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1.
Genes Dev ; 34(7-8): 544-559, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32079653

RESUMO

Excessive reactive oxygen species (ROS) can cause oxidative stress and consequently cell injury contributing to a wide range of diseases. Addressing the critical gaps in our understanding of the adaptive molecular events downstream ROS provocation holds promise for the identification of druggable metabolic vulnerabilities. Here, we unveil a direct molecular link between the activity of two estrogen-related receptor (ERR) isoforms and the control of glutamine utilization and glutathione antioxidant production. ERRα down-regulation restricts glutamine entry into the TCA cycle, while ERRγ up-regulation promotes glutamine-driven glutathione production. Notably, we identify increased ERRγ expression/activation as a hallmark of oxidative stress triggered by mitochondrial disruption or chemotherapy. Enhanced tumor antioxidant capacity is an underlying feature of human breast cancer (BCa) patients that respond poorly to treatment. We demonstrate that pharmacological inhibition of ERRγ with the selective inverse agonist GSK5182 increases antitumor efficacy of the chemotherapeutic paclitaxel on poor outcome BCa tumor organoids. Our findings thus underscore the ERRs as novel redox sensors and effectors of a ROS defense program and highlight the potential therapeutic advantage of exploiting ERRγ inhibitors for the treatment of BCa and other diseases where oxidative stress plays a central role.


Assuntos
Neoplasias da Mama/fisiopatologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Receptores de Estrogênio/metabolismo , Transdução de Sinais/fisiologia , Animais , Antineoplásicos/farmacologia , Técnicas Biossensoriais , Neoplasias da Mama/tratamento farmacológico , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glutamina/metabolismo , Glutationa/metabolismo , Humanos , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Paclitaxel/farmacologia , Receptores de Estrogênio/genética , Rotenona/farmacologia , Tamoxifeno/análogos & derivados , Tamoxifeno/farmacologia , Receptor ERRalfa Relacionado ao Estrogênio
2.
Proc Natl Acad Sci U S A ; 121(37): e2406854121, 2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-39231208

RESUMO

Alzheimer's disease (AD) is a prevalent neurodegenerative disease characterized by cognitive decline and learning/memory impairment associated with neuronal cell loss. Estrogen-related receptor α (ERRα) and ERRγ, which are highly expressed in the brain, have emerged as potential AD regulators, with unelucidated underlying mechanisms. Here, we identified genome-wide binding sites for ERRα and ERRγ in human neuronal cells. They commonly target a subset of genes associated with neurodegenerative diseases, including AD. Notably, Dickkopf-1 (DKK1), a Wnt signaling pathway antagonist, was transcriptionally repressed by both ERRα and ERRγ in human neuronal cells and brain. ERRα and ERRγ repress RNA polymerase II (RNAP II) accessibility at the DKK1 promoter by modulating a specific active histone modification, histone H3 lysine acetylation (H3K9ac), with the potential contribution of their corepressor. This transcriptional repression maintains Wnt signaling activity, preventing tau phosphorylation and promoting a healthy neuronal state in the context of AD.


Assuntos
Doença de Alzheimer , Receptor ERRalfa Relacionado ao Estrogênio , Peptídeos e Proteínas de Sinalização Intercelular , Receptores de Estrogênio , Animais , Humanos , Camundongos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Regulação da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Neurônios/metabolismo , Fosforilação , Regiões Promotoras Genéticas , Receptores de Estrogênio/metabolismo , Receptores de Estrogênio/genética , RNA Polimerase II/metabolismo , RNA Polimerase II/genética , Proteínas tau/metabolismo , Proteínas tau/genética , Via de Sinalização Wnt/genética
3.
J Biol Chem ; 300(9): 107677, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39151728

