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

RESUMO

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

RESUMO

Thyroid cancer is the most common endocrine malignancy. However, the cytological diagnosis of follicular thyroid carcinoma (FTC), Hürthle cell carcinoma (HCC), and follicular variant of papillary thyroid carcinoma (FVPTC) and their benign counterparts is a challenge for preoperative diagnosis. Nearly 20-30% of biopsied thyroid nodules are classified as having indeterminate risk of malignancy and incur costs to the health care system. Based on that, 120 patients were screened for the main driver mutations previously described in thyroid cancer. Subsequently, 14 mutation-negative cases that are the main source of diagnostic errors (FTC, HCC, or FVPTC) underwent RNA-Sequencing analysis. Somatic variants in candidate driver genes (ECD, NUP98,LRP1B, NCOR1, ATM, SOS1, and SPOP) and fusions were described. NCOR1 and SPOP variants underwent validation. Moreover, expression profiling of driver-negative samples was compared to 16 BRAF V600E, RAS, or PAX8-PPARg positive samples. Negative samples were separated in two clusters, following the expression pattern of the RAS/PAX8-PPARg or BRAF V600E positive samples. Both negative groups showed distinct BRS, ERK, and TDS scores, tumor mutation burden, signaling pathways and immune cell profile. Altogether, here we report novel gene variants and describe cancer-related pathways that might impact preoperative diagnosis and provide insights into thyroid tumor biology.

RESUMO

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

RESUMO

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

RESUMO

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