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Lietzow J, Golchert J, Pietzner M, Völker U, Poutanen M, Ohlsson C, Homuth G, Köhrle J. Comparative Analysis of the Effects of Long-Term 3,5-diiodothyronine Treatment on the Murine Hepatic Proteome and Transcriptome Under Conditions of Normal Diet and High-Fat Diet. Thyroid 2021; 31:1135-1146. [PMID: 33637021 DOI: 10.1089/thy.2020.0160] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Background: The thyroid hormone (TH) metabolite 3,5-diiodothyronine (3,5-T2) is considered as a potential drug for treatment of nonalcoholic fatty liver disease (NAFLD) based on its prominent antisteatotic effects in murine models of obesity without the detrimental thyromimetic side effects known for classical TH. To expand our understanding of its mode of action, we comprehensively characterized the effects of 3,5-T2 on hepatic gene expression in a diet-induced murine model of obesity by a combined liver proteome and transcriptome analysis. Materials and Methods: Male C57BL/6 mice fed high-fat diet (HFD) to induce NAFLD or standard diet (SD) as control were treated with 2.5 μg/g body weight 3,5-T2 or saline for 4 weeks. We performed mass spectrometry analyses and integrated those proteome data with earlier published microarray-based transcriptome data from the same animals. In addition, concentrations of several sex steroids in serum and different tissues were determined by gas chromatography-tandem mass spectrometry. Results: We observed limited concordance between transcripts and proteins exhibiting differential abundance under 3,5-T2 treatment, which was only partially explainable by methodological reasons and might, therefore, reflect noncanonical post-transcriptional events. The treatment affected the levels of more and partially different proteins under HFD as compared with SD, demonstrating response modulation by the hepatic lipid load. The hepatic physiological signatures of 3,5-T2 treatment inferable from the omics data comprised the reduction of oxidative stress and alteration of apolipoprotein profiles, both due to decreased liver fat content. In addition, induction of several classical TH target genes and genes involved in the biosynthesis of cholesterol, bile acids (BAs), and male sex steroids was observed. The latter finding was supported by hepatic sex steroid measurements. Conclusion: While confirming the beneficial hepatic liver fat reduction by 3,5-T2 treatment, our data suggest that besides the well-known induction of fatty acid oxidation the stimulation of cholesterol- and BA synthesis with subsequent excretion of the latter through bile might represent a further important mechanism in this context. The obvious intensified male sex steroid exposition of the liver in 3,5-T2-treated HFD animals can be predicted to cause enhanced hepatic "masculinization," with not yet clear but potentially detrimental physiological consequences.
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Affiliation(s)
- Julika Lietzow
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institut für Experimentelle Endokrinologie, Berlin, Germany
| | - Janine Golchert
- Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Maik Pietzner
- Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Uwe Völker
- Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Matti Poutanen
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, University of Turku, Turku, Finland
| | - Claes Ohlsson
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Georg Homuth
- Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Josef Köhrle
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institut für Experimentelle Endokrinologie, Berlin, Germany
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Gauthier BR, Sola‐García A, Cáliz‐Molina MÁ, Lorenzo PI, Cobo‐Vuilleumier N, Capilla‐González V, Martin‐Montalvo A. Thyroid hormones in diabetes, cancer, and aging. Aging Cell 2020; 19:e13260. [PMID: 33048427 PMCID: PMC7681062 DOI: 10.1111/acel.13260] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 07/27/2020] [Accepted: 09/13/2020] [Indexed: 12/18/2022] Open
Abstract
Thyroid function is central in the control of physiological and pathophysiological processes. Studies in animal models and human research have determined that thyroid hormones modulate cellular processes relevant for aging and for the majority of age‐related diseases. While several studies have associated mild reductions on thyroid hormone function with exceptional longevity in animals and humans, alterations in thyroid hormones are serious medical conditions associated with unhealthy aging and premature death. Moreover, both hyperthyroidism and hypothyroidism have been associated with the development of certain types of diabetes and cancers, indicating a great complexity of the molecular mechanisms controlled by thyroid hormones. In this review, we describe the latest findings in thyroid hormone research in the field of aging, diabetes, and cancer, with a special focus on hepatocellular carcinomas. While aging studies indicate that the direct modulation of thyroid hormones is not a viable strategy to promote healthy aging or longevity and the development of thyromimetics is challenging due to inefficacy and potential toxicity, we argue that interventions based on the use of modulators of thyroid hormone function might provide therapeutic benefit in certain types of diabetes and cancers.
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Affiliation(s)
- Benoit R. Gauthier
- Department of Cell Therapy and Regeneration Andalusian Center for Molecular Biology and Regenerative Medicine‐CABIMER Junta de Andalucía‐University of Pablo de Olavide‐University of Seville‐CSIC Seville Spain
- Biomedical Research Network on Diabetes and Related Metabolic Diseases‐CIBERDEM Instituto de Salud Carlos III Madrid Spain
| | - Alejandro Sola‐García
- Department of Cell Therapy and Regeneration Andalusian Center for Molecular Biology and Regenerative Medicine‐CABIMER Junta de Andalucía‐University of Pablo de Olavide‐University of Seville‐CSIC Seville Spain
| | - María Ángeles Cáliz‐Molina
- Department of Cell Therapy and Regeneration Andalusian Center for Molecular Biology and Regenerative Medicine‐CABIMER Junta de Andalucía‐University of Pablo de Olavide‐University of Seville‐CSIC Seville Spain
| | - Petra Isabel Lorenzo
- Department of Cell Therapy and Regeneration Andalusian Center for Molecular Biology and Regenerative Medicine‐CABIMER Junta de Andalucía‐University of Pablo de Olavide‐University of Seville‐CSIC Seville Spain
| | - Nadia Cobo‐Vuilleumier
- Department of Cell Therapy and Regeneration Andalusian Center for Molecular Biology and Regenerative Medicine‐CABIMER Junta de Andalucía‐University of Pablo de Olavide‐University of Seville‐CSIC Seville Spain
| | - Vivian Capilla‐González
- Department of Cell Therapy and Regeneration Andalusian Center for Molecular Biology and Regenerative Medicine‐CABIMER Junta de Andalucía‐University of Pablo de Olavide‐University of Seville‐CSIC Seville Spain
| | - Alejandro Martin‐Montalvo
- Department of Cell Therapy and Regeneration Andalusian Center for Molecular Biology and Regenerative Medicine‐CABIMER Junta de Andalucía‐University of Pablo de Olavide‐University of Seville‐CSIC Seville Spain
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Herrmann B, Harder L, Oelkrug R, Chen J, Gachkar S, Nock S, Resch J, Korkowski M, Heuer H, Mittag J. Central Hypothyroidism Impairs Heart Rate Stability and Prevents Thyroid Hormone-Induced Cardiac Hypertrophy and Pyrexia. Thyroid 2020; 30:1205-1216. [PMID: 32188347 DOI: 10.1089/thy.2019.0705] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Background: Tachycardia, cardiac hypertrophy, and elevated body temperature are major signs of systemic hyperthyroidism, which are considered to reflect the excessive thyroid hormone (TH) action in the respective peripheral tissues. However, recent observations indicate that the central actions of TH also contribute substantially to cardiovascular regulation and thermogenesis. Methods: In this study, we dissect the individual contributions of peripheral TH action versus the central effects in body temperature regulation and cardiovascular functions by taking advantage of mice lacking the TH transporters monocarboxylate transporter 8 (MCT8) and organic anion transporting polypeptide 1C1 (OATP1C1) (M/O double knock-out [dko]), which exhibit elevated serum triiodothyronine (T3) levels while their brain is in a profoundly hypothyroid state. We compared these animals with wild-type (WT) mice that were treated orally with T3 to achieve similarly elevated serum T3 levels, but are centrally hyperthyroid. For the studies, we used radiotelemetry, infrared thermography, gene expression profiling, Western blot analyses, and enzyme linked immunosorbent assays (ELISA) assays. Results: Our analyses revealed mild hyperthermia and cardiac hypertrophy in T3-treated WT mice but not in M/O dko animals, suggesting that central actions of TH are required for these hyperthyroid phenotypes. Although the average heart rate was unaffected in either model, the M/O dko exhibited an altered heart rate frequency distribution with tachycardic bursts in active periods and bradycardic episodes during resting time, demonstrating that the stabilization of heart rate by the autonomic nervous system can be impaired in centrally hypothyroid animals. Conclusions: Our studies unravel distinct phenotypical traits of hyperthyroidism that depend on an intact central nervous system, and provide valuable insight into the cardiovascular pathology of the Allan-Herndon-Dudley syndrome, a condition caused by the lack of MCT8 in humans.