RESUMO

The tricarboxylic acid (TCA) cycle plays a crucial role in mitochondrial ATP production in the healthy heart. However, in heart failure, the TCA cycle becomes dysregulated. Understanding the mechanism by which TCA cycle genes are transcribed in the healthy heart is an important prerequisite to understanding how these genes become dysregulated in the failing heart. PPARγ coactivator 1α (PGC-1α) is a transcriptional coactivator that broadly induces genes involved in mitochondrial ATP production. PGC-1α potentiates its effects through the coactivation of coupled transcription factors, such as estrogen-related receptor (ERR), nuclear respiratory factor 1 (Nrf1), GA-binding protein-a (Gabpa), and Yin Yang 1 (YY1). We hypothesized that PGC-1α plays an essential role in the transcription of TCA cycle genes. Thus, utilizing localization peaks of PGC-1α to TCA cycle gene promoters would allow the identification of coupled transcription factors. PGC-1α potentiated the transcription of 13 out of 14 TCA cycle genes, partly through ERR, Nrf1, Gabpa, and YY1. ChIP-sequencing showed PGC-1α localization peaks in TCA cycle gene promoters. Transcription factors with binding elements that were found proximal to PGC-1α peak localization were generally essential for the transcription of the gene. These transcription factor binding elements were well conserved between mice and humans. Among the four transcription factors, ERR and Gabpa played a major role in potentiating transcription when compared to Nrf1 and YY1. These transcription factor-dependent PGC-1α recruitment was verified with Idh3a, Idh3g, and Sdha promoters with DNA binding assay. Taken together, this study clarifies the mechanism by which TCA cycle genes are transcribed, which could be useful in understanding how those genes are dysregulated in pathological conditions.


Assuntos
Ciclo do Ácido Cítrico , Fator 1 Nuclear Respiratório , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Receptores de Estrogênio , Fator de Transcrição YY1 , Fator de Transcrição YY1/metabolismo , Fator de Transcrição YY1/genética , Animais , Camundongos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Humanos , Receptores de Estrogênio/metabolismo , Receptores de Estrogênio/genética , Fator 1 Nuclear Respiratório/metabolismo , Fator 1 Nuclear Respiratório/genética , Fator de Transcrição de Proteínas de Ligação GA/metabolismo , Fator de Transcrição de Proteínas de Ligação GA/genética , Transcrição Gênica , Regulação da Expressão Gênica , Regiões Promotoras Genéticas , Miocárdio/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Receptor ERRalfa Relacionado ao Estrogênio
4.
Mol Pharmacol ; 106(4): 164-172, 2024 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-39168657

RESUMO

Autophagy is an essential self-degradative and recycling mechanism that maintains cellular homeostasis. Estrogen receptor-related orphan receptors (ERRs) are fundamental in regulating cardiac metabolism and function. Previously, we showed that ERR agonists improve cardiac function in models of heart failure and induce autophagy. Here, we characterized a mechanism by which ERRs induce the autophagy pathway in cardiomyocytes. Transcription factor EB (TFEB) is a master regulator of the autophagy-lysosome pathway and has been shown to be crucial regulator of genes that control autophagy. We discovered that TFEB is a direct ERR target gene whose expression is induced by ERR agonists. Activation of ERR results in increased TFEB expression in both neonatal rat ventricular myocytes and C2C12 myoblasts. An ERR-dependent increase in TFEB expression results in increased expression of an array of TFEB target genes, which are critical for the stimulation of autophagy. Pharmacologically targeting ERR is a promising potential method for the treatment of many diseases where stimulation of autophagy may be therapeutic, including heart failure. SIGNIFICANCE STATEMENT: Estrogen receptor-related receptor agonists function as exercise mimetics and also display efficacy in animal models of metabolic disease, obesity, and heart failure.


Assuntos
Autofagia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Miócitos Cardíacos , Receptores de Estrogênio , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Autofagia/fisiologia , Receptores de Estrogênio/metabolismo , Ratos , Camundongos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Humanos , Linhagem Celular , Receptor ERRalfa Relacionado ao Estrogênio , Ratos Sprague-Dawley
5.
J Pharmacol Exp Ther ; 388(2): 232-240, 2024 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-37739806

