RESUMO
Mitochondria are organelles known primarily for generating ATP via the oxidative phosphorylation process. Environmental signals are sensed by whole organisms or cells and markedly affect this process, leading to alterations in gene transcription and, consequently, changes in mitochondrial function and biogenesis. The expression of mitochondrial genes is finely regulated by nuclear transcription factors, including nuclear receptors and their coregulators. Among the best-known coregulators is the nuclear receptor corepressor 1 (NCoR1). Muscle-specific knockout of NCoR1 in mice induces an oxidative phenotype, improving glucose and fatty acid metabolism. However, the mechanism by which NCoR1 is regulated remains elusive. In this work, we identified the poly(A)-binding protein 4 (PABPC4) as a new NCoR1 interactor. Unexpectedly, we found that silencing of PABPC4 induced an oxidative phenotype in both C2C12 and MEF cells, as indicated by increased oxygen consumption, mitochondria content, and reduced lactate production. Mechanistically, we demonstrated that PABPC4 silencing increased the ubiquitination and consequent degradation of NCoR1, leading to the derepression of PPAR-regulated genes. As a consequence, cells with PABPC4 silencing had a greater capacity to metabolize lipids, reduced intracellular lipid droplets, and reduced cell death. Interestingly, in conditions known to induce mitochondrial function and biogenesis, both mRNA expression and PABPC4 protein content were markedly reduced. Our study, therefore, suggests that the lowering of PABPC4 expression may represent an adaptive event required to induce mitochondrial activity in response to metabolic stress in skeletal muscle cells. As such, the NCoR1-PABPC4 interface might be a new road to the treatment of metabolic diseases.
Assuntos
Receptores Citoplasmáticos e Nucleares , Fatores de Transcrição , Animais , Camundongos , Proteínas Correpressoras/metabolismo , Correpressor 1 de Receptor Nuclear/genética , Correpressor 1 de Receptor Nuclear/metabolismo , Fosforilação Oxidativa , Receptores Citoplasmáticos e Nucleares/metabolismo , Estresse Fisiológico , Fatores de Transcrição/metabolismoRESUMO
Aim Investigate whether inheritance of improved skeletal muscle mitochondrial function and its association with glycemic control are multigenerational benefits of exercise. MAIN METHODS: Male Swiss mice were subjected to 8 weeks of endurance training and mated with untrained females. KEY FINDINGS: Trained fathers displayed typical endurance training-induced adaptations. Remarkably, offspring from trained fathers also exhibited higher endurance performance, mitochondrial oxygen consumption, glucose tolerance and insulin sensitivity. However, PGC-1α expression was not increased in the offspring. In the offspring, the expression of the co-repressor NCoR1 was reduced, increasing activation of PGC-1α target genes. These effects correlated with higher DNA methylation at the NCoR1 promoter in both, the sperm of trained fathers and in the skeletal muscle of their offspring. SIGNIFICANCE: Higher skeletal muscle mitochondrial function is inherited by epigenetic de-activation of a key PGC-1α co-repressor.
Assuntos
Mitocôndrias/metabolismo , Condicionamento Físico Animal/fisiologia , Esforço Físico/fisiologia , Animais , Metilação de DNA , Epigênese Genética/genética , Feminino , Masculino , Camundongos , Mitocôndrias/fisiologia , Músculo Esquelético/fisiologia , Correpressor 1 de Receptor Nuclear/metabolismo , Consumo de Oxigênio/fisiologia , Herança Paterna/fisiologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/fisiologia , Condicionamento Físico Animal/métodos , RNA Mensageiro/genéticaRESUMO
Atherosclerotic cardiovascular disease is part of chronic immunometabolic disorders such as type 2 diabetes and nonalcoholic fatty liver disease. Their common risk factors comprise hypertension, insulin resistance, visceral obesity, and dyslipidemias, such as hypercholesterolemia and hypertriglyceridemia, which are part of the metabolic syndrome. Immunometabolic diseases include chronic pathologies that are affected by both metabolic and inflammatory triggers and mediators. Important and challenging questions in this context are to reveal how metabolic triggers and their downstream signaling affect inflammatory processes and vice-versa. Along these lines, specific nuclear receptors sense changes in lipid metabolism and in turn induce downstream inflammatory and metabolic processes. The transcriptional activity of these nuclear receptors is regulated by the nuclear receptor corepressors (NCORs), including NCOR1. In this review we describe the function of NCOR1 as a central immunometabolic regulator and focus on its role in atherosclerosis and associated immunometabolic diseases.