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Affiliation(s)
- Beate Herrmann
- Department of Molecular Endocrinology, Institute for Endocrinology and Diabetes, Center of Brain Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany
| | - Lisbeth Harder
- Department of Molecular Endocrinology, Institute for Endocrinology and Diabetes, Center of Brain Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany
| | - Rebecca Oelkrug
- Department of Molecular Endocrinology, Institute for Endocrinology and Diabetes, Center of Brain Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany
| | - Jiesi Chen
- Leibniz Research Institute for Environmental Medicine (IUF), Düsseldorf, Germany
| | - Sogol Gachkar
- Department of Molecular Endocrinology, Institute for Endocrinology and Diabetes, Center of Brain Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany
| | - Sebastian Nock
- Department of Molecular Endocrinology, Institute for Endocrinology and Diabetes, Center of Brain Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany
| | - Julia Resch
- Department of Molecular Endocrinology, Institute for Endocrinology and Diabetes, Center of Brain Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany
| | - Markus Korkowski
- Leibniz Research Institute for Environmental Medicine (IUF), Düsseldorf, Germany
- Department of Endocrinology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Heike Heuer
- Leibniz Research Institute for Environmental Medicine (IUF), Düsseldorf, Germany
- Department of Endocrinology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Jens Mittag
- Department of Molecular Endocrinology, Institute for Endocrinology and Diabetes, Center of Brain Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany
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Nock S, Johann K, Harder L, Wirth EK, Renko K, Hoefig CS, Kracke V, Hackler J, Engelmann B, Rauner M, Köhrle J, Schomburg L, Homuth G, Völker U, Brabant G, Mittag J. CD5L Constitutes a Novel Biomarker for Integrated Hepatic Thyroid Hormone Action. Thyroid 2020; 30:908-923. [PMID: 32183611 DOI: 10.1089/thy.2019.0635] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Background: Pathological conditions of the thyroid hormone (TH) system are routinely diagnosed by using serum concentrations of thyrotropin (TSH), which is sufficient in most cases. However, in certain conditions, such as resistance to TH due to mutations in THRB (RTHb) or TSH-releasing pituitary adenoma (TSHoma), TSH may be insufficient for a correct diagnosis, even in combination with serum TH concentrations. Likewise, under TH replacement therapy, these parameters can be misleading and do not always allow optimal treatment. Hence, additional biomarkers to assess challenging clinical conditions would be highly beneficial. Methods: Data from untargeted multi-omics analyses of plasma samples from experimental thyrotoxicosis in human and mouse were exploited to identify proteins that might represent possible biomarkers of TH function. Subsequent mouse studies were used to identify the tissue of origin and the involvement of the two different TH receptors (TR). For in-depth characterization of the underlying cellular mechanisms, primary mouse cells were used. Results: The analysis of the plasma proteome data sets revealed 16 plasma proteins that were concordantly differentially abundant under thyroxine treatment compared with euthyroid controls across the two species. These originated predominantly from liver, spleen, and bone. Independent studies in a clinical cohort and different mouse models identified CD5L as the most robust putative biomarker under different serum TH states and treatment periods. In vitro studies revealed that CD5L originates from proinflammatory M1 macrophages, which are similar to liver-residing Kupffer cells, and is regulated by an indirect mechanism requiring the secretion of a yet unknown factor from hepatocytes. In agreement with the role of TRα1 in immune cells and the TRβ-dependent hepatocyte-derived signaling, the in vivo regulation of Cd5l expression depended on both TR isoforms. Conclusion: Our results identify several novel targets of TH action in serum, with CD5L as the most robust marker. Although further studies will be needed to validate the specificity of these targets, CD5L seems to be a promising candidate to assess TH action in hepatocyte-macrophage crosstalk.
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Affiliation(s)
- Sebastian Nock
- Department of Molecular Endocrinology, Center of Brain, Behavior and Metabolism, Institute for Endocrinology and Diabetes, University of Lübeck, Lübeck, Germany
| | - Kornelia Johann
- Department of Molecular Endocrinology, Center of Brain, Behavior and Metabolism, Institute for Endocrinology and Diabetes, University of Lübeck, Lübeck, Germany
| | - Lisbeth Harder
- Department of Molecular Endocrinology, Center of Brain, Behavior and Metabolism, Institute for Endocrinology and Diabetes, University of Lübeck, Lübeck, Germany
| | - Eva Katrin Wirth
- Institut für Experimentelle Endokrinologie, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, CVK, Berlin, Germany
- Medizinische Klinik für Endokrinologie und Stoffwechselmedizin, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany
| | - Kostja Renko
- Institut für Experimentelle Endokrinologie, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, CVK, Berlin, Germany
| | - Carolin S Hoefig
- Institut für Experimentelle Endokrinologie, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, CVK, Berlin, Germany
| | - Vanessa Kracke
- Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Julian Hackler
- Institut für Experimentelle Endokrinologie, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, CVK, Berlin, Germany
| | - Beatrice Engelmann
- Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Martina Rauner
- Department of Medicine III; Technische Universität Dresden Medical Center, Dresden, Germany
- Center for Healthy Aging, Technische Universität Dresden Medical Center, Dresden, Germany
| | - Josef Köhrle
- Institut für Experimentelle Endokrinologie, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, CVK, Berlin, Germany
| | - Lutz Schomburg
- Institut für Experimentelle Endokrinologie, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, CVK, Berlin, Germany
| | - Georg Homuth
- DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany
- Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Uwe Völker
- DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany
- Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Georg Brabant
- Department of Molecular Endocrinology, Center of Brain, Behavior and Metabolism, Institute for Endocrinology and Diabetes, University of Lübeck, Lübeck, Germany
| | - Jens Mittag
- Department of Molecular Endocrinology, Center of Brain, Behavior and Metabolism, Institute for Endocrinology and Diabetes, University of Lübeck, Lübeck, Germany
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Perra A, Plateroti M, Columbano A. T3/TRs axis in hepatocellular carcinoma: new concepts for an old pair. Endocr Relat Cancer 2016; 23:R353-69. [PMID: 27353037 DOI: 10.1530/erc-16-0152] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Accepted: 06/27/2016] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, and its burden is expected to further increase in the next years. Chronic inflammation, induced by multiple viruses or metabolic alterations, and epigenetic and genetic modifications, cooperate in cancer development via a combination of common and distinct aetiology-specific pathways. In spite of the advances of classical therapies, the prognosis of this neoplasm has not considerably improved over the past few years. The advent of targeted therapies and the approval of the systemic treatment of advanced HCC with the kinase inhibitor sorafenib have provided some hope for the future. However, the benefits obtained from this treatment are still disappointing, as it extends the median life expectancy of patients by only few months. It is thus mandatory to find alternative effective treatments. Although the role played by thyroid hormones (THs) and their nuclear receptors (TRs) in human cancer is still unclear, mounting evidence indicates that they behave as oncosuppressors in HCC. However, the molecular mechanisms by which they exert this effect and the consequence of their activation following ligand binding on HCC progression remain elusive. In this review, we re-evaluate the existing evidence of the role of TH/TRs in HCC development; we will also discuss how TR alterations could affect fundamental biological processes, such as hepatocyte proliferation and differentiation, and consequently HCC progression. Finally, we will discuss if and how TRs can be foreseen as therapeutic targets in HCC and whether selective TR modulation by TH analogues may hold promise for HCC treatment.
