = 40). ANCOVA revealed that treatment with pioglitazone was associated with a low CRP and PWV, independent of the changes in parameters related to glucose metabolism. CONCLUSIONS: This study represents the first demonstration of the antiatherogenic effect of pioglitazone in both nonresponders and responders with respect to its antidiabetic effect and suggests that pioglitazone can exert its antiatherogenic effect independently of its antidiabetic effect.

Adiponectin↗
PubMed2002

Thyroid hormone action is disrupted by bisphenol A as an antagonist.

Bisphenol A (BPA), a monomer of polycarbonate plastics, has been shown to possess estrogenic properties and act as an agonist for the estrogen receptors. Although an epidemiologically based investigation has suggested that some chemicals could disrupt thyroid function in animals, the effects on thyroid hormone receptors (TRs) are unknown. We show here that BPA inhibits TR-mediated transcription by acting as an antagonist. In the transient gene expression experiments, BPA suppressed transcriptional activity that is stimulated by thyroid hormone (T(3)) in a dose-dependent manner. The inhibitory effects were observed in the presence of physiological concentrations of T(3). In contrast, in the case of negatively regulated TSHalpha promoter, BPA activated the gene transcription that is suppressed by T(3). To elucidate possible mechanisms of the antagonistic action of BPA, the effects on T(3) binding and cofactor interaction with TR were examined. The K(i) value for BPA was 200 micro M when assessed by inhibition of [(125)I]T(3) binding to rat hepatic nuclear TRs. In a mammalian two-hybrid assay, BPA recruited the nuclear corepressor to the TR. These results suggest that BPA could displace T(3) from the TR and recruit a transcriptional repressor, resulting in gene suppression. This is the first report that BPA can antagonize T(3) action at the transcriptional level. BPA may disrupt the function of various types of nuclear hormone receptors and their cofactors to disturb our internal hormonal environment.

Animals↗
PubMed2002

TR surfaces and conformations required to bind nuclear receptor corepressor.

Residues of the TR that are critical for binding the nuclear receptor corepressor (N-CoR) were identified by testing more than 100 separate mutations of the full-length human TRbeta that scan the surface of its ligand binding domain. The primary inferred interaction surface overlaps the surface described for binding of p160 coactivators, but differs by extending to a novel site underneath which helix 12 rests in the liganded TR, rather than including residues of helix 12. Nonconservative mutations of this surface diminished binding similarly to three isolated N-CoR receptor interaction domains (RIDs), but conservative mutations affected binding variably, consistent with a role for this surface in RID selectivity. The commonality of this surface in binding N-CoR was confirmed for the RXRs and ERs. Deletion of helix 12 increased N-CoR binding by the TR modestly, and by the RXR and ER to a much greater extent, indicating a competition between this helix and the corepressor that regulates the extent of corepressor binding by nuclear receptors. When helix 12 was deleted, N-CoR binding by the ER was stimulated by tamoxifen, and binding by the TR was stimulated by Triac, indicating that helix 12 is not the only feature that regulates corepressor binding. Two additional mutationsensitive surfaces were found alongside helix 1, near the previously described CoR box, and above helix 11, nearby but separate from residues that help link receptor in dimers. Based on effects of selected mutations on T(3) and coactivator binding, and on results of combined mutations of the three sites on corepressor binding, we propose that the second and third surfaces stabilize TR unliganded conformation(s) required for efficient N-CoR binding. In transfection assays mutations of all three surfaces impaired the corepressor-mediated functions of unliganded TR repression or activation. These detailed mapping results suggest approaches for selective modulation of corepressor interaction that include the shape of the molecular binding surface, the competitive occupancy by helix 12, pharmacological stimulation, and specific conformational stabilization.

Animals↗