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1.
Life Sci ; 267: 118977, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33383053

RESUMO

AIMS: Severe cardiovascular diseases, such as myocardial infarction or heart failure, can alter thyroid hormone (TH) secretion and peripheral conversion, leading to low triiodothyronine (T3) syndrome. Accumulating evidence suggests that TH has protective properties against cardiovascular diseases and that treatment with TH can effectively reduce myocardial damage after myocardial infarction (MI). Our aim is to investigate the effect of T3 pretreatment on cardiac function and pathological changes in mice subjected to MI and the underlying mechanisms. MAIN METHODS: Adult male C57BL/6 mice underwent surgical ligation of the left anterior descending coronary artery (LAD) (or sham operation) to establish MI model. T3, BMS-754807 (inhibitor of insulin-like growth factor-1 receptor (IGF-1R)) or vehicle was administered before surgery. KEY FINDINGS: Compared with the MI group, the T3 pretreatment group exhibited significant attenuation of the myocardial infarct area, inhibition of cardiomyocyte apoptosis and fibrosis, and improved left ventricular function after MI. In addition, T3 exhibited an enhanced potency to stimulate angiogenesis and exert anti-inflammatory effects by reducing the levels of serum inflammatory cytokines after MI. However, all of these protective effects were inhibited by the IGF-1R inhibitor BMS-754807. Moreover, the protein expression of IGF-1/PI3K/AKT signaling-related proteins, such as IGF-1, IGF-1R, phosphorylated PI3K (p-PI3K) and p-AKT was significantly upregulated in MI mice that received T3 pretreatment, and BMS-754807 pretreatment blocked the upregulation of the expression of these signaling-related proteins. SIGNIFICANCE: T3 pretreatment can protect the heart against dysfunction post-MI, which may be mediated by the activation of the IGF-1/PI3K/AKT signaling pathway.


Assuntos
Infarto do Miocárdio/tratamento farmacológico , Hormônios Tireóideos/metabolismo , Tri-Iodotironina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Remodelamento Atrial/efeitos dos fármacos , Remodelamento Atrial/fisiologia , Cardiotônicos/metabolismo , Cardiotônicos/farmacologia , Fibrose , Insuficiência Cardíaca/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/patologia , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Hormônios Tireóideos/fisiologia , Tri-Iodotironina/metabolismo , Função Ventricular Esquerda/efeitos dos fármacos
2.
Endocr Res ; 45(3): 210-215, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32628899

RESUMO

BACKGROUND: Uptake of coronaviruses by target cells involves binding of the virus by cell ectoenzymes. For the etiologic agent of COVID-19 (SARS-CoV-2), a receptor has been identified as angiotensin-converting enzyme-2 (ACE2). Recently it has been suggested that plasma membrane integrins may be involved in the internalization and replication of clinically important coronaviruses. For example, integrin αvß3 is involved in the cell uptake of a model porcine enteric α-coronavirus that causes human epidemics. ACE2 modulates the intracellular signaling generated by integrins. OBJECTIVE: We propose that the cellular internalization of αvß3 applies to uptake of coronaviruses bound to the integrin, and we evaluate the possibility that clinical host T4 may contribute to target cell uptake of coronavirus and to the consequence of cell uptake of the virus. DISCUSSION AND CONCLUSIONS: The viral binding domain of the integrin is near the Arg-Gly-Asp (RGD) peptide-binding site and RGD molecules can affect virus binding. In this same locale on integrin αvß3 is the receptor for thyroid hormone analogues, particularly, L-thyroxine (T4). By binding to the integrin, T4 has been shown to modulate the affinity of the integrin for other proteins, to control internalization of αvß3 and to regulate the expression of a panel of cytokine genes, some of which are components of the 'cytokine storm' of viral infections. If T4 does influence coronavirus uptake by target cells, other thyroid hormone analogues, such as deaminated T4 and deaminated 3,5,3'-triiodo-L-thyronine (T3), are candidate agents to block the virus-relevant actions of T4 at integrin αvß3 and possibly restrict virus uptake.