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Affiliation(s)
- Andrea Perra
- Department of Biomedical SciencesUniversity of Cagliari, Cagliari, Italy
| | - Michelina Plateroti
- Cancer Research Center of Lyon INSERM U1052CNRS UMR5286, Université de Lyon, Université Lyon 1, Centre Léon Bérard, Département de la Recherche, Lyon, France
| | - Amedeo Columbano
- Department of Biomedical SciencesUniversity of Cagliari, Cagliari, Italy
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Ortiga-Carvalho TM, Chiamolera MI, Pazos-Moura CC, Wondisford FE. Hypothalamus-Pituitary-Thyroid Axis. Compr Physiol 2016; 6:1387-428. [PMID: 27347897 DOI: 10.1002/cphy.c150027] [Citation(s) in RCA: 248] [Impact Index Per Article: 27.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The hypothalamus-pituitary-thyroid (HPT) axis determines the set point of thyroid hormone (TH) production. Hypothalamic thyrotropin-releasing hormone (TRH) stimulates the synthesis and secretion of pituitary thyrotropin (thyroid-stimulating hormone, TSH), which acts at the thyroid to stimulate all steps of TH biosynthesis and secretion. The THs thyroxine (T4) and triiodothyronine (T3) control the secretion of TRH and TSH by negative feedback to maintain physiological levels of the main hormones of the HPT axis. Reduction of circulating TH levels due to primary thyroid failure results in increased TRH and TSH production, whereas the opposite occurs when circulating THs are in excess. Other neural, humoral, and local factors modulate the HPT axis and, in specific situations, determine alterations in the physiological function of the axis. The roles of THs are vital to nervous system development, linear growth, energetic metabolism, and thermogenesis. THs also regulate the hepatic metabolism of nutrients, fluid balance and the cardiovascular system. In cells, TH actions are mediated mainly by nuclear TH receptors (210), which modify gene expression. T3 is the preferred ligand of THR, whereas T4, the serum concentration of which is 100-fold higher than that of T3, undergoes extra-thyroidal conversion to T3. This conversion is catalyzed by 5'-deiodinases (D1 and D2), which are TH-activating enzymes. T4 can also be inactivated by conversion to reverse T3, which has very low affinity for THR, by 5-deiodinase (D3). The regulation of deiodinases, particularly D2, and TH transporters at the cell membrane control T3 availability, which is fundamental for TH action. © 2016 American Physiological Society. Compr Physiol 6:1387-1428, 2016.
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Affiliation(s)
- Tania M Ortiga-Carvalho
- Institute of Biophysics Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, UFRJ, Rio de Janeiro, Brazil
| | - Maria I Chiamolera
- Department of Medicine, Escola Paulista de Medicina, Universidade Federal de Sao Paulo, Sao Paulo, Brazil
| | - Carmen C Pazos-Moura
- Institute of Biophysics Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, UFRJ, Rio de Janeiro, Brazil
| | - Fredic E Wondisford
- Department of Medicine, Rutgers-Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA
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7
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Astapova I. Role of co-regulators in metabolic and transcriptional actions of thyroid hormone. J Mol Endocrinol 2016; 56:73-97. [PMID: 26673411 DOI: 10.1530/jme-15-0246] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2015] [Accepted: 12/16/2015] [Indexed: 12/18/2022]
Abstract
Thyroid hormone (TH) controls a wide range of physiological processes through TH receptor (TR) isoforms. Classically, TRs are proposed to function as tri-iodothyronine (T3)-dependent transcription factors: on positively regulated target genes, unliganded TRs mediate transcriptional repression through recruitment of co-repressor complexes, while T3 binding leads to dismissal of co-repressors and recruitment of co-activators to activate transcription. Co-repressors and co-activators were proposed to play opposite roles in the regulation of negative T3 target genes and hypothalamic-pituitary-thyroid axis, but exact mechanisms of the negative regulation by TH have remained elusive. Important insights into the roles of co-repressors and co-activators in different physiological processes have been obtained using animal models with disrupted co-regulator function. At the same time, recent studies interrogating genome-wide TR binding have generated compelling new data regarding effects of T3, local chromatin structure, and specific response element configuration on TR recruitment and function leading to the proposal of new models of transcriptional regulation by TRs. This review discusses data obtained in various mouse models with manipulated function of nuclear receptor co-repressor (NCoR or NCOR1) and silencing mediator of retinoic acid receptor and thyroid hormone receptor (SMRT or NCOR2), and family of steroid receptor co-activators (SRCs also known as NCOAs) in the context of TH action, as well as insights into the function of co-regulators that may emerge from the genome-wide TR recruitment analysis.
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Affiliation(s)
- Inna Astapova
- Division of Endocrinology, Diabetes and MetabolismBeth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
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8
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Bianco AC, Anderson G, Forrest D, Galton VA, Gereben B, Kim BW, Kopp PA, Liao XH, Obregon MJ, Peeters RP, Refetoff S, Sharlin DS, Simonides WS, Weiss RE, Williams GR. American Thyroid Association Guide to investigating thyroid hormone economy and action in rodent and cell models. Thyroid 2014; 24:88-168. [PMID: 24001133 PMCID: PMC3887458 DOI: 10.1089/thy.2013.0109] [Citation(s) in RCA: 150] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND An in-depth understanding of the fundamental principles that regulate thyroid hormone homeostasis is critical for the development of new diagnostic and treatment approaches for patients with thyroid disease. SUMMARY Important clinical practices in use today for the treatment of patients with hypothyroidism, hyperthyroidism, or thyroid cancer are the result of laboratory discoveries made by scientists investigating the most basic aspects of thyroid structure and molecular biology. In this document, a panel of experts commissioned by the American Thyroid Association makes a series of recommendations related to the study of thyroid hormone economy and action. These recommendations are intended to promote standardization of study design, which should in turn increase the comparability and reproducibility of experimental findings. CONCLUSIONS It is expected that adherence to these recommendations by investigators in the field will facilitate progress towards a better understanding of the thyroid gland and thyroid hormone dependent processes.
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Affiliation(s)
- Antonio C. Bianco
- Division of Endocrinology, Diabetes and Metabolism, University of Miami Miller School of Medicine, Miami, Florida
| | - Grant Anderson
- Department of Pharmacy Practice and Pharmaceutical Sciences, College of Pharmacy, University of Minnesota Duluth, Duluth, Minnesota
| | - Douglas Forrest
- Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Valerie Anne Galton
- Department of Physiology and Neurobiology, Dartmouth Medical School, Lebanon, New Hampshire
| | - Balázs Gereben
- Department of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary
| | - Brian W. Kim
- Division of Endocrinology, Diabetes and Metabolism, University of Miami Miller School of Medicine, Miami, Florida
| | - Peter A. Kopp
- Division of Endocrinology, Metabolism, and Molecular Medicine, and Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Xiao Hui Liao
- Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, The University of Chicago, Chicago, Illinois
| | - Maria Jesus Obregon
- Institute of Biomedical Investigation (IIB), Spanish National Research Council (CSIC) and Autonomous University of Madrid, Madrid, Spain
| | - Robin P. Peeters
- Division of Endocrinology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Samuel Refetoff
- Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, The University of Chicago, Chicago, Illinois
| | - David S. Sharlin
- Department of Biological Sciences, Minnesota State University, Mankato, Minnesota
| | - Warner S. Simonides
- Laboratory for Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands
| | - Roy E. Weiss
- Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, The University of Chicago, Chicago, Illinois
| | - Graham R. Williams
- Department of Medicine, Imperial College London, Hammersmith Campus, London, United Kingdom
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Huang YY, Gusdon AM, Qu S. Cross-talk between the thyroid and liver: A new target for nonalcoholic fatty liver disease treatment. World J Gastroenterol 2013; 19:8238-8246. [PMID: 24363514 PMCID: PMC3857446 DOI: 10.3748/wjg.v19.i45.8238] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2013] [Revised: 10/04/2013] [Accepted: 10/18/2013] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) has been recognized as the most common liver metabolic disease, and it is also a burgeoning health problem that affects one-third of adults and is associated with obesity and insulin resistance now. Thyroid hormone (TH) and its receptors play a fundamental role in lipid metabolism and lipid accumulation in the liver. It is found that thyroid receptor and its isoforms exhibit tissue-specific expression with a variety of functions. TRβ1 is predominantly expressed in the brain and adipose tissue and TRβ2 is the major isoform in the liver, kidney and fat. They have different functions and play important roles in lipid metabolism. Recently, there are many studies on the treatment of NAFLD with TH and its analogues. We review here that thyroid hormone and TR are a potential target for pharmacologic treatments. Lipid metabolism and lipid accumulation can be regulated and reversed by TH and its analogues.
