Thyroid hormone plays pivotal roles in growth, differentiation, development and metabolic homeostasis via thyroid hormone receptors (TRs) by controlling the expression of TR target genes. The transcriptional activity of TRs is modulated by multiple factors including various TR isoforms, diverse thyroid hormone response elements, different heterodimeric partners, coregulators, and the cellular location of TRs. In the present review, we summarize recent advance in understanding the molecular mechanisms of thyroid hormone action obtained from human subject research, thyroid hormone mimetics application, TR isoform-specific knock-in mouse models, and mitochondrion study with highlights in metabolic regulations. Finally, as future perspectives, we share our thoughts about current challenges and possible approaches to promote our knowledge of thyroid hormone action in metabolism.
Animals ; Gene Knockout Techniques ; Humans ; Mice ; Mitochondria ; metabolism ; Protein Isoforms ; genetics ; metabolism ; physiology ; Receptors, Thyroid Hormone ; metabolism ; Thyroid Diseases ; metabolism ; pathology ; Thyroid Hormones ; genetics ; metabolism ; physiology

Adenocarcinoma, Follicular ; genetics ; metabolism ; pathology ; Carcinoma, Papillary ; genetics ; metabolism ; pathology ; Carcinoma, Renal Cell ; genetics ; metabolism ; pathology ; Diagnosis, Differential ; Humans ; Immunohistochemistry ; Kidney Diseases, Cystic ; genetics ; metabolism ; pathology ; Kidney Neoplasms ; genetics ; metabolism ; pathology ; Thyroid Neoplasms ; genetics ; metabolism ; pathology ; Translocation, Genetic

BACKGROUND: The absence of thyroid cysts may indicate latent thyroid damage, as demonstrated in our previous study. However, the association between the absence of thyroid cysts and latent functional damage of the thyroid is unknown. At low thyroid hormone productivity, which may be associated with latent functional damage of the thyroid, the association between thyroid-stimulating hormone (TSH) and hypertension might be enhanced. Therefore, we evaluated the association between TSH level and hypertension stratified by thyroid cyst status. METHODS: We conducted a cross-sectional study of 1724 euthyroid Japanese individuals aged 40-74 years who participated in an annual health checkup in 2014. RESULTS: In the study population, 564 and 686 participants had thyroid cysts and hypertension, respectively. A significant positive association was observed between TSH and hypertension in subjects without a thyroid cyst but not in subjects with thyroid cysts. There was a significant positive association between hypertension and TSH in subjects without a thyroid cyst (odds ratio [OR] 1.27; 95% confidence intervals [CI] 1.01, 1.61) but not in subjects with thyroid cysts (OR 0.79; CI 0.57, 1.09) in the model fully adjusted for known confounding factors. The correlation between the TSH and free triiodothyronine (fee T3) levels (simple correlation coefficient [r] = - 0.13, p < 0.01) was stronger in the subjects without thyroid cysts than in those with thyroid cysts (r = - 0.03, p = 0.525). CONCLUSIONS TSH is positively associated with hypertension only in individuals without thyroid cysts. The correlation between the TSH and free T3 levels was stronger in the subjects without thyroid cysts than in those with thyroid cysts. Therefore, the absence of thyroid cysts could be related to the association between TSH level and hypertension, possibly by indicating that the subjects without thyroid cysts had limited thyroid hormone reserves. Therefore, the absence of thyroid cysts could indicate the latent functional damage of the thyroid.
Aged ; Cross-Sectional Studies ; Cysts/etiology* ; Female ; Humans ; Hypertension/metabolism* ; Japan ; Male ; Middle Aged ; Thyroid Diseases/etiology* ; Thyroid Gland/pathology* ; Thyrotropin/metabolism*

BACKGROUND: The differential diagnosis of thyroid nodules is very important in deciding the treatment modality and the fine needle aspiration is the best diagnostic method. But, there are some limitations in use because of inadequate test materials and difficulty in interpreting. According to the study of oncogene and tumor suppressor gene about the origin of thyroid tumor, expression of Fra-1, one of AP-1 complex, is increased in thyroid neoplasm, though not present in the normal tissue. So, there is a possibility that it will be used as a method for the differential diagnosis of thyroid nodules. We tried to know whether presence or absence of Fra-1 expression can be used as a diagnostic method in differential diagnosis of thyroid nodules using the immunohistochemical (IHC) staining method. METHOD: In 4 types of thyroid tumor that were confirmed by histologic diagnosis after operation (18 cases of adenomatous goiter, 16 cases of follicular adenoma, 30 cases of papillary cancer, 10 cases of follicular cancer), IHC staining method was performed to evaluate the expression of Fra-1. RESULT: In papillary and follicular thyroid cancers, the expression of Fra-1 was stronger than in benign thyroid tumor, but there was no difference in Fra-1 expression between the two types of carcinoma. Weak expression of Fra-1 was observed in all cases of follicular adenoma, though it was weaker than in carcinoma, and it was also weakly expressed only in some cases (33%) of adenomatous goiter. CONCLUSION: The expression of Fra-1 was stronger in thyroid cancer than in benign thyroid tumor, but it was impossible to differentiate thyroid cancer from benign thyroid tumor by presence or absence of Fra-1 expression using IHC staining method.
Biopsy, Needle ; Comparative Study ; Diagnosis, Differential ; Human ; Immunohistochemistry ; Proto-Oncogene Proteins c-fos/*analysis ; Sensitivity and Specificity ; Thyroid Diseases/metabolism/pathology ; Thyroid Neoplasms/*metabolism/*pathology ; Tissue Culture ; Tumor Markers, Biological/*analysis