Assuntos
Infecções por Coronavirus/virologia , Integrina alfaVbeta3/metabolismo , Vírus da Diarreia Epidêmica Suína/metabolismo , Receptores Virais/efeitos dos fármacos , Hormônios Tireóideos/farmacologia , Animais , Betacoronavirus/metabolismo , Sítios de Ligação , Citocinas/fisiologia , Células Epiteliais/virologia , Humanos , Oligopeptídeos/metabolismo , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/virologia , Receptores Virais/química , Receptores Virais/metabolismo , Suínos , Hormônios Tireóideos/fisiologia , Tiroxina/fisiologia , Internalização do Vírus
3.
Life Sci ; 245: 117385, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-32014425

RESUMO

AIM: The influence of thyroid hormones on exocrine pancreas function is poorly understood, and limited to the postnatal development period. Here, we evaluated the effects of hypo- and hyperthyroidism on the morphology and enzyme content of this tissue. MAIN METHODS: To induce hypothyroidism male Wistar rats were subjected to a thyroidectomy (Tx) or sham operated (SO). After 40 days, some of the Tx and SO rats were treated with T3 for 7 days. Following euthanization, the pancreas was removed and evaluated for morphology, as well as amylase, lipase and trypsin content, using histological and immunoreactive techniques analyses, respectively. Serum amylase levels were also evaluated. KEY FINDINGS: The pancreatic acinar cells of Tx rats were smaller, exhibited reduced Haematoxyllin stained areas, and contained lower amylase and lipase levels, indicative of low cell activity. Tx rats also presented higher collagen levels, and high trypsin content in pancreatic extracts. Interestingly, T3 administration reversed the observed acinar cell alterations and restored pancreatic enzyme content, by augmenting amylase and lipase and attenuating trypsin levels, but failed to change collagen content. Increased levels of lipase and decreased trypsin were also observed in T3-treated SO rats. SIGNIFICANCE: Thyroid hormones play an important role in acinar cell morphology and function. In the hypothyroid state there is a decrease in pancreatic enzyme levels that is restored with T3 treatment. In addition to participating in insulin sensitivity and glycemic control, THs also modulate enzyme expression and activity in the exocrine pancreas, consequently, delivering metabolic substrates to specific organs and tissues.


Assuntos
Pâncreas Exócrino/patologia , Hormônios Tireóideos/fisiologia , Amilases/sangue , Animais , Western Blotting , Hipertireoidismo/complicações , Hipertireoidismo/patologia , Hipotireoidismo/complicações , Hipotireoidismo/patologia , Masculino , Pâncreas Exócrino/efeitos dos fármacos , Pâncreas Exócrino/fisiopatologia , Ratos , Ratos Wistar , Tireoidectomia , Tireotropina/sangue , Tri-Iodotironina/farmacologia
4.
Minerva Med ; 110(6): 530-545, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31726814

RESUMO

INTRODUCTION: Thyroid hormones have multiple effects on lipid metabolism as well as on the cardiovascular system function. These negative cardiovascular effects have long been recognized in overt hypothyroidism but can be reversed by treatment with levothyroxine. EVIDENCES ACQUISITION: We performed on PubMed a literature search for the articles published until March 2019 by using the search terms "subclinical hypothyroidism," "cardiovascular disease," "cholesterol," "LDL," "HDL," "triglycerides," "coronary heart disease," "heart failure," "atherosclerosis," "all-cause mortality," "levothyroxine." EVIDENCES SYNTHESIS: Subclinical hypothyroidism, defined as an elevated thyrotropin (TSH) with a normal free thyroxine (FT4), is frequent in the general population and increase with age. Subclinical hypothyroidism has been linked to cardiovascular risk factors, dyslipidemia and increased atherosclerosis. Although some studies have demonstrated that lipids are elevated in subclinical hypothyroidism, other studies did not confirm these data. Clinical trials have also demonstrated there is no clear evidence that levothyroxine therapy in subjects with milder form (TSH<10 mU/L) of subclinical hypothyroidism could improve lipid status and the other cardiovascular risk factors. Nevertheless, TSH level seems the best predictor of cardiovascular disease, in particular when its levels are above 10 mU/L. CONCLUSIONS: Prospective studies are necessary to clarify the cardiovascular risk in patients with mild subclinical hypothyroidism and to assess the importance of treating elderly people in order to improve or counteract the correlated risks. However, until clinical recommendations will be updated, the decision to treat or not treat patients with subclinical hypothyroidism will still base on clinical judgment, clinical practice guidelines, and expert opinion.


Assuntos
Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Hipotireoidismo/complicações , Doenças Assintomáticas , Fenômenos Fisiológicos Cardiovasculares , Doença das Coronárias/etiologia , Humanos , Fatores de Risco , Hormônios Tireóideos/fisiologia
5.
Thyroid ; 29(9): 1173-1191, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31389309