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Abstract
Thyroid hormones (THs) are important in the development and maintenance of lipid and energy homeostasis. THs act through two closely related TH receptors (TRs α and β), which are conditional transcription factors. Recently, TH analogues or thyromimetics with varying degrees of TR subtype and liver uptake selectivity have been developed. These compounds exert beneficial effects of TH excess states without many undesirable TR-dependent side effects. Several selective TR modulators (STRMs) showed exceptionally promising results in lowering serum cholesterol in preclinical animal models and human clinical studies. Moreover, some first generation STRMs elicit other potentially beneficial effects on obesity, glucose metabolism, and nonalcoholic fatty liver disease (NAFLD). While it was initially thought that STRMs would be an effective long-term therapy to combat elevated cholesterol, possibly in conjunction with another cholesterol-lowering therapy, the statins, three major first generation STRMs failed to progress beyond early phase III human trials. The aim of this review is to discuss how STRMs work, their actions in preclinical animal models and human clinical trials, why they did not progress beyond clinical trials as cholesterol-lowering therapeutics, whether selective TR modulation continues to hold promise for dyslipidemias, and whether members of this drug class could be applied to the treatment of other aspects of metabolic syndrome and human genetic disease.
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Affiliation(s)
- Sunitha Meruvu
- Center for Genomic Medicine, Houston Methodist Research Institute , Houston, Texas
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11
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Burris TP, Solt LA, Wang Y, Crumbley C, Banerjee S, Griffett K, Lundasen T, Hughes T, Kojetin DJ. Nuclear receptors and their selective pharmacologic modulators. Pharmacol Rev 2013; 65:710-78. [PMID: 23457206 PMCID: PMC11060414 DOI: 10.1124/pr.112.006833] [Citation(s) in RCA: 202] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Nuclear receptors are ligand-activated transcription factors and include the receptors for steroid hormones, lipophilic vitamins, sterols, and bile acids. These receptors serve as targets for development of myriad drugs that target a range of disorders. Classically defined ligands that bind to the ligand-binding domain of nuclear receptors, whether they are endogenous or synthetic, either activate receptor activity (agonists) or block activation (antagonists) and due to the ability to alter activity of the receptors are often termed receptor "modulators." The complex pharmacology of nuclear receptors has provided a class of ligands distinct from these simple modulators where ligands display agonist/partial agonist/antagonist function in a tissue or gene selective manner. This class of ligands is defined as selective modulators. Here, we review the development and pharmacology of a range of selective nuclear receptor modulators.
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Affiliation(s)
- Thomas P Burris
- The Scripps Research Institute, 130 Scripps Way 2A1, Jupiter, FL 33458, USA.
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Transcriptional Regulation of the Mitochondrial Citrate and Carnitine/Acylcarnitine Transporters: Two Genes Involved in Fatty Acid Biosynthesis and β-oxidation. BIOLOGY 2013; 2:284-303. [PMID: 24832661 PMCID: PMC4009865 DOI: 10.3390/biology2010284] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/22/2012] [Revised: 01/18/2013] [Accepted: 01/23/2013] [Indexed: 12/17/2022]
Abstract
Transcriptional regulation of genes involved in fatty acid metabolism is considered the major long-term regulatory mechanism controlling lipid homeostasis. By means of this mechanism, transcription factors, nutrients, hormones and epigenetics control not only fatty acid metabolism, but also many metabolic pathways and cellular functions at the molecular level. The regulation of the expression of many genes at the level of their transcription has already been analyzed. This review focuses on the transcriptional control of two genes involved in fatty acid biosynthesis and oxidation: the citrate carrier (CIC) and the carnitine/ acylcarnitine/carrier (CAC), which are members of the mitochondrial carrier gene family, SLC25. The contribution of tissue-specific and less tissue-specific transcription factors in activating or repressing CIC and CAC gene expression is discussed. The interaction with drugs of some transcription factors, such as PPAR and FOXA1, and how this interaction can be an attractive therapeutic approach, has also been evaluated. Moreover, the mechanism by which the expression of the CIC and CAC genes is modulated by coordinated responses to hormonal and nutritional changes and to epigenetics is highlighted.
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Intensification of doxorubicin-related oxidative stress in the heart by hypothyroidism is not related to the expression of cytochrome P450 NADPH-reductase and inducible nitric oxide synthase, as well as activity of xanthine oxidase. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2012; 2012:139327. [PMID: 22966413 PMCID: PMC3432562 DOI: 10.1155/2012/139327] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/21/2012] [Accepted: 07/05/2012] [Indexed: 11/17/2022]
Abstract
Cytochrome P450 NADPH-reductase (P450R), inducible synthase (iNOS) and xanthine oxidase play an important role in the antracycline-related cardiotoxicity. The expression of P450R and iNOS is regulated by triiodothyronine. The aim of this study was to evaluate the effect of methimazole-induced hypothyreosis on oxidative stress secondary to doxorubicin administration. 48 hours after methimazole giving cessation, rats were exposed to doxorubicin (2.0, 5.0 and 15 mg/kg). Blood and heart were collected 4, 48 and 96 h after the drug administration. Animals exposed exclusively to doxorubicin or untreated ones were also assessed. The hypothyreosis (0.025% of methimazole) significantly increased the doxorubicin effect on the cardiac carbonyl group and they may increase the glutathione level. An insignificant effect of methimazole was noticed in case of the cardiac lipid peroxidation product, the amount of DNA oxidative damages, iNOS and xanthine oxidase-enzymes responsible for red-ox activation of doxorubicin. However, the concentration of P450R was affected by a lower dose of methimazole in rats administered with doxorubicin. Since in rats receiving doxorubicin changes in oxidative stress caused by methimazole were not accompanied by elevation of bioreductive enzymes, it may be concluded that these changes in the oxidative stress were not related to the tested enzymes.
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Sinha RA, You SH, Zhou J, Siddique MM, Bay BH, Zhu X, Privalsky ML, Cheng SY, Stevens RD, Summers SA, Newgard CB, Lazar MA, Yen PM. Thyroid hormone stimulates hepatic lipid catabolism via activation of autophagy. J Clin Invest 2012; 122:2428-2438. [PMID: 22684107 PMCID: PMC3386813 DOI: 10.1172/jci60580] [Citation(s) in RCA: 222] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2011] [Accepted: 04/26/2012] [Indexed: 12/13/2022] Open
Abstract
For more than a century, thyroid hormones (THs) have been known to exert powerful catabolic effects, leading to weight loss. Although much has been learned about the molecular mechanisms used by TH receptors (TRs) to regulate gene expression, little is known about the mechanisms by which THs increase oxidative metabolism. Here, we report that TH stimulation of fatty acid β-oxidation is coupled with induction of hepatic autophagy to deliver fatty acids to mitochondria in cell culture and in vivo. Furthermore, blockade of autophagy by autophagy-related 5 (ATG5) siRNA markedly decreased TH-mediated fatty acid β-oxidation in cell culture and in vivo. Consistent with this model, autophagy was altered in livers of mice expressing a mutant TR that causes resistance to the actions of TH as well as in mice with mutant nuclear receptor corepressor (NCoR). These results demonstrate that THs can regulate lipid homeostasis via autophagy and help to explain how THs increase oxidative metabolism.
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Affiliation(s)
- Rohit Anthony Sinha
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School, Singapore.
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Department of Anatomy, Yong Loo Lin School of Medicine, Department of Anatomy, National University of Singapore, Singapore.
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
Department of Microbiology, UCD, Davis, California, USA.
Sarah W. Stedman Nutrition and Metabolism Center, Departments of Medicine and Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA
| | - Seo-Hee You
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School, Singapore.