RESUMO

Physical exercise induces physiologic adaptations and is effective at reducing the risk of premature death from all causes. Pharmacological exercise mimetics may be effective in the treatment of a range of diseases including obesity and metabolic syndrome. Previously, we described the development of SLU-PP-332, an agonist for the estrogen-related receptor (ERR)α, ß, and γ nuclear receptors that activates an acute aerobic exercise program. Here we examine the effects of this exercise mimetic in mouse models of obesity and metabolic syndrome. Diet-induced obese or ob/ob mice were administered SLU-PP-332, and the effects on a range of metabolic parameters were assessed. SLU-PP-332 administration mimics exercise-induced benefits on whole-body metabolism in mice including increased energy expenditure and fatty acid oxidation. These effects were accompanied by decreased fat mass accumulation. Additionally, the ERR agonist effectively reduced obesity and improved insulin sensitivity in models of metabolic syndrome. Pharmacological activation of ERR may be an effective method to treat metabolic syndrome and obesity. SIGNIFICANCE STATEMENT: An estrogen receptor-related orphan receptor agonist, SLU-PP-332, with exercise mimetic activity, holds promise as a therapeutic to treat metabolic diseases by decreasing fat mass in mouse models of obesity.


Assuntos
Resistência à Insulina , Síndrome Metabólica , Camundongos , Animais , Síndrome Metabólica/tratamento farmacológico , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Metabolismo Energético , Receptores Citoplasmáticos e Nucleares , Receptor ERRalfa Relacionado ao Estrogênio , Estrogênios
6.
Immunity ; 43(1): 80-91, 2015 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-26200012

RESUMO

The orphan nuclear receptor estrogen-related receptor α (ERRα; NR3B1) is a key metabolic regulator, but its function in regulating inflammation remains largely unknown. Here, we demonstrate that ERRα negatively regulates Toll-like receptor (TLR)-induced inflammation by promoting Tnfaip3 transcription and fine-tuning of metabolic reprogramming in macrophages. ERRα-deficient (Esrra(-/-)) mice showed increased susceptibility to endotoxin-induced septic shock, leading to more severe pro-inflammatory responses than control mice. ERRα regulated macrophage inflammatory responses by directly binding the promoter region of Tnfaip3, a deubiquitinating enzyme in TLR signaling. In addition, Esrra(-/-) macrophages showed an increased glycolysis, but impaired mitochondrial respiratory function and biogenesis. Further, ERRα was required for the regulation of NF-κB signaling by controlling p65 acetylation via maintenance of NAD(+) levels and sirtuin 1 activation. These findings unravel a previously unappreciated role for ERRα as a negative regulator of TLR-induced inflammatory responses through inducing Tnfaip3 transcription and controlling the metabolic reprogramming.


Assuntos
Cisteína Endopeptidases/biossíntese , Inflamação/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Macrófagos/metabolismo , Receptores de Estrogênio/genética , Receptor 4 Toll-Like/imunologia , Acetilação , Animais , Cálcio/metabolismo , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Células Cultivadas , Cisteína Endopeptidases/genética , Ativação Enzimática/genética , Glicólise/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Lipopolissacarídeos , Macrófagos/imunologia , Camundongos , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/metabolismo , NAD/metabolismo , Fosforilação Oxidativa , Regiões Promotoras Genéticas/genética , Regiões Promotoras Genéticas/imunologia , Choque Séptico/imunologia , Transdução de Sinais , Sirtuína 1/metabolismo , Fator 6 Associado a Receptor de TNF/metabolismo , Fator de Transcrição RelA/metabolismo , Transcrição Gênica/genética , Proteína 3 Induzida por Fator de Necrose Tumoral alfa , Ubiquitinação , Receptor ERRalfa Relacionado ao Estrogênio
7.
Cell Mol Biol Lett ; 29(1): 87, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38867189