Assuntos
Aterosclerose/etiologia , Aterosclerose/metabolismo , Suscetibilidade a Doenças , Doenças Metabólicas/etiologia , Doenças Metabólicas/metabolismo , Correpressor 1 de Receptor Nuclear/metabolismo , Animais , Aterosclerose/patologia , Proteínas de Transporte , Suscetibilidade a Doenças/imunologia , Metabolismo Energético/imunologia , Humanos , Imunomodulação , Metabolismo dos Lipídeos , Macrófagos/imunologia , Macrófagos/metabolismo , Correpressor 1 de Receptor Nuclear/genética , Ligação Proteica , Transdução de SinaisRESUMO
Introduction: The androgen receptor (AR) plays an important role in normal development of the prostate gland, as well as in prostatic neoplasms. Transcriptional regulation by AR is modulated by its interaction with co-activators or co-repressors, such as NCoR1 (nuclear receptor co-repressor 1), which is involved in reducing AR activity over the target gene transcription. Methods: To identify the role of NCoR1 in the prostate cancer androgen independence in a cell line model, we aimed to evaluate the effects of silencing NCoR1 on prostate-specific antigen (PSA) gene expression, the proliferative response and PSA secretion on the supernatant of C4-2B and LNCaP cells that were submitted to small interfering RNAs (siRNAs) transfection, and to treatments with different androgen dosages. Results: In LNCaP and C4-2B cells with no dihydrotestosterone (DHT) treatment, a decrease in PSA mRNA expression was observed 48 hours and 72 hours after gene silencing in the siNCoR group when compared to the control and siNC groups. The LNCaP and C4-2B cells showed a biphasic pattern in response to dihydrotestosterone treatment in transfected groups (siNCoR and siNC) as well as in the control condition (without transfection). The secretion of PSA in cell supernatant of LNCaP and C4-2B cells was higher in the siNCoR group, and, in relation to hormonal treatment, higher in the 10-8 M DHT group. Conclusions: A reduction in the NCoR1 levels seems to have a double influence on the activity of AR in PCa cells. These results suggest that NCoR may act as an AR co-repressor depending upon hormonal stimulation.(AU)
Assuntos
Humanos , Masculino , Neoplasias da Próstata , Antígeno Prostático Específico , Proliferação de Células , Correpressor 1 de Receptor Nuclear , Di-Hidrotestosterona , Receptores Androgênicos , Linhagem Celular , Proteínas CorrepressorasRESUMO
Mitochondrial number and shape are constantly changing in response to increased energy demands. The ability to synchronize mitochondrial pathways to respond to energy fluctuations within the cell is a central aspect of mammalian homeostasis. This dynamic process depends on the coordinated activation of transcriptional complexes to promote the expression of genes encoding for mitochondrial proteins. Recent evidence has shown that the nuclear corepressor NCoR1 is an essential metabolic switch which acts on oxidative metabolism signaling. Here, we provide an overview of the emerging role of NCoR1 in the transcriptional control of energy metabolism. The identification and characterization of NCoR1 as a central, evolutionary conserved player in mitochondrial function have revealed a novel layer of metabolic control. Defining the precise mechanisms by which NCoR1 acts on energy homeostasis will ultimately contribute towards the development of novel therapies for the treatment of metabolic diseases such as obesity and type 2 diabetes.
Assuntos
Metabolismo Energético , Mitocôndrias/metabolismo , Correpressor 1 de Receptor Nuclear/metabolismo , Animais , Humanos , Correpressor 1 de Receptor Nuclear/química , Correpressor 1 de Receptor Nuclear/genética , PPAR alfa/genética , PPAR alfa/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Transdução de Sinais , Ativação Transcricional , Receptor ERRalfa Relacionado ao EstrogênioRESUMO
Thyroid hormones (TH) regulate mammary function. Hypothyroidism (HypoT) has deleterious effects on lactation, litter growth and survival. We analyzed the effect of chronic 6-propyl-2-thiouracil (PTU)-induced HypoT in the expression of nuclear receptors, co-regulators and oxytocin receptor (OTR) on lactation (L) days 2, 7 and 14. TH receptors (TRs) were increased on L7 at mRNA and protein levels, except TRα protein, that fell on L14. HypoT decreased TRα2 mRNA on L7 and TRα1 protein on L2, while TRß1 protein increased on L14. HypoT increased estrogen receptor ß (ERß) mRNA on L7 but decreased its protein levels on L14. Progesterone receptor A (PRA) mRNA decreased from L2 to L14 while PRB increased, and at protein levels PRA levels showed a nadir on L7, while PRB peaked. HypoT decreased PRA mRNA and protein and increased PRB mRNA at L14. Nuclear receptor co-activator (NCOA) 1 and RXRα mRNA showed an opposite pattern to the TRs, while NCOA2 increased at L14; HypoT blocked the variations in NCOA1 and NCOA2. HypoT increased NCOR1 on L2 and decreased OTR at L2 and circulating estradiol and NCOR2 at L14. In controls the most notable changes occurred on L7, suggesting it is a key inflection point in mammary metabolism. The low levels of TRα1, NCOA1 and OTR, and increased NCOR1 produced by HypoT on L2 may hinder the mammary ability to achieve normal milk synthesis and ejection, leading to defective lactation. Later on, altered ER and PR expression may impair further mammary function.