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Department of Anatomy, Yong Loo Lin School of Medicine, Department of Anatomy, National University of Singapore, Singapore.
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
Department of Microbiology, UCD, Davis, California, USA.
Sarah W. Stedman Nutrition and Metabolism Center, Departments of Medicine and Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA
| | - Jin Zhou
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School, Singapore.
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Department of Anatomy, Yong Loo Lin School of Medicine, Department of Anatomy, National University of Singapore, Singapore.
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
Department of Microbiology, UCD, Davis, California, USA.
Sarah W. Stedman Nutrition and Metabolism Center, Departments of Medicine and Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA
| | - Mobin M. Siddique
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School, Singapore.
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Department of Anatomy, Yong Loo Lin School of Medicine, Department of Anatomy, National University of Singapore, Singapore.
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
Department of Microbiology, UCD, Davis, California, USA.
Sarah W. Stedman Nutrition and Metabolism Center, Departments of Medicine and Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA
| | - Boon-Huat Bay
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School, Singapore.
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Department of Anatomy, Yong Loo Lin School of Medicine, Department of Anatomy, National University of Singapore, Singapore.
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
Department of Microbiology, UCD, Davis, California, USA.
Sarah W. Stedman Nutrition and Metabolism Center, Departments of Medicine and Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA
| | - Xuguang Zhu
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School, Singapore.
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Department of Anatomy, Yong Loo Lin School of Medicine, Department of Anatomy, National University of Singapore, Singapore.
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
Department of Microbiology, UCD, Davis, California, USA.
Sarah W. Stedman Nutrition and Metabolism Center, Departments of Medicine and Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA
| | - Martin L. Privalsky
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School, Singapore.
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Department of Anatomy, Yong Loo Lin School of Medicine, Department of Anatomy, National University of Singapore, Singapore.
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
Department of Microbiology, UCD, Davis, California, USA.
Sarah W. Stedman Nutrition and Metabolism Center, Departments of Medicine and Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA
| | - Sheue-Yann Cheng
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School, Singapore.
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Department of Anatomy, Yong Loo Lin School of Medicine, Department of Anatomy, National University of Singapore, Singapore.
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
Department of Microbiology, UCD, Davis, California, USA.
Sarah W. Stedman Nutrition and Metabolism Center, Departments of Medicine and Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA
| | - Robert D. Stevens
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School, Singapore.
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Department of Anatomy, Yong Loo Lin School of Medicine, Department of Anatomy, National University of Singapore, Singapore.
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
Department of Microbiology, UCD, Davis, California, USA.
Sarah W. Stedman Nutrition and Metabolism Center, Departments of Medicine and Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA
| | - Scott A. Summers
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School, Singapore.
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Department of Anatomy, Yong Loo Lin School of Medicine, Department of Anatomy, National University of Singapore, Singapore.
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
Department of Microbiology, UCD, Davis, California, USA.
Sarah W. Stedman Nutrition and Metabolism Center, Departments of Medicine and Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA
| | - Christopher B. Newgard
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School, Singapore.
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Department of Anatomy, Yong Loo Lin School of Medicine, Department of Anatomy, National University of Singapore, Singapore.
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
Department of Microbiology, UCD, Davis, California, USA.
Sarah W. Stedman Nutrition and Metabolism Center, Departments of Medicine and Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA
| | - Mitchell A. Lazar
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School, Singapore.
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Department of Anatomy, Yong Loo Lin School of Medicine, Department of Anatomy, National University of Singapore, Singapore.
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
Department of Microbiology, UCD, Davis, California, USA.
Sarah W. Stedman Nutrition and Metabolism Center, Departments of Medicine and Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA
| | - Paul M. Yen
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School, Singapore.
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Department of Anatomy, Yong Loo Lin School of Medicine, Department of Anatomy, National University of Singapore, Singapore.
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
Department of Microbiology, UCD, Davis, California, USA.
Sarah W. Stedman Nutrition and Metabolism Center, Departments of Medicine and Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA
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Souza LL, Cordeiro A, Oliveira LS, de Paula GSM, Faustino LC, Ortiga-Carvalho TM, Oliveira KJ, Pazos-Moura CC. Thyroid hormone contributes to the hypolipidemic effect of polyunsaturated fatty acids from fish oil: in vivo evidence for cross talking mechanisms. J Endocrinol 2011; 211:65-72. [PMID: 21752938 DOI: 10.1530/joe-11-0142] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
n-3 polyunsaturated fatty acids (n-3 PUFA) from fish oil (FO) exert important lipid-lowering effects, an effect also ascribed to thyroid hormones (TH) and TH receptor β1 (TRβ1)-specific agonists. n-3 PUFA effects are mediated by nuclear receptors, such as peroxisome proliferator-activated receptors (PPAR) and others. In this study, we investigated a role for TH signaling in n-3 PUFA effects. Euthyroid and hypothyroid adult rats (methimazole-treated for 5 weeks) received FO or soybean oil (control) by oral administration for 3 weeks. In euthyroid rats, FO treatment reduced serum triglycerides and cholesterol, diminished body fat, and increased protein content of the animals. In addition, FO-treated rats exhibited higher liver expression of TRβ1 and mitochondrial α-glycerophosphate dehydrogenase (mGPD), at protein and mRNA levels, but no alteration of glutathione S-transferase or type 1 deiodinase. In hypothyroid condition, FO induced reduction in serum cholesterol and increase in body protein content, but lost the ability to reduce triglycerides and body fat, and to induce TRβ1 and mGDP expression. FO did not change PPARα liver abundance regardless of thyroid state; however, hypothyroidism led to a marked increase in PPARα liver content but did not alter TRβ1 or TRα expression. The data suggest that part of the effect of n-3 PUFA from FO on lipid metabolism is dependent on TH signaling in specific steps and together with the marked upregulation of PPARα in liver of hypothyroid rats suggest important in vivo consequences of the cross-talking between those fatty acids and TH pathways in liver metabolism.
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Affiliation(s)
- Luana Lopes Souza
- Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Centro de Ciências da Saúde, Avenida Carlos Chagas Filho, 373, Bloco G, Cidade Universitária - Ilha do Fundão, Rio de Janeiro - RJ 21941-902, Brazil
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16
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Weitzel JM, Iwen KA. Coordination of mitochondrial biogenesis by thyroid hormone. Mol Cell Endocrinol 2011; 342:1-7. [PMID: 21664416 DOI: 10.1016/j.mce.2011.05.009] [Citation(s) in RCA: 90] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2011] [Revised: 04/28/2011] [Accepted: 05/15/2011] [Indexed: 01/15/2023]
Abstract
Thyroid hormone (TH) has profound influence on metabolism that is closely linked to its effect on mitochondrial biogenesis and function. After a single injection of TH into mammals, physiological alterations (e.g. changes in oxygen consumption rates) are detectable after a lag period of ∼48h. This characteristic lag period is somewhat surprising since non-genomic responses are already detectable within minutes, and first genomic responses within some hours after administration of TH. This review provides a model to explain the characteristic lag period: TH regulates a first series of TH target genes via classical activation of gene expression by binding to thyroid hormone response elements. Some directly regulated target genes serve as intermediate factors and subsequently regulate a second series of indirect TH target genes. Intermediate factors are transcription factors (such as NRF-1, NRF-2 and PPARγ) and transcriptional coactivators (such as PGC-1α and PGC-1β). In concert with several post-translational modifications, these intermediate factors orchestrate the physiological response to thyroid hormone in vivo.
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Affiliation(s)
- Joachim M Weitzel
- Forschungsbereich Fortpflanzungsbiologie, Leibniz-Institut für Nutztierbiologie, FBN Dummerstorf, Germany.