RESUMO

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disease and apolipoprotein E (APOE) genotypes (APOE2, APOE3, and APOE4) show different AD susceptibility. Previous studies indicated that individuals carrying the APOE2 allele reduce the risk of developing AD, which may be attributed to the potential neuroprotective role of APOE2. However, the mechanisms underlying the protective effects of APOE2 is still unclear. METHODS: We analyzed single-nucleus RNA sequencing and bulk RNA sequencing data of APOE2 and APOE3 carriers from the Religious Orders Study and Memory and Aging Project (ROSMAP) cohort. We validated the findings in SH-SY5Y cells and AD model mice by evaluating mitochondrial functions and cognitive behaviors respectively. RESULTS: The pathway analysis of six major cell types revealed a strong association between APOE2 and cellular stress and energy metabolism, particularly in excitatory and inhibitory neurons, which was found to be more pronounced in the presence of beta-amyloid (Aß). Moreover, APOE2 overexpression alleviates Aß1-42-induced mitochondrial dysfunction and reduces the generation of reactive oxygen species in SH-SY5Y cells. These protective effects may be due to ApoE2 interacting with estrogen-related receptor alpha (ERRα). ERRα overexpression by plasmids or activation by agonist was also found to show similar mitochondrial protective effects in Aß1-42-stimulated SH-SY5Y cells. Additionally, ERRα agonist treatment improve the cognitive performance of Aß injected mice in both Y maze and novel object recognition tests. ERRα agonist treatment increased PSD95 expression in the cortex of agonist-treated-AD mice. CONCLUSIONS: APOE2 appears to enhance neural mitochondrial function via the activation of ERRα signaling, which may be the protective effect of APOE2 to treat AD.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Apolipoproteína E2 , Receptor ERRalfa Relacionado ao Estrogênio , Mitocôndrias , Neurônios , Receptores de Estrogênio , Transdução de Sinais , Animais , Feminino , Humanos , Masculino , Camundongos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Apolipoproteína E2/genética , Apolipoproteína E2/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Mitocôndrias/metabolismo , Neurônios/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Estrogênio/genética
8.
Genes Dev ; 30(9): 1034-46, 2016 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-27151976

RESUMO

The tumor suppressor folliculin (FLCN) forms a repressor complex with AMP-activated protein kinase (AMPK). Given that AMPK is a master regulator of cellular energy homeostasis, we generated an adipose-specific Flcn (Adipoq-FLCN) knockout mouse model to investigate the role of FLCN in energy metabolism. We show that loss of FLCN results in a complete metabolic reprogramming of adipose tissues, resulting in enhanced oxidative metabolism. Adipoq-FLCN knockout mice exhibit increased energy expenditure and are protected from high-fat diet (HFD)-induced obesity. Importantly, FLCN ablation leads to chronic hyperactivation of AMPK, which in turns induces and activates two key transcriptional regulators of cellular metabolism, proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α) and estrogen-related receptor α (ERRα). Together, the AMPK/PGC-1α/ERRα molecular axis positively modulates the expression of metabolic genes to promote mitochondrial biogenesis and activity. In addition, mitochondrial uncoupling proteins as well as other markers of brown fat are up-regulated in both white and brown FLCN-null adipose tissues, underlying the increased resistance of Adipoq-FLCN knockout mice to cold exposure. These findings identify a key role of FLCN as a negative regulator of mitochondrial function and identify a novel molecular pathway involved in the browning of white adipocytes and the activity of brown fat.


Assuntos
Tecido Adiposo Bege/metabolismo , Metabolismo Energético/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Proteínas Proto-Oncogênicas/genética , Receptores de Estrogênio/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Quinases Ativadas por AMP/genética , Animais , Temperatura Baixa , Ativação Enzimática/genética , Regulação da Expressão Gênica/genética , Camundongos , Camundongos Knockout , Obesidade/enzimologia , Obesidade/genética , Oxirredução , Proteínas Proto-Oncogênicas/metabolismo , Receptores de Estrogênio/genética , Transdução de Sinais , Proteínas Supressoras de Tumor/metabolismo , Receptor ERRalfa Relacionado ao Estrogênio
9.
Int J Mol Sci ; 25(9)2024 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-38732013