RESUMO

Background: Thyroid hormones (THs) exert a strong influence on mammalian lipid metabolism at the systemic and hepatic levels by virtue of their roles in regulating circulating lipoprotein, triglyceride (TAG), and cholesterol levels, as well as hepatic TAG storage and metabolism. These effects are mediated by intricate sensing and feedback systems that function at the physiological, metabolic, molecular, and transcriptional levels in the liver. Dysfunction in the pathways involved in lipid metabolism disrupts hepatic lipid homeostasis and contributes to the pathogenesis of metabolic diseases, such as nonalcoholic fatty liver disease (NAFLD) and hypercholesterolemia. There has been strong interest in understanding and employing THs, TH metabolites, and TH mimetics as lipid-modifying drugs. Summary: THs regulate many processes involved in hepatic TAG and cholesterol metabolism to decrease serum cholesterol and intrahepatic lipid content. TH receptor ß analogs designed to have less side effects than the natural hormone are currently being tested in phase II clinical studies for NAFLD and hypercholesterolemia. The TH metabolites, 3,5-diiodo-l-thyronine (T2) and T1AM (3-iodothyronamine), have different beneficial effects on lipid metabolism compared with triiodothyronine (T3), although their clinical application is still under investigation. Also, prodrugs and glucagon/T3 conjugates have been developed that direct TH to the liver. Conclusions: TH-based therapies show clinical promise for the treatment of NAFLD and hypercholesterolemia. Strategies for limiting side effects of TH are being developed and may enable TH metabolites and analogs to have specific effects in the liver for treatments of these conditions. These liver-specific effects and potential suppression of the hypothalamic/pituitary/thyroid axis raise the issue of monitoring liver-specific markers of TH action to assess clinical efficacy and dosing of these compounds.


Assuntos
Hipercolesterolemia/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hormônios Tireóideos/fisiologia , Animais , Humanos , Hipercolesterolemia/metabolismo , Metabolismo dos Lipídeos , Fígado/metabolismo , Camundongos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Receptores dos Hormônios Tireóideos/fisiologia , Hormônios Tireóideos/agonistas , Hormônios Tireóideos/uso terapêutico
6.
PLoS One ; 14(8): e0220717, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31404087

RESUMO

Silencing Mediator of Retinoid and Thyroid Hormone Receptors (SMRT) and the nuclear receptor co-repressor1 (NCoR1) are paralogs and regulate nuclear receptor (NR) function through the recruitment of a multiprotein complex that includes histone deacetylase activity. Previous genetic strategies which deleted SMRT in a specific tissue or which altered the interaction between SMRT and NRs have suggested that it may regulate adiposity and insulin sensitivity. However, the full role of SMRT in adult mice has been difficult to establish because its complete deletion during embryogenesis is lethal. To elucidate the specific roles of SMRT in mouse target tissues especially in the context of thyroid hormone (TH) signaling, we used a tamoxifen-inducible post-natal disruption strategy. We found that global SMRT deletion causes dramatic obesity even though mice were fed a standard chow diet and exhibited normal food intake. This weight gain was associated with a decrease in energy expenditure. Interestingly, the deletion of SMRT had no effect on TH action in any tissue but did regulate retinoic acid receptor (RAR) function in the liver. We also demonstrate that the deletion of SMRT leads to profound hepatic steatosis in the setting of obesity. This is unlike NCoR1 deletion, which results in hepatic steatosis due to the upregulation of lipogenic gene expression. Taken together, our data demonstrate that SMRT plays a unique and CoR specific role in the regulation of body weight and has no role in TH action. This raises the possibility that additional role of CoRs besides NCoR1 and SMRT may exist to regulate TH action.


Assuntos
Peso Corporal/fisiologia , Correpressor 2 de Receptor Nuclear/fisiologia , Hormônios Tireóideos/fisiologia , Animais , Western Blotting , Colesterol/análise , Ecocardiografia , Metabolismo Energético , Teste de Tolerância a Glucose , Lipídeos/sangue , Fígado/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Reação em Cadeia da Polimerase em Tempo Real , Hormônios Tireóideos/sangue , Tireotropina/sangue , Tireotropina/fisiologia , Tiroxina/sangue , Tiroxina/fisiologia , Triglicerídeos/análise , Ganho de Peso/fisiologia
8.
Biol Aujourdhui ; 213(1-2): 7-16, 2019.
Artigo em Francês | MEDLINE | ID: mdl-31274098

RESUMO

Thyroid hormones (THs) are vital for vertebrate brain function throughout life, from early development to ageing. Epidemiological studies show an adequate supply of maternal TH during pregnancy to be necessary for normal brain development, and this from the first trimester of onwards. Maternal TH deficiency irreversibly affects fetal brain development, increasing the risk of offspring cognitive disorders and IQ loss. Mammalian and non-mammalian (zebrafish, xenopus, chicken) models are useful to dissect TH-dependent cellular and molecular mechanisms governing embryonic and fetal brain development: a complex process including cell proliferation, survival, determination, migration, differentiation and maturation of neural stem cells (NSCs). Notably, rodent models have strongly contributed to understand the key neurogenic roles of TH still at work in adult life. Neurogenesis continues in two main areas, the sub-ventricular zone lining the lateral ventricles (essential for olfaction) and the sub-granular zone in the dentate gyrus of the hippocampus (involved in memory, learning and mood control). In both niches, THs tightly regulate the balance between neurogenesis and oligodendrogenesis under physiological and pathological contexts. Understanding how THs modulate NSCs determination toward a neuronal or a glial fate throughout life is a crucial question in neural stem cell biology. Providing answers to this question can offer therapeutic strategies for brain repair, notably in neurodegenerative diseases, demyelinating diseases or stroke where new neurons and/or oligodendrocytes are required. The review focuses on TH regulation of NSC fate in mammals and humans both during development and in the adult.