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17
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Rosen MD, Privalsky ML. Thyroid hormone receptor mutations in cancer and resistance to thyroid hormone: perspective and prognosis. J Thyroid Res 2011; 2011:361304. [PMID: 21760978 PMCID: PMC3134260 DOI: 10.4061/2011/361304] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2011] [Accepted: 03/16/2011] [Indexed: 12/13/2022] Open
Abstract
Thyroid hormone, operating through its receptors, plays crucial roles in the control of normal human physiology and development; deviations from the norm can give rise to disease. Clinical endocrinologists often must confront and correct the consequences of inappropriately high or low thyroid hormone synthesis. Although more rare, disruptions in thyroid hormone endocrinology due to aberrations in the receptor also have severe medical consequences. This review will focus on the afflictions that are caused by, or are closely associated with, mutated thyroid hormone receptors. These include Resistance to Thyroid Hormone Syndrome, erythroleukemia, hepatocellular carcinoma, renal clear cell carcinoma, and thyroid cancer. We will describe current views on the molecular bases of these diseases, and what distinguishes the neoplastic from the non-neoplastic. We will also touch on studies that implicate alterations in receptor expression, and thyroid hormone levels, in certain oncogenic processes.
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Affiliation(s)
- Meghan D Rosen
- Department of Microbiology, University of California-Davis, Davis, CA 95616, USA
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18
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Silvestri E, Lombardi A, de Lange P, Glinni D, Senese R, Cioffi F, Lanni A, Goglia F, Moreno M. Studies of complex biological systems with applications to molecular medicine: the need to integrate transcriptomic and proteomic approaches. J Biomed Biotechnol 2010; 2011:810242. [PMID: 20981256 PMCID: PMC2963870 DOI: 10.1155/2011/810242] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2010] [Accepted: 09/08/2010] [Indexed: 02/07/2023] Open
Abstract
Omics approaches to the study of complex biological systems with potential applications to molecular medicine are attracting great interest in clinical as well as in basic biological research. Genomics, transcriptomics and proteomics are characterized by the lack of an a priori definition of scope, and this gives sufficient leeway for investigators (a) to discern all at once a globally altered pattern of gene/protein expression and (b) to examine the complex interactions that regulate entire biological processes. Two popular platforms in "omics" are DNA microarrays, which measure messenger RNA transcript levels, and proteomic analyses, which identify and quantify proteins. Because of their intrinsic strengths and weaknesses, no single approach can fully unravel the complexities of fundamental biological events. However, an appropriate combination of different tools could lead to integrative analyses that would furnish new insights not accessible through one-dimensional datasets. In this review, we will outline some of the challenges associated with integrative analyses relating to the changes in metabolic pathways that occur in complex pathophysiological conditions (viz. ageing and altered thyroid state) in relevant metabolically active tissues. In addition, we discuss several new applications of proteomic analysis to the investigation of mitochondrial activity.
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Affiliation(s)
- Elena Silvestri
- Dipartimento di Scienze Biologiche ed Ambientali, Università degli Studi del Sannio, Via Port'Arsa 11, 82100 Benevento, Italy
| | - Assunta Lombardi
- Dipartimento delle Scienze Biologiche, Sezione Fisiologia, Università degli Studi di Napoli “Federico II”, Via Mezzocannone 8, 80134 Napoli, Italy
| | - Pieter de Lange
- Dipartimento di Scienze della Vita, Seconda Università di Napoli, Via Vivaldi 43, 81100 Caserta, Italy
| | - Daniela Glinni
- Dipartimento di Scienze Biologiche ed Ambientali, Università degli Studi del Sannio, Via Port'Arsa 11, 82100 Benevento, Italy
| | - Rosalba Senese
- Dipartimento di Scienze della Vita, Seconda Università di Napoli, Via Vivaldi 43, 81100 Caserta, Italy
| | - Federica Cioffi
- Dipartimento di Scienze della Vita, Seconda Università di Napoli, Via Vivaldi 43, 81100 Caserta, Italy
| | - Antonia Lanni
- Dipartimento di Scienze della Vita, Seconda Università di Napoli, Via Vivaldi 43, 81100 Caserta, Italy
| | - Fernando Goglia
- Dipartimento di Scienze Biologiche ed Ambientali, Università degli Studi del Sannio, Via Port'Arsa 11, 82100 Benevento, Italy
| | - Maria Moreno
- Dipartimento di Scienze Biologiche ed Ambientali, Università degli Studi del Sannio, Via Port'Arsa 11, 82100 Benevento, Italy
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Abstract
PURPOSE OF REVIEW Thyroid hormone (3,3',5-triiodo-L-thyronine) plays an important role in thermogenesis and maintenance of lipid homeostasis. The present article reviews the evidence that 3,3',5-triiodo-L-thyronine regulates lipid metabolism via thyroid hormone receptors, focusing particularly on in-vivo findings using genetically engineered mice. RECENT FINDINGS That lipid metabolism is regulated via thyroid hormone receptor isoforms in a tissue-dependent manner was recently uncovered by using knockin mutant mice harboring an identical mutation in the Thra gene (Thra1(PV) mouse) or the Thrb gene (Thrb(PV) mouse). The mutation in the Thra gene dramatically decreases the mass of both white adipose tissue and liver. In contrast, the mutation in the Thrb gene markedly increases the mass of liver with an excess depot of lipids, but no significant abnormality is observed in white adipose tissue. Molecular studies show that the expression of lipogenic genes is decreased in white adipose tissue of Thra1(PV) mice, but not in Thrb(PV) mice. Markedly increased lipogenic enzyme expression, and decreased fatty acid beta-oxidation activity contribute to the adipogenic steatosis and lipid accumulation in the liver of Thrb(PV) mice. In contrast, reduced expression of genes critical for lipogenesis mediates decreased liver mass with lipid scarcity in Thra1(PV) mice. SUMMARY Studies using Thra1(PV) and Thrb(PV) mice indicate that apo-thyroid hormone receptor-beta and apo-thyroid hormone receptor-alpha-1 mediate distinct deleterious effects on lipid metabolism. Thus, both thyroid hormone receptor isoforms contribute to the pathogenesis of lipid abnormalities in hypothyroidism, but in a target tissue-dependent manner. These studies suggest that thyroid hormone receptor isoform-specific ligands could be designed as therapeutic targets for lipid abnormalities.
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Affiliation(s)
- Xuguang Zhu
- Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4264, USA
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Reilly SJ, Tillander V, Ofman R, Alexson SEH, Hunt MC. The nudix hydrolase 7 is an Acyl-CoA diphosphatase involved in regulating peroxisomal coenzyme A homeostasis. J Biochem 2008; 144:655-63. [PMID: 18799520 DOI: 10.1093/jb/mvn114] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Coenzyme A (CoASH) is an obligate cofactor for lipids undergoing beta-oxidation in peroxisomes. Although the peroxisomal membrane appears to be impermeable to CoASH, peroxisomes contain their own pool of CoASH. It is believed that CoASH enters peroxisomes as acyl-CoAs, but it is not known how this pool is regulated. The mouse nudix hydrolase 7 (NUDT7alpha) was previously identified in peroxisomes as a CoA-diphosphatase, and therefore suggested to be involved in regulation of peroxisomal CoASH levels. Here we show that mouse NUDT7alpha mainly acts as an acyl-CoA diphosphatase, with highest activity towards medium-chain acyl-CoAs, and much lower activity with CoASH. Nudt7alpha mRNA is highly expressed in liver, brown adipose tissue and heart, similar to enzymes involved in peroxisomal lipid degradation. Nudt7alpha mRNA is down-regulated by Wy-14,643, a peroxisome proliferator-activated receptor alpha (PPARalpha) ligand, in a PPARalpha-dependent manner in mouse liver. In highly purified peroxisomes, nudix hydrolase activity is highest with C(6)-CoA and is decreased by fibrate treatment. Under certain conditions, such as treatment with peroxisome proliferators or fasting, an increase in peroxisomal CoASH levels has been reported, which is in line with a decreased expression/activity of NUDT7alpha. Taken together these data suggest that NUDT7alpha function is tightly linked to peroxisomal CoASH/acyl-CoA homeostasis.