RESUMO

The orphan nuclear receptor ERRα is the most extensively researched member of the estrogen-related receptor family and holds a pivotal role in various functions associated with energy metabolism, especially in tissues characterized by high energy requirements, such as the heart, skeletal muscle, adipose tissue, kidney, and brain. Abscisic acid (ABA), traditionally acknowledged as a plant stress hormone, is detected and actively functions in organisms beyond the land plant kingdom, encompassing cyanobacteria, fungi, algae, protozoan parasites, lower Metazoa, and mammals. Its ancient, cross-kingdom role enables ABA and its signaling pathway to regulate cell responses to environmental stimuli in various organisms, such as marine sponges, higher plants, and humans. Recent advancements in understanding the physiological function of ABA and its mammalian receptors in governing energy metabolism and mitochondrial function in myocytes, adipocytes, and neuronal cells suggest potential therapeutic applications for ABA in pre-diabetes, diabetes, and cardio-/neuroprotection. The ABA/LANCL1-2 hormone/receptor system emerges as a novel regulator of ERRα expression levels and transcriptional activity, mediated through the AMPK/SIRT1/PGC-1α axis. There exists a reciprocal feed-forward transcriptional relationship between the LANCL proteins and transcriptional coactivators ERRα/PGC-1α, which may be leveraged using natural or synthetic LANCL agonists to enhance mitochondrial function across various clinical contexts.


Assuntos
Ácido Abscísico , Receptor ERRalfa Relacionado ao Estrogênio , Metabolismo Energético , Receptores de Estrogênio , Receptores de Estrogênio/metabolismo , Humanos , Animais , Ácido Abscísico/metabolismo , Transdução de Sinais , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética
10.
Mol Med ; 29(1): 76, 2023 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-37340376

RESUMO

BACKGROUND: Sepsis-induced acute lung injury (ALI) is associated with poor survival rates. The identification of potential therapeutic targets for preventing sepsis-induced ALI has clinical importance. This study aims to investigate the role of estrogen-related receptor alpha (ERRα) in sepsis-induced ALI. METHODS: Lipopolysaccharide (LPS) was used to simulate sepsis-induced ALI model in rat pulmonary microvascular endothelial cells (PMVECs). The effects of ERRα overexpression and knockdown on LPS-induced endothelial permeability, apoptosis and autophagy were determined by horseradish peroxidase permeability assay, TdT-mediated dUTP Nick End Labeling (TUNEL) assay, flow cytometry, immunofluorescence staining, RT-PCR and Western Blotting. The rat model with sepsis-induced ALI was established by cecal ligation and puncture in anesthetized rats to verify the results of in vitro experiments. Animals were randomly assigned to receive intraperitoneal injection of vehicle or ERRα agonist. Lung vascular permeability, pathological injury, apoptosis and autophagy were examined. RESULTS: Overexpression of ERRα ameliorated LPS-induced endothelial hyperpermeability, degradation of adherens junctional molecules, upregulation of bax, cleaved caspase 3 and cleaved caspase 9 levels, downregulation of anti-apoptotic protein Bcl-2 level, and promoted the formation of autophagic flux, while the knockdown of ERRα exacerbated LPS-induced apoptosis and inhibited the activation of autophagy. Administration of ERRα agonist alleviated the pathological damage of lung tissue, increased the levels of tight junction proteins and adherens junction proteins, and decreased the expression of apoptosis-related proteins. Promoting the expression of ERRα significantly enhanced the process of autophagy and reduced CLP-induced ALI. Mechanistically, ERRα is essential to regulate the balance between autophagy and apoptosis to maintain the adherens junctional integrity. CONCLUSION: ERRα protects against sepsis-induced ALI through ERRα-mediated apoptosis and autophagy. Activation of ERRα provides a new therapeutic opportunity to prevent sepsis-induced ALI.


Assuntos
Lesão Pulmonar Aguda , Sepse , Ratos , Animais , Lipopolissacarídeos , Células Endoteliais/metabolismo , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/prevenção & controle , Lesão Pulmonar Aguda/tratamento farmacológico , Pulmão/patologia , Sepse/metabolismo , Receptor ERRalfa Relacionado ao Estrogênio
11.
Anal Chem ; 95(20): 8121-8127, 2023 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-37166172