Assuntos
Células-Tronco Neurais/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Hormônios Tireóideos/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Células-Tronco Neurais/fisiologia , Neurogênese/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Gravidez , Hormônios Tireóideos/fisiologia
9.
Biol Aujourdhui ; 213(1-2): 27-33, 2019.
Artigo em Francês | MEDLINE | ID: mdl-31274100

RESUMO

Life history transitions are critical for many animal species and often correspond to concomitant developmental and ecological shifts. However, to date, little is known on how internal and external cues act together during these events. The life cycle of most teleostean reef fish includes a major developmental and ecological transition. Adults reproduce in the vicinity of the reef, emitting eggs that disperse and hatch in the ocean, where the larvae grow. Thereafter, larvae migrate back towards reefs where they settle and persist, at a step called larval recruitment. Larval recruitment involves the perception of environmental cues for larvae to localize and select their new benthic habitat, and is accompanied by major morphological changes. This ecological and developmental transition of pelagic larvae into reef-associated juveniles, often referred to as metamorphosis, are under the control of Thyroid Hormones (TH: T4, T3) and their receptors (TRαa, TRαb and TRß). This step is critical for the maintenance of reef fish populations, but its molecular control remains largely unknown. Recent results have brought new insights on coral reef fish metamorphosis. We have shown that TH and TR coordinate the metamorphosis that occurs during the entry in the reef of two coral reef fishes, the surgeon fish Acanthurus triostegus, and the clown fish Amphiprion ocellaris. We demonstrated an increase of TH-levels and TR-expression in the larvae, followed by a decrease in deriving juvenile. We observed similar trends (although with different dynamics and/or magnitude) in other coral reef fish species, therefore allowing us to generalize these observations. Interestingly, functional experiments such as treatments with pharmacological compounds exhibiting antagonist activity interfere with the surgeonfish and the clown fish larval transformation demonstrating a direct role of these hormones in controlling metamorphosis. All these results and in particular the dependency on thyroid hormones of the larval to juvenile transformation suggest that this step can be sensitive to disruption by environmental pollutants, such as endocrine disruptors. Using as model compound, chlorpyrifos, a pesticide often encountered in coral reefs, we showed that it impairs surgeonfish as well as clown fish transformation, hence diminishing the quality of the juvenile emerging from this transition. Larval recruitment in coral reef fish therefore corresponds to a TH-controlled metamorphosis, sensitive to endocrine disruption. Since metamorphosis and larval recruitment are essential for the maintenance of fish populations and subsequent coral reef resilience, it is important to better understand, at the molecular, anatomical and behavioral levels, how global changes and water pollution can threaten reef ecosystems.


Assuntos
Peixes/crescimento & desenvolvimento , Metamorfose Biológica/efeitos dos fármacos , Metamorfose Biológica/fisiologia , Hormônios Tireóideos/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Recifes de Corais , Ecossistema , Peixes/genética , Regulação da Expressão Gênica no Desenvolvimento , Larva/efeitos dos fármacos , Larva/genética , Larva/crescimento & desenvolvimento , Receptores dos Hormônios Tireóideos/genética , Hormônios Tireóideos/fisiologia
10.
Theriogenology ; 134: 121-128, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31167155

RESUMO

Metabolic hormones play essential regulatory roles in many biological processes, including morphogenesis, growth, and reproduction through the maintenance of energy balance. Various metabolic hormones originally discovered in mammals, including ghrelin, leptin, and nesfatin-1 have been identified and characterized in fish. However, physiological roles of these metabolic hormones in regulating reproduction are largely unknown in fishes, especially in males. While the information available is restricted, this review attempts to summarize the main findings on the roles of metabolic peptides on the reproductive system in male fishes with an emphasis on testicular development and spermatogenesis. Specifically, the primary goal is to review the physiological interactions between hormones that regulate reproduction and hormones that regulate metabolism as a critical determinant of testicular function. A brief introduction to the localization of metabolic hormones in fish testis is also provided. Besides, the consequences of fasting and food deprivation on testicular development and sperm quality will be discussed with a focus on interactions between metabolic and reproductive hormones.