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Affiliation(s)
- Sarah-Jayne Reilly
- Division of Clinical Chemistry C1-74, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital at Huddinge, SE-141 86 Stockholm, Sweden
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Wulf A, Harneit A, Kröger M, Kebenko M, Wetzel MG, Weitzel JM. T3-mediated expression of PGC-1alpha via a far upstream located thyroid hormone response element. Mol Cell Endocrinol 2008; 287:90-5. [PMID: 18336995 DOI: 10.1016/j.mce.2008.01.017] [Citation(s) in RCA: 73] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2007] [Revised: 01/09/2008] [Accepted: 01/23/2008] [Indexed: 12/27/2022]
Abstract
Thyroid hormone (T3) has a profound influence on normal development, differentiation and metabolism. T3 induces complex gene expression patterns raises the question of how these expression patterns might be regulated. Since the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) induces very similar cellular energy metabolic pathways, we investigated the molecular mechanism of T3 regulation of PGC-1alpha. PGC-1alpha is rapidly regulated by T3, both in vivo and in cell culture. Transient transfection experiments demonstrated binding of the thyroid hormone receptor (TR) to a response element located at -4kb upstream of the transcriptional start site within the PGC-1alpha gene. Introducing of a single copy of the -4kb TRE in a heterologous promoter context is sufficient to maintain T3 responsiveness. Chromatin immunoprecipitation analysis revealed increased histone acetylation upon stimulation of T3. Finally, TR binds the -4kb TRE in electrophoretic mobility shift assays, identifying PGC-1alpha as a direct target of TR action. Since T3 directly regulates PGC-1alpha and PGC-1alpha coactivates liganded TR, we suggest an autoregulatory feed-forward loop of PGC-1alpha activation upon T3 treatment.
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Affiliation(s)
- Anne Wulf
- Zentrum für Experimentelle Medizin, Institut für Biochemie und Molekularbiologie I, Universitätsklinikum Hamburg-Eppendorf, 20246 Hamburg, Germany
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22
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Ventura-Holman T, Mamoon A, Maher JF, Subauste JS. Thyroid hormone responsive genes in the murine hepatocyte cell line AML 12. Gene 2007; 396:332-7. [PMID: 17532580 DOI: 10.1016/j.gene.2007.04.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2007] [Revised: 04/04/2007] [Accepted: 04/05/2007] [Indexed: 11/29/2022]
Abstract
Thyroid hormone (T3) plays an important role in gene regulation in the liver. Previous studies have been done in complex systems such as animal models, or in transformed malignant hepatic cell lines in which thyroid hormone receptor (TR) was over-expressed by co-transfection. Therefore, the aim of this study was to characterize T3-responsive genes in a simple system, by using a non-transformed hepatic cell line that is able to express sufficient amounts of endogenous TRs. For this purpose we used the murine non-transformed hepatocyte cell line AML 12. We performed analyses using a cDNA microarray containing 15,000 murine genes. We found 12 genes to be up-regulated and 5 genes to be down-regulated in the presence of T3. For some of the genes not previously known to be regulated by T3, we confirmed the regulation by T3 using real-time PCR. Our data in AML 12 cells provide a simple and physiologically relevant system to study T3 action, without the influence of neoplastic transformation or artificial TR over-expression. Furthermore, our data describe novel T3 responsive genes and provide insight into the role of T3 in important processes such as cholesterol metabolism, bile acid secretion, oncogenesis, among others, that can be tested in future experiments in vivo.
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Affiliation(s)
- Tereza Ventura-Holman
- Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA
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23
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Sar P, Rath B, Subudhi U, Chainy GBN, Supakar PC. Alterations in expression of senescence marker protein-30 gene by 3,3',5-triiodo-L-thyronine (T3). Mol Cell Biochem 2007; 303:239-42. [PMID: 17426926 DOI: 10.1007/s11010-007-9462-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2007] [Accepted: 03/21/2007] [Indexed: 11/24/2022]
Abstract
Thyroid hormone (T3) is essential for normal development, differentiation, and metabolic balance of the body. A toxic dose of T(3) in animals increases the basal metabolic rate and reactive oxygen species production, resulting more oxidative stress through Ca(2+) influx to cytoplasm. Senescence Marker Protein-30 (SMP30) is preferentially expressed in the liver and protects cells against various injuries by enhancement of Ca(2+) efflux to either extra cellular space or intraorganellar spaces through membrane Ca(2+) pump activity. In this paper we report an alteration in the level of SMP30 gene expression using RT-PCR and western blot analysis in T(3) treated female Wistar rats. The results indicate that there is an induction of SMP30 expression during early hours of T(3 )treatment and it declines in severe hyperthyroidism. Therefore, we speculate that SMP30 is regulated by T(3) and might play a protective role in hyperthyroidism.
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Affiliation(s)
- Pranati Sar
- Institute of Life Sciences, Nalco Square, Chandrasekharpur, Bhubaneswar, 751023, Orissa, India
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24
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Flamant F, Baxter JD, Forrest D, Refetoff S, Samuels H, Scanlan TS, Vennström B, Samarut J. International Union of Pharmacology. LIX. The pharmacology and classification of the nuclear receptor superfamily: thyroid hormone receptors. Pharmacol Rev 2006; 58:705-11. [PMID: 17132849 DOI: 10.1124/pr.58.4.3] [Citation(s) in RCA: 121] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Affiliation(s)
- Frédéric Flamant
- Unité Mixte de Recherche, Centre National de la Recherche Scientifique 5665, Laboratoire Associé Institut National de la Recherche Agronomique 913, l'Institut Fédératif de Recherches 128, Lyon, France.
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25
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Grant N. The role of triiodothyronine-induced substrate cycles in the hepatic response to overnutrition: thyroid hormone as an antioxidant. Med Hypotheses 2006; 68:641-9. [PMID: 17023119 DOI: 10.1016/j.mehy.2006.07.045] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2006] [Accepted: 07/29/2006] [Indexed: 01/11/2023]
Abstract
Overnutrition, by generating reactive oxygen species (ROS), produces oxidative stress - an important cause of cellular injury. In the liver, overnutrition begins in the perivenous hepatocytes. To prevent injury, cells must protect themselves against ROS accumulation. Overnutrition also activates the enzyme deiodinase-1 (D1), which catalyzes the conversion of T4 to T3. D1 is primarily located in the PV region of the liver. Thyroid hormone is known to generate substrate cycling. The hypothesis of this paper is that a nutrient-induced increase in intracellular T3 acts as an antioxidant by inducing substrate cycles that reduce ROS accumulation. These cycles do this by: (i) reducing ROS formation by hydrolyzing excess ATP, thus enhancing oxidative phosphorylation and reducing the proton motive force on the electron transport chain (ETC), and; (ii) enhancing the removal (reduction) of ROS by producing the NADPH required for regeneration of reduced glutathione, a potent endogenous antioxidant. Oxidative stress is an important factor in the etiology of a number of hepatic injuries, including nonalcoholic steatohepatitis (NASH) and hepatocarcinogenesis. In the latter, the frequency of mutations in thyroid hormone receptors (TRs) supports the concept that thyroid hormone acts as a tumor suppressor by reducing oxidative stress. This paper reviews the substrate cycles involved in this process. It also describes other mechanisms that permit rapid availability of T3 to cells undergoing oxidative stress.
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Affiliation(s)
- Neville Grant
- Department of Medicine, Washington University School of Medicine, David P Wohl Jr., Hospital, 4960 Children's Pl sixth floor, St. Louis, MO, USA.
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26
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Yen PM, Ando S, Feng X, Liu Y, Maruvada P, Xia X. Thyroid hormone action at the cellular, genomic and target gene levels. Mol Cell Endocrinol 2006; 246:121-7. [PMID: 16442701 DOI: 10.1016/j.mce.2005.11.030] [Citation(s) in RCA: 143] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Thyroid hormone (TH) plays important roles in metabolism, growth and differentiation. Thyroid hormone receptors (TRs) are ligand-regulatable transcription factors that bind both TH and DNA enhancer sequences in the promoter region of target genes where they can interact with co-repressor and co-activator complexes. These interactons, in turn, have consequent effects on transcription. This review describes studies on TH action from our laboratory examining the cellular localization and motility of TRs using green fluorescent fusion proteins, gene expression profiles of TH in WT and TRalpha and TRbeta KO mice, as well as general transcription factor and co-activator recruitment on the promoters of target genes by TH in chromatin immunoprecipitation assays.