OBJECTIVETo investigate the expressions of thyroid transcription factor-1 (TTF-1), the type II alveolar epithelial cells (AECII)-specific marker, and vimentin, the fibroblast-specific marker, in the lungs of neonatal mice with bronchopulmonary dysplasia (BPD) and explore the pathogenesis of BPD.

METHODSNeonatal mice were exposed to hyperoxia to induce BPD, and pathological changes in the lung tissues were examined. At 3, 7, 14 and 21 days after the exposure, the protein and mRNA expressions of TTF-1 and vimentin were detected by double-labeled immunofluorescence assay and real-time PCR, respectively.

RESULTSCompared with the neonatal mice exposed in normal air, those with hyperoxic exposure showed developmental disorders and collagen deposition in the lung tissues. The protein expression of TTF-1 decreased while vimentin expression increased in the lung tissues, where their co-expression was observed at 14 and 21 days after the exposure. TTF-1 mRNA expression decreased markedly (P<0.05) and vimentin mRNA increased significantly in the lung tissues at 21 days after hyperoxic exposure of the mice (P<0.05).

CONCLUSIONHyperoxia-induced transition of AECII to fibroblasts may play an important role in pulmonary fibrosis in neonatal mice with BPD.

Animals ; Animals, Newborn ; Disease Models, Animal ; Female ; Hyperoxia ; Lung ; metabolism ; pathology ; Lung Diseases ; metabolism ; pathology ; Mice ; Mice, Inbred C57BL ; Nuclear Proteins ; metabolism ; RNA, Messenger ; genetics ; Thyroid Nuclear Factor 1 ; Transcription Factors ; metabolism ; Vimentin ; metabolism

Alveolar Epithelial Cells ; pathology ; Diagnosis, Differential ; Humans ; Hyperplasia ; diagnostic imaging ; etiology ; metabolism ; pathology ; Lung Diseases ; diagnostic imaging ; etiology ; metabolism ; pathology ; Mucin-1 ; metabolism ; Nuclear Proteins ; metabolism ; Radiography ; Thyroid Nuclear Factor 1 ; Transcription Factors ; metabolism ; Tuberous Sclerosis ; complications ; diagnostic imaging ; metabolism ; pathology

BACKGROUNDImmunoglobulin G4-related disease (IgG4-RD) is a newly recognized systemic disease that can involve multiple organs and various clinical phenotypes. The purpose of this study was to analyze different types of organ involvement in IgG4-RD patients in China.

METHODSWe conducted a prospective cohort study on IgG4-RD patients to analyze the clinical manifestations and rare features of IgG4-RD. Patients were grouped into different types according to organ involvement regarding organ number and organ site. The constituent ratio in different types was also analyzed.

RESULTSA total of 200 IgG4-RD patients, with a male:female ratio of 2.08:1, were grouped into different types. Cases having involvement of two or three organs were the most common whereas the fewest number of patients had multi-organ (≥4) involvement. Serum IgG4 and IgE levels, IgG4/IgG ratio, and percentage of eosinophils increased as the number of involved organs increased. In addition, constituent ratio analysis revealed that patients with salivary gland/lacrimal gland swelling, who also constituted the largest number of IgG4-RD patients, had higher serum IgG4 concentrations and IgG4/IgG values, had higher percentage of Eos, and were more likely to have had a history of allergies relative to patients with internal organ involvement.

CONCLUSIONSThe characteristic feature of IgG4-RD is multiple organ involvement with various clinical manifestations and different types. Although serum IgG4 levels increased with the number of involved organs, serum IgG4 levels were higher for those patients with salivary gland/lacrimal gland swelling compared with those with internal organ involvement. Thus, valuable clues to the differential diagnosis of IgG4-RD could be obtained by examining the clinical patterns of organ involvement.

Adolescent ; Adult ; Aged ; Aged, 80 and over ; Autoimmune Diseases ; complications ; pathology ; Eosinophils ; metabolism ; Female ; Humans ; Immunoglobulin E ; blood ; Immunoglobulin G ; blood ; Kidney ; pathology ; Lacrimal Apparatus ; pathology ; Lung ; pathology ; Male ; Middle Aged ; Pituitary Gland ; pathology ; Prospective Studies ; Prostate ; pathology ; Salivary Glands ; pathology ; Thyroid Gland ; pathology ; Uterus ; pathology ; Young Adult