Assuntos
Peixes/fisiologia , Hormônios/fisiologia , Espermatogênese , Animais , Grelina/metabolismo , Grelina/fisiologia , Hormônios/metabolismo , Leptina/metabolismo , Leptina/fisiologia , Masculino , Neuropeptídeos/metabolismo , Neuropeptídeos/fisiologia , Espermatozoides/crescimento & desenvolvimento , Espermatozoides/fisiologia , Hormônios Tireóideos/metabolismo , Hormônios Tireóideos/fisiologia
11.
J Neuroendocrinol ; 31(5): e12729, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31059174

RESUMO

Seasonal neuroendocrine cycles that govern annual changes in reproductive activity, energy metabolism and hair growth are almost ubiquitous in mammals that have evolved at temperate and polar latitudes. Changes in nocturnal melatonin secretion regulating gene expression in the pars tuberalis (PT) of the pituitary stalk are a critical common feature in seasonal mammals. The PT sends signal(s) to the pars distalis of the pituitary to regulate prolactin secretion and thus the annual moult cycle. The PT also signals in a retrograde manner via thyroid-stimulating hormone to tanycytes, which line the ventral wall of the third ventricle in the hypothalamus. Tanycytes show seasonal plasticity in gene expression and play a pivotal role in regulating local thyroid hormone (TH) availability. Within the mediobasal hypothalamus, the cellular and molecular targets of TH remain elusive. However, two populations of hypothalamic neurones, which produce the RF-amide neuropeptides kisspeptin and RFRP3 (RF-amide related peptide 3), are plausible relays between TH and the gonadotrophin-releasing hormone-pituitary-gonadal axis. By contrast, the ways by which TH also impinges on hypothalamic systems regulating energy intake and expenditure remain unknown. Here, we review the neuroendocrine underpinnings of seasonality and identify several areas that warrant further research.


Assuntos
Relógios Circadianos/fisiologia , Sistemas Neurossecretores/fisiologia , Hipófise/fisiologia , Animais , Células Ependimogliais/fisiologia , Humanos , Hipotálamo/fisiologia , Neurônios/fisiologia , Fotoperíodo , Estações do Ano , Hormônios Tireóideos/fisiologia
12.
Int J Vitam Nutr Res ; 89(1-2): 45-54, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30957705

RESUMO

Objective: This study aimed to evaluate the effect of maternal consumption of flaxseed flour and oil on serum concentrations of glucose, insulin, and thyroid hormones of the adult female offspring of diabetic rats. Methods: Wistar rats were induced to diabetes by a high-fat diet (60%) and streptozotocin (35 mg/kg). Rats were mated and once pregnancy was confirmed, were divided into the following groups: Control Group (CG): casein-based diet; High-fat Group (HG): high-fat diet (49%); High-fat Flaxseed Group (HFG): high-fat diet supplemented with 25% flaxseed flour; High-fat Flaxseed Oil group (HOG): high-fat diet, where soya oil was replaced with flaxseed oil. After weaning, female pups (n = 6) from each group were separated, received a commercial rat diet and were sacrificed after 180 days. Serum insulin concentrations were determined by ELISA, the levels of triiodothyronine (T3), thyroxine (T4) and thyroid-stimulating hormone (TSH) were determined by chemiluminescence. Results: There was a significant reduction in body weight at weaning in HG (-31%), HFG (-33%) and HOG (44%) compared to CG (p = 0.002), which became similar by the end of 180 days. Blood glucose levels were reduced in HFG (-10%, p = 0.044) when compared to CG, and there was no significant difference between groups in relation to insulin, T3, T4, and TSH after 180 days. Conclusions: Maternal severe hyperglycemia during pregnancy and lactation resulted in a microsomal offspring. Maternal consumption of flaxseed reduces blood glucose levels in adult offspring without significant effects on insulin levels and thyroid hormones.


Assuntos
Diabetes Mellitus Experimental , Linho , Glucose/metabolismo , Insulina/metabolismo , Animais , Suplementos Nutricionais , Feminino , Glucose/química , Insulina/química , Lactação , Gravidez , Ratos , Ratos Wistar , Hormônios Tireóideos/fisiologia
13.
J Biomed Sci ; 26(1): 24, 2019 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-30849993