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Affiliation(s)
- Paul M Yen
- Department of Medicine, Johns Hopkins Bayview Medical Center, 4940 Eastern Avenue Rm B114, Baltimore, MD, USA.
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27
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Karoly ED, Schmid JE, Hunter ES. Ontogeny of transcription profiles during mouse early craniofacial development. Reprod Toxicol 2005; 19:339-52. [PMID: 15686869 DOI: 10.1016/j.reprotox.2004.09.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2004] [Revised: 08/31/2004] [Accepted: 09/01/2004] [Indexed: 10/26/2022]
Abstract
Using the CD-1 mouse conceptus, we investigated gene expression changes found in vivo from gestational day 8 (GD) through GD9 at 6 h intervals, and then at 24 h intervals through GD11. Data sets were analyzed for patterns in transcriptional expression over a time course as well as to compare the GD9 in vivo mouse conceptus with conceptuses cultured for 24 h from GD8 in whole embryo culture (WEC). Our results show that during development from GD8 to GD11, a series of metabolic pathways related to carbohydrate metabolism and energy production, as well as the signal transduction pathways of the MAPK cascade and Wnt signaling were changing. Previous results have shown that WEC successfully sustains morphological development comparable to that in vivo for at least 24 h. We report here that, in the absence of morphological malformations following 24 h WEC, 329 genes were differentially expressed between in vivo and in vitro developing conceptuses.
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Affiliation(s)
- Edward D Karoly
- Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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28
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Zandieh-Doulabi B, Platvoet-ter Schiphorst M, Kalsbeek A, Wiersinga WM, Bakker O. Hyper and hypothyroidism change the expression and diurnal variation of thyroid hormone receptor isoforms in rat liver without major changes in their zonal distribution. Mol Cell Endocrinol 2004; 219:69-75. [PMID: 15149728 DOI: 10.1016/j.mce.2004.01.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2003] [Revised: 01/14/2004] [Accepted: 01/28/2004] [Indexed: 11/22/2022]
Abstract
We investigated the effect of hypothyroidism or hyperthyroidism on mRNA and protein expression, diurnal variation and zonal distribution of thyroid hormone receptor (TR) isoforms TRalpha1, TRalpha2 and TRbeta1 in rat liver. Hypothyroidism results in increased isoform mRNA and protein expression whereas hyperthyroidism shows a decreased TRalpha1 and TRalpha2 mRNA and protein expression. During hyperthyroidism no change is seen in TRbeta1 mRNA, but TRbeta1 protein is upregulated in the light period and downregulated in the dark period. Diurnal changes (measured at 13:30 and 19:30 h) in the TR isoform proteins are abolished in hypothyroidism and hyperthyroidism, with the exception of a reversal in diurnal changes of TRbeta1 in hyperthyroidism. Zonal distribution of the isoforms is not affected by hypo- or hyperthyroidism. We therefore conclude that thyroid hormone influences both the levels and the diurnal expression of its receptor isoforms but not the zonal distribution.
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Affiliation(s)
- B Zandieh-Doulabi
- Department of Endocrinology and Metabolism, F5-171, Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
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29
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30
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Harvey CB, Stevens DA, Williams AJ, Jackson DJ, O'Shea P, Williams GR. Analysis of thyroid hormone responsive gene expression in osteoblastic cells. Mol Cell Endocrinol 2003; 213:87-97. [PMID: 15062577 DOI: 10.1016/j.mce.2003.10.037] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Thyroid hormones regulate gene expression to influence the development and metabolism of many tissues including bone. The identification of genes that are regulated by thyroid hormones during skeletal development requires sensitive and quantitative techniques that are not limited by small amounts of available tissue and RNA. We have compared the efficiencies of differential display and poly A PCR subtraction hybridisation methods for the detection of thyroid hormone responsive genes expressed in osteoblastic cells. The utility of each technique was evaluated with respect to its sensitivity, specificity, cost and ability to identify novel genes. Subtraction hybridisation was rapid and more efficient in all categories. Poly A PCR facilitates quantitative and representative global amplification of cDNAs from low concentrations of RNA extracted from small tissue samples. The method, in combination with microarray analyses, may prove useful as an additional, complementary strategy to subtraction hybridisation for the analysis of differential gene expression in tissues where sample size is limiting.
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Affiliation(s)
- C B Harvey
- Division of Medicine and MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK
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31
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Yen PM, Feng X, Flamant F, Chen Y, Walker RL, Weiss RE, Chassande O, Samarut J, Refetoff S, Meltzer PS. Effects of ligand and thyroid hormone receptor isoforms on hepatic gene expression profiles of thyroid hormone receptor knockout mice. EMBO Rep 2003; 4:581-7. [PMID: 12776178 PMCID: PMC1319202 DOI: 10.1038/sj.embor.embor862] [Citation(s) in RCA: 99] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2003] [Revised: 04/15/2003] [Accepted: 04/16/2003] [Indexed: 12/27/2022] Open
Abstract
Little is known about the overall patterns of thyroid hormone (Th)-mediated gene regulation by the main Th receptor (Tr) isoforms, Tr-alpha and Tr-beta, in vivo. We used 48 complementary DNA microarrays to examine hepatic gene expression profiles of wild-type and Thra and Thrb knockout mice under different Th conditions: no treatment, treatment with 3,3',5-triiodothyronine (T(3)), Th-deprivation using propylthiouracil (PTU), and treatment with a combination of PTU and T(3). Hierarchical clustering analyses showed that positively regulated genes fit into three main expression patterns. In addition, only a subpopulation of target genes repressed basal transcription in the absence of ligand. Interestingly, Thra and Thrb knockout mice showed similar gene expression patterns to wild-type mice, suggesting that these isoforms co-regulate most hepatic target genes. Differences in the gene expression patterns of Thra/Thrb double-knockout mice and Th-deprived wild-type mice show that absence of receptor and of hormone can have different effects. This large-scale study of hormonal regulation reveals the functions of Th and of Tr isoforms in the regulation of gene expression patterns.
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Affiliation(s)
- Paul M. Yen
- Molecular Regulation and Neuroendocrinology Section, Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Room 8D12, Building 10, Bethesda, Maryland
20892, USA
- These authors contributed equally to this work
- Tel: +1 301 594 6797; Fax: +1 301 402 4136;
| | - Xu Feng
- Molecular Regulation and Neuroendocrinology Section, Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Room 8D12, Building 10, Bethesda, Maryland
20892, USA
- These authors contributed equally to this work
| | - Frederic Flamant
- Laboratoire de Biologie Moléculaire et Cellulaire de l'Ecole Normale Supérieure de Lyon, UMR CNRS 5665 LA INRA913, 46 Allée d'Italie, 69364
Lyon
CEDEX07, France
| | - Yidong Chen
- Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Rm 5140, Building 50, Bethesda, Maryland
20892, USA
| | - Robert L. Walker
- Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Rm 5140, Building 50, Bethesda, Maryland
20892, USA
| | - Roy E. Weiss
- Departments of Medicine, University of Chicago, 5841 South Maryland Avenue, Chicago, Illinois
60637, USA
| | - Olivier Chassande
- Laboratoire de Biologie Moléculaire et Cellulaire de l'Ecole Normale Supérieure de Lyon, UMR CNRS 5665 LA INRA913, 46 Allée d'Italie, 69364
Lyon
CEDEX07, France
| | - Jacques Samarut
- Laboratoire de Biologie Moléculaire et Cellulaire de l'Ecole Normale Supérieure de Lyon, UMR CNRS 5665 LA INRA913, 46 Allée d'Italie, 69364
Lyon
CEDEX07, France
| | - Samuel Refetoff
- Departments of Medicine, University of Chicago, 5841 South Maryland Avenue, Chicago, Illinois
60637, USA
- Pediatrics, and the Committee on Genetics, University of Chicago, 5841 South Maryland Avenue, Chicago, Illinois
60637, USA
| | - Paul S. Meltzer
- Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Rm 5140, Building 50, Bethesda, Maryland
20892, USA
- Tel: +1 301 594 5283; Fax: +1 301 480 3281;
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