RESUMO

In this work, a simple and sensitive electrochemiluminescence (ECL) biosensor has been devised based on target-induced steric hindrance of an antibody-modified electrode surface. Estrogen-related receptor alpha (ERRα) is closely related to estrogen-dependent tumors, which had been chosen as a model target. The ERRα antigen can bind to the antibody modified on the electrode surface with high specificity and results in the increase of steric hindrance, which prevented the ECL indicators (tris(2,2'-bipyridine) dichlororuthenium(II) hexahydrate) from approaching the electrode surface, and the ECL intensity of the system decreased. The ECL response of the system has a good linear relationship with ERRα concentration in the range of 1.0-60 ng/L, and the limit of detection is 0.5 ng/L. Different from the traditional sandwiched immune ECL detection system, which need the modification of ECL indicators on the secondary antibody, only one antibody had been used in this system. The system is easy to operate and has good sensitivity. The designed biosensor has been applied to detect ERRα in the serum and different cell line samples with satisfied results.


Assuntos
Técnicas Biossensoriais , Medições Luminescentes , Medições Luminescentes/métodos , Anticorpos , Eletrodos , Técnicas Biossensoriais/métodos , Técnicas Eletroquímicas/métodos , Limite de Detecção , Receptor ERRalfa Relacionado ao Estrogênio
12.
Cell Biol Toxicol ; 39(3): 813-825, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-34524571

RESUMO

Chemotherapy resistance is an important problem for clinical therapy of osteosarcoma (OS). The potential effects of histone deacetylases (HDACs) on OS chemoresistance are studied. The expression of HDACs in OS cells resistance to doxorubicin (Dox) and cisplatin (CDDP) is checked. Among 11 members of HDACs, levels of HDAC6 are significantly upregulated in OS cells resistance to Dox and CDDP. Inhibition of HDAC6 via its specific inhibitor ACY1215 restores chemosensitivity of OS-resistant cells. Further, HDAC6 directly binds with estrogen-related receptors alpha (ERRα) to regulate its acetylation and protein stability. Inhibition of ERRα further strengthens ACY1215-increased chemosensitivity of OS-resistant cells. Mechanistically, K129 acetylation is the key residue for HDAC6-regulated protein levels of ERRα. Collectively, we find that ERRα contributes to HDAC6-induced chemoresistance of OS cells. Inhibition of HDAC6/ERRα axis might be a potential approach to overcome chemoresistance and improve therapy efficiency for OS treatment. 1. HDAC6 was significantly upregulated in Dox and CDDP resistant OS cells; 2. Inhibition of HDAC6 can restore chemosensitivity of OS cells; 3. HDAC6 binds with ERRα at K129 to decrease its acetylation and increase protein stability; 4. ERRα contributes to HDAC6-induced chemoresistance of OS cells.


Assuntos
Neoplasias Ósseas , Osteossarcoma , Humanos , Resistencia a Medicamentos Antineoplásicos , Osteossarcoma/tratamento farmacológico , Osteossarcoma/metabolismo , Cisplatino/farmacologia , Doxorrubicina/farmacologia , Linhagem Celular Tumoral , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/metabolismo , Desacetilase 6 de Histona/metabolismo , Desacetilase 6 de Histona/farmacologia , Desacetilase 6 de Histona/uso terapêutico , Receptor ERRalfa Relacionado ao Estrogênio
13.
J Pediatr Gastroenterol Nutr ; 77(3): 354-357, 2023 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-37347142

RESUMO

Non-caseating granulomas may indicate a more aggressive phenotype of Crohn disease (CD). Genetic associations of granulomatous CD (GCD) may help elucidate disease pathogenesis. Whole-exome sequencing was performed on peripheral blood-derived DNA from 17 pediatric patients with GCD and 19 with non-GCD (NGCD), and from an independent validation cohort of 44 GCD and 19 NGCD cases. PLINK (a tool set for whole-genome association and population-based linkage analyses) analysis was used to identify single nucleotide polymorphisms (SNPs) differentiating between groups, and subgroup allele frequencies were also compared to a public genomic database (gnomAD). The Combined Annotation Dependent Depletion scoring tool was used to predict deleteriousness of SNPs. Human leukocyte antigen (HLA) haplotype findings were compared to a control group (n = 8496). PLINK-based analysis between GCD and NGCD groups did not find consistently significant hits. gnomAD control comparisons, however, showed consistent subgroup associations with DGKZ , ESRRA , and GXYLT1 , genes that have been implicated in mammalian granulomatous inflammation. Our findings may guide future research and precision medicine.