RESUMO

The liver is controlled by several metabolic hormones, including thyroid hormone, and characteristically displays high lysosomal activity as well as metabolic stress-triggered autophagy, which is stringently regulated by the levels of hormones and metabolites. Hepatic autophagy provides energy through catabolism of glucose, amino acids and free fatty acids for starved cells, facilitating the generation of new macromolecules and maintenance of the quantity and quality of cellular organelles, such as mitochondria. Dysregulation of autophagy and defective mitochondrial homeostasis contribute to hepatocyte injury and liver-related diseases, such as non-alcoholic fatty liver disease (NAFLD) and liver cancer.Thyroid hormones (TH) mediate several critical physiological processes including organ development, cell differentiation, metabolism and cell growth and maintenance. Accumulating evidence has revealed dysregulation of cellular TH activity as the underlying cause of several liver-related diseases, including alcoholic or non-alcoholic fatty liver disease and liver cancer. Data from epidemiologic, animal and clinical studies collectively support preventive functions of THs in liver-related diseases, highlighting the therapeutic potential of TH analogs. Elucidation of the molecular mechanisms and downstream targets of TH should thus facilitate the development of therapeutic strategies for a number of major public health issues.Here, we have reviewed recent studies focusing on the involvement of THs in hepatic homeostasis through induction of autophagy and their implications in liver-related diseases. Additionally, the potential underlying molecular pathways and therapeutic applications of THs in NAFLD and HCC are discussed.


Assuntos
Autofagia , Homeostase , Neoplasias Hepáticas/fisiopatologia , Fígado/fisiologia , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Hormônios Tireóideos/fisiologia , Animais , Humanos , Fígado/fisiopatologia , Camundongos , Ratos
14.
Science ; 364(6436): 184-188, 2019 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-30846611

RESUMO

Tissue regenerative potential displays striking divergence across phylogeny and ontogeny, but the underlying mechanisms remain enigmatic. Loss of mammalian cardiac regenerative potential correlates with cardiomyocyte cell-cycle arrest and polyploidization as well as the development of postnatal endothermy. We reveal that diploid cardiomyocyte abundance across 41 species conforms to Kleiber's law-the ¾-power law scaling of metabolism with bodyweight-and inversely correlates with standard metabolic rate, body temperature, and serum thyroxine level. Inactivation of thyroid hormone signaling reduces mouse cardiomyocyte polyploidization, delays cell-cycle exit, and retains cardiac regenerative potential in adults. Conversely, exogenous thyroid hormones inhibit zebrafish heart regeneration. Thus, our findings suggest that loss of heart regenerative capacity in adult mammals is triggered by increasing thyroid hormones and may be a trade-off for the acquisition of endothermy.


Assuntos
Coração/fisiologia , Miócitos Cardíacos/fisiologia , Poliploidia , Regeneração/fisiologia , Hormônios Tireóideos/fisiologia , Animais , Regulação da Temperatura Corporal , Pontos de Checagem do Ciclo Celular , Proliferação de Células , Diploide , Camundongos , Miócitos Cardíacos/classificação , Filogenia , Receptores dos Hormônios Tireóideos/genética , Receptores dos Hormônios Tireóideos/fisiologia , Regeneração/efeitos dos fármacos , Regeneração/genética , Transdução de Sinais , Hormônios Tireóideos/farmacologia , Peixe-Zebra
15.
Protein Cell ; 10(8): 583-594, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30887444

RESUMO

A change in the metabolic flux of glucose from mitochondrial oxidative phosphorylation (OXPHOS) to aerobic glycolysis is regarded as one hallmark of cancer. However, the mechanisms underlying the metabolic switch between aerobic glycolysis and OXPHOS are unclear. Here we show that the M2 isoform of pyruvate kinase (PKM2), one of the rate-limiting enzymes in glycolysis, interacts with mitofusin 2 (MFN2), a key regulator of mitochondrial fusion, to promote mitochondrial fusion and OXPHOS, and attenuate glycolysis. mTOR increases the PKM2:MFN2 interaction by phosphorylating MFN2 and thereby modulates the effect of PKM2:MFN2 on glycolysis, mitochondrial fusion and OXPHOS. Thus, an mTOR-MFN2-PKM2 signaling axis couples glycolysis and OXPHOS to modulate cancer cell growth.


Assuntos
Carcinogênese/metabolismo , Proteínas de Transporte/fisiologia , GTP Fosfo-Hidrolases/fisiologia , Proteínas de Membrana/fisiologia , Proteínas Mitocondriais/fisiologia , Serina-Treonina Quinases TOR/fisiologia , Hormônios Tireóideos/fisiologia , Animais , Células Cultivadas , Glicólise , Humanos , Dinâmica Mitocondrial , Fosforilação Oxidativa
16.
Oncogene ; 38(25): 4915-4931, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30858544