Assuntos
Expressão Gênica , Hipotireoidismo/metabolismo , Lactação , Receptores de Progesterona/metabolismo , Animais , Feminino , Hipotireoidismo/induzido quimicamente , Glândulas Mamárias Animais/metabolismo , Correpressor 1 de Receptor Nuclear/genética , Correpressor 1 de Receptor Nuclear/metabolismo , Coativador 1 de Receptor Nuclear/genética , Coativador 1 de Receptor Nuclear/metabolismo , Coativador 2 de Receptor Nuclear/genética , Coativador 2 de Receptor Nuclear/metabolismo , Propiltiouracila , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Ratos Wistar , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Receptores de Ocitocina/genética , Receptores de Ocitocina/metabolismo , Receptores de Progesterona/genética , Receptores dos Hormônios Tireóideos/genética , Receptores dos Hormônios Tireóideos/metabolismo , Receptor X Retinoide alfa/genética , Receptor X Retinoide alfa/metabolismoRESUMO
The objective of this work was to study the ovarian function when follicular development is induced during a hyperandrogenic condition. Female rats were injected with either equine chorionic gonadotropin (eCG group) to induce folliculogenesis or eCG together with DHEA to induce folliculogenesis in a hyperandrogenic condition (eCG+HA group). The control group was injected with vehicle. Ovarian mRNA levels of the peroxisome proliferator-activated receptor gamma (PPARγ) co-activator PGC1α, the PPARγ co-repressor NCoR, the main enzymes involved in the ovarian steroidogenesis (CYP17, 3ß-hydroxysteroid dehydrogenase (3ß-HSD), 17ß-HSD, and CYP19A), and cyclooxygenase 2 (COX2) were evaluated only by real-time PCR. COX2 was evaluated by both real-time PCR and western blot. Serum steroid hormones and both the oxidative and inflammatory statuses were also quantified. We found that eCG-induced folliculogenesis induced increased mRNA levels of PGC1α and decreased those of NCoR when compared with controls. In addition, we found an increase in serum estradiol (E2) levels and enhanced mRNA expression of CYP19A. A pro-inflammatory status and a pro-oxidant status were also established. When folliculogenesis was induced in a hyperandrogenic condition, the mRNA levels of the PPARγ co-repressor NCoR remained higher than in controls and the pro-inflammatory and pro-oxidant statuses were enhanced. In addition, the enzymes involved in ovarian steroidogenesis were altered leading to the accumulation of testosterone and an unfavorable E2/testosterone ratio. These alterations led to abnormal follicular development.