RESUMO

Tumor cells undergo a metabolic shift in order to adapt to the altered microenvironment, although the underlying mechanisms have not been fully explored. HnRNP A1 is involved in the alternative splicing of the pyruvate kinase (PK) mRNA, allowing tumor cells to specifically produce the PKM2 isoform. We found that the acetylation status of hnRNP A1 in hepatocellular carcinoma (HCC) cells was dependent on glucose availability, which affected the PKM2-dependent glycolytic pathway. In the glucose-starved HCC cells, SIRT1 and SIRT6, members of deacetylase sirtuin family, were highly expressed and deacetylated hnRNP A1 after direct binding. We identified four lysine residues in hnRNP A1 that were deacetylated by SIRT1 and SIRT6, resulting in significant inhibition of glycolysis in HCC cells. Deacetylated hnRNP A1 reduced PKM2 and increased PKM1 alternative splicing in HCC cells under normal glucose conditions, thereby reducing the metabolic activity of PK and the non-metabolic PKM2-ß-catenin signaling pathway. However, under glucose starvation, the low levels of acetylated hnRNP A1 reduced HCC cell metabolism to adapt to the nutrient deficiency. Taken together, sirtuin-mediated hnRNP A1 deacetylation inhibits HCC cell proliferation and tumorigenesis in a PKM2-dependent manner. These findings point to the metabolic reprogramming induced by hnRNP A1 acetylation in order to adapt to the nutritional status of the tumor microenvironment.


Assuntos
Acetiltransferases/metabolismo , Carcinoma Hepatocelular/patologia , Glicólise , Ribonucleoproteína Nuclear Heterogênea A1/metabolismo , Neoplasias Hepáticas/patologia , Sirtuína 1/fisiologia , Sirtuínas/fisiologia , Células A549 , Acetilação , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Proteínas de Transporte/fisiologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Progressão da Doença , Feminino , Glicólise/genética , Células HCT116 , Células HEK293 , Células Hep G2 , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Proteínas de Membrana/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Pessoa de Meia-Idade , Prognóstico , Processamento de Proteína Pós-Traducional/genética , Hormônios Tireóideos/fisiologia , Microambiente Tumoral/genética
17.
Rev. argent. endocrinol. metab ; 56(1): 70-79, mar. 2019.
Artigo em Espanhol | LILACS | ID: biblio-1041761

RESUMO

Las hormonas tiroideas tienen acciones renales directas en conjunto con efectos dinámicos y cardiovasculares que influyen en la función renal. Cuadros de hipotiroidismo con enfermedad renal son una combinación peculiar y poco descrita, es por ello que el propósito de este trabajo es exponer el caso de dos pacientes con síndrome nefrótico asociado a hipotiroidismo severo, los cuales presentaron disminución de la proteinuria y casi normalización de función renal luego de iniciar tratamiento de reemplazo con levotiroxina.


Thyroid hormones have direct renal actions in conjunction with dynamic and cardiovascular effects that influence renal function. Cases of primary hypothyroidism with renal disease are a peculiar and poorly described combination, is for it that the objective of this work is to expose the cases of two patients with nephrotic syndrome associated with severe hypothyroidism, whom presented decreased proteinuria and almost normalized renal function after starting replacement therapy with levothyroxine.


Assuntos
Humanos , Masculino , Pessoa de Meia-Idade , Tiroxina/farmacologia , Hipotireoidismo/complicações , Síndrome Nefrótica/complicações , Hormônios Tireóideos/fisiologia , Hormônios Tireóideos/metabolismo
18.
Arch Gynecol Obstet ; 299(5): 1443-1451, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30809696

RESUMO

PURPOSE: Reprogramming of cell metabolism is essential for tumor progression and the best-studied metabolic phenomenon of cancer cells is aerobic glycolysis, in which pyruvate kinase isozyme type M2 (PKM2) plays a critical role. Follicle-stimulating hormone (FSH) contributes to epithelial ovarian cancer progression and has been shown to regulate cell metabolism in ovaries. The aim of this study was to investigate the interaction between FSH and PKM2 and their effect on aerobic glycolysis and cell proliferation in ovarian cancer. METHODS: SKOV3 and OVCAR3 ovarian cancer cells were treated with FSH at various doses to investigate its effect on cell proliferation and PKM2 expression. siRNA-PKM2-transfected SKOV3 and OVCAR3 cells were treated with FSH to examine whether the changes induced by FSH could be altered by siRNA-PKM2. Glucose and lactate levels were evaluated to observe the change in glycolysis in these cells. RESULTS: In the current study, FSH upregulated the expression of PKM2 and glycolysis in SKOV3 and OVCAR3 cells. PKM2 knockdown reduced FSH-induced cell growth and glycolysis. Moreover, FSH attenuated apoptosis that was induced by the inhibition of PKM2. CONCLUSIONS: Collectively, the findings of this study indicated that FSH promoted glycolysis in epithelial ovarian cancer cells. Knockdown of PKM2 inhibited aerobic glycolysis and cell proliferation induced by FSH.


Assuntos
Proteínas de Transporte/fisiologia , Hormônio Foliculoestimulante/farmacologia , Glicólise , Proteínas de Membrana/fisiologia , Neoplasias Ovarianas/metabolismo , Hormônios Tireóideos/fisiologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Neoplasias Ovarianas/patologia
19.
PLoS One ; 14(2): e0211515, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30735509

RESUMO

Pyruvate Kinase M2 (PKM2) mediates metabolic reshuffling and is ubiquitously upregulated in several cancer types. The non-metabolic function of PKM2 as key nuclear kinase and modulator of gene expression is instrumental in cancer progression and tumorigenesis. Here, we attempt to discern the non-canonical function of PKM2 as an epigenetic modulator and the underlying implication of this activity. Using 5'-FAM labelled reconstituted mononucleosome we have shown that PKM2 interacts with the complex through Histone H3 and possibly obstruct the access to DNA binding factors. Subsequently, the interaction negatively impacts the ATP dependent remodeling activity of Chromodomain Helicase DNA binding protein-7 (Chd7). Chd7 remodeling activity is required to ameliorate DNA damage and is crucial to genome stability. Our study shows that PKM2 blocks the Chd7 mediated sliding of nucleosome. It can be conjectured that stalling Chd7 may lead to impaired DNA damage and increased genomic instability. We propose a mechanism in which PKM2 negatively regulate nucleosome repositioning in chromatin and may exacerbate cancer by altering the nucleosome architecture. This research is imperative to our understanding of how altered cancer metabolism can potentially modulate the gene expression and sustain incessant proliferation by tweaking the chromatin topography.


Assuntos
Proteínas de Transporte/fisiologia , DNA Helicases/fisiologia , Proteínas de Ligação a DNA/fisiologia , Proteínas de Membrana/fisiologia , Nucleossomos/metabolismo , Piruvato Quinase/fisiologia , Hormônios Tireóideos/fisiologia , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Montagem e Desmontagem da Cromatina , DNA Helicases/genética , DNA Helicases/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Regulação da Expressão Gênica , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Nucleossomos/genética , Hormônios Tireóideos/genética , Hormônios Tireóideos/metabolismo
20.
Cell Biol Int ; 43(5): 486-494, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30761678

RESUMO

Hypothyroidism has been linked to infertility, but the mechanisms underlying infertility-related hypothyroidism have yet to be fully elucidated. Therefore, in this study, effects of hypothyroidism on expression of the proteins related to thyroid hormone function in the uterus, which were thought to play a role implantation, including thyroid hormone receptor (TR), thyroid stimulating hormone receptor (TSHR), retinoic acid receptor (RAR) and extracellular kinase (ERK) were identified. Pregnant female rats were rendered hypothyroid by giving methimazole (MMI), orally. Following hypothyroid induction, rats were grouped into control (non-treated) and received subcutaneous thyroxine at 20, 40, and 80 µg/kg/day for five consecutive days. At Day 6, which is the day of implantation (GD 6), rats were sacrificed and the number of embryo implantation site in the uterus was calculated. Then, uterine horns were harvested and expression of the above proteins and their mRNAs were identified by Western blotting and real-time PCR, respectively. In non-treated hypothyroid pregnant rats, the number of embryo implantation sites decreased as compared to euthyroid and hypothyroid rats receiving thyroxine treatment. Similarly, expression of TRα-1, TRß-1, TSHR, ERK1/2 and RAR proteins and mRNA in the uterus of non-treated hypothyroid rats also decreased (P < 0.05 when compared to euthyroid and thyroxine-treated hypothyroid rats). In conclusion, downregulated expression of the thyroid hormone related proteins in the uterus at the day of implantation might result in infertility as reported in hypothyroid condition.


Assuntos
Hipotireoidismo/fisiopatologia , Glândula Tireoide/metabolismo , Hormônios Tireóideos/metabolismo , Animais , Regulação para Baixo/efeitos dos fármacos , Implantação do Embrião , Feminino , Regulação da Expressão Gênica no Desenvolvimento/genética , Hipotireoidismo/complicações , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Metimazol/farmacologia , Gravidez , Ratos , Ratos Sprague-Dawley , Receptores do Ácido Retinoico/análise , Receptores do Ácido Retinoico/metabolismo , Receptores dos Hormônios Tireóideos/análise , Receptores dos Hormônios Tireóideos/metabolismo , Receptores da Tireotropina/análise , Receptores da Tireotropina/metabolismo , Glândula Tireoide/fisiologia , Hormônios Tireóideos/genética , Hormônios Tireóideos/fisiologia , Tiroxina/farmacologia , Útero/metabolismo , Útero/fisiologia
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