Assuntos
Hiperandrogenismo/metabolismo , Folículo Ovariano/metabolismo , Ovário/metabolismo , 17-Hidroxiesteroide Desidrogenases/genética , 17-Hidroxiesteroide Desidrogenases/metabolismo , 3-Hidroxiesteroide Desidrogenases/genética , 3-Hidroxiesteroide Desidrogenases/metabolismo , Animais , Aromatase/genética , Aromatase/metabolismo , Gonadotropina Coriônica/farmacologia , Desidroepiandrosterona , Estradiol/sangue , Feminino , Hiperandrogenismo/induzido quimicamente , Correpressor 1 de Receptor Nuclear/genética , Correpressor 1 de Receptor Nuclear/metabolismo , Folículo Ovariano/efeitos dos fármacos , Ovário/efeitos dos fármacos , PPAR gama/genética , PPAR gama/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Esteroide 17-alfa-Hidroxilase/genética , Esteroide 17-alfa-Hidroxilase/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
OBJECTIVE: To study if the endocrinological status of PCOS women affects the endometrial sensitivity to steroids by evaluating the expression of androgen receptor (AR), estrogen receptor alpha (ERalpha), estrogen receptor beta (ERbeta), co-activators AIB1 and ARA70, and co-repressor NCoR. METHODS: Gene and/or protein expression of steroid receptors and co-regulators was measured in 17 samples of normal endometrium (NE), 23 PCOS endometrium without treatment (PCOSE), 11 endometria from PCOS women and with endometrial hyperplasia (HPCOSE), and 10 endometria from patients with endometrial hyperplasia (HE), using RT-PCR and/or immunohistochemistry and Western blot. RESULTS: Gene and protein expression of AR was relatively elevated in PCOSE and HPCOSE compared with NE. A significant increase in ERalpha protein expression was observed in PCOSE, preferentially in the nucleus of endometrial cells, whereas ERbeta gene and protein expression increased gradually from PCOSE to HPCOSE and HE, mainly in the epithelial compartment. Importantly, we found a gradual increase in the ERbeta/ERalpha gene and protein expression ratio in endometria from the four groups of women. AIB1 showed increased nuclear protein expression in PCOSE compared to NE, in the presence of a high expression of ARA70 in all groups. High expression of ARA70 together with a normal expression level of AIB1 was observed in HPCOSE. The cytoplasmic immunostaining of NCoR was similar between the four groups of patients. CONCLUSION: The PCOS endometrium exhibits a higher sensitivity to steroid action. We can inferred that these alterations could deregulate the transcription of genes involved in the cell cycle, which may lead to the development of endometrial hyperplasia in PCOS women.
Assuntos
Hiperplasia Endometrial/metabolismo , Histona Acetiltransferases/biossíntese , Proteínas Nucleares/biossíntese , Proteínas Oncogênicas/biossíntese , Síndrome do Ovário Policístico/metabolismo , Receptores Androgênicos/biossíntese , Receptores de Estrogênio/biossíntese , Proteínas Repressoras/biossíntese , Transativadores/biossíntese , Fatores de Transcrição/biossíntese , Adulto , Hiperplasia Endometrial/complicações , Hiperplasia Endometrial/genética , Endométrio/metabolismo , Receptor alfa de Estrogênio/biossíntese , Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/biossíntese , Receptor beta de Estrogênio/genética , Feminino , Expressão Gênica , Histona Acetiltransferases/genética , Humanos , Proteínas Nucleares/genética , Correpressor 1 de Receptor Nuclear , Coativador 3 de Receptor Nuclear , Coativadores de Receptor Nuclear , Proteínas Oncogênicas/genética , Síndrome do Ovário Policístico/complicações , Síndrome do Ovário Policístico/genética , Receptores Androgênicos/genética , Receptores de Estrogênio/genética , Proteínas Repressoras/genética , Transativadores/genética , Fatores de Transcrição/genética , Transcrição GênicaRESUMO
Only competent oocytes are able to undergo complete maturation and normal embryonic development. Therefore, the identification of genes that are differentially expressed in competent oocytes would contribute to our understanding of the factors controlling competency. It is well known that time of cleavage after insemination in vitro is highly correlated with embryonic developmental potential and this can be used to distinguish between oocytes of different quality. The main objective of this study was to identify genes associated with competency and rapid cleavage. We examined the expression of 16 candidate genes (IDH, YEAF Cathepsin B, RAD50, TCP1 NCOR1, HUEL, STK6, ZNF403, AOP2, EEF1A1, Hsp90, Hsp40, AKR1B1, PGRMC1, and DMRT2) in early and late cleaving embryos, by real time PCR. These transcripts were derived from previous study in our laboratory using cDNA coming from a suppressive subtraction hybridization (SSH) between early cleaving versus late cleaving embryos spotted on a microarray slide. Of the 16 genes evaluated, 3 (IDH, YEAF, and H2A) showed statistical difference (P < 0.05) between early and late cleaving embryos. However, some genes such as Cathepsin B (P = 0.0677), RAD50 (P = 0.0899), and TCP1 (P = 0.0824) tended to show higher expression in the early cleaving than in the late cleaving embryo. In conclusion, we have identified three genes (YEAF, IDH, H2A) that were differentially expressed in the early cleaving embryos, and their expression can be associated with greater developmental competence.