Assuntos
Doença de Crohn , Criança , Humanos , Doença de Crohn/complicações , Sequenciamento do Exoma , Predisposição Genética para Doença , Granuloma/genética , Granuloma/patologia , Fenótipo , Receptor ERRalfa Relacionado ao Estrogênio
14.
Nature ; 546(7659): 544-548, 2017 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-28614293

RESUMO

Brown adipose tissue is a thermogenic organ that dissipates chemical energy as heat to protect animals against hypothermia and to counteract metabolic disease. However, the transcriptional mechanisms that determine the thermogenic capacity of brown adipose tissue before environmental cold are unknown. Here we show that histone deacetylase 3 (HDAC3) is required to activate brown adipose tissue enhancers to ensure thermogenic aptitude. Mice with brown adipose tissue-specific genetic ablation of HDAC3 become severely hypothermic and succumb to acute cold exposure. Uncoupling protein 1 (UCP1) is nearly absent in brown adipose tissue lacking HDAC3, and there is also marked downregulation of mitochondrial oxidative phosphorylation genes resulting in diminished mitochondrial respiration. Remarkably, although HDAC3 acts canonically as a transcriptional corepressor, it functions as a coactivator of oestrogen-related receptor α (ERRα) in brown adipose tissue. HDAC3 coactivation of ERRα is mediated by deacetylation of PGC-1α and is required for the transcription of Ucp1, Ppargc1a (encoding PGC-1α), and oxidative phosphorylation genes. Importantly, HDAC3 promotes the basal transcription of these genes independently of adrenergic stimulation. Thus, HDAC3 uniquely primes Ucp1 and the thermogenic transcriptional program to maintain a critical capacity for thermogenesis in brown adipose tissue that can be rapidly engaged upon exposure to dangerously cold temperature.


Assuntos
Tecido Adiposo Marrom/metabolismo , Regulação da Expressão Gênica , Histona Desacetilases/metabolismo , Termogênese , Animais , Respiração Celular , Temperatura Baixa , Elementos Facilitadores Genéticos/genética , Temperatura Alta , Humanos , Masculino , Camundongos , Mitocôndrias/metabolismo , Fosforilação Oxidativa , 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/metabolismo , Termogênese/genética , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo , Receptor ERRalfa Relacionado ao Estrogênio
15.
Phytother Res ; 37(11): 5407-5417, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37563852

RESUMO

Angelica sinensis polysaccharide (ASP) showed increasingly recognized hepatoprotective effects and lipid regulation. Because polysaccharides are typically degraded into fragments or short-chain fatty acids in the gut, rather than being absorbed in their intact form, it is worth pondering why ASP can regulate hepatic lipid metabolism and protect the liver from damage caused by lipid accumulation. In vivo and in vitro nonalcoholic fatty liver disease (NAFLD) models with lipid accumulation were established to investigate the effect and potential mechanisms of ASP on hepatic fat accumulation. Our results showed that ASP remodeled the composition and abundance of the gut microbiota in high-fat diet-fed mice and increased their levels of propionate (0.92 ± 0.30 × 107 vs. 2.13 ± 0.52 × 107 ) and butyrate (1.83 ± 1.31 × 107 vs. 6.39 ± 1.44 × 107 ). Sodium propionate significantly increased the expression of estrogen-related receptor α (ERRα) in liver cells (400 mM sodium propionate for 2.19-fold increase) and alleviated the progress of NAFLD in methionine-choline-deficient diet model. Taken together, our study demonstrated that ASP can regulate hepatic lipid metabolism via propionate/ERRα pathway and ultimately relieving NAFLD. Our findings demonstrate that ASP can be used as a health care product or food supplement to prevent NAFLD.


Assuntos
Angelica sinensis , Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Propionatos , Fígado/metabolismo , Polissacarídeos/farmacologia , Polissacarídeos/metabolismo , Dieta Hiperlipídica/efeitos adversos , Camundongos Endogâmicos C57BL , Receptor ERRalfa Relacionado ao Estrogênio
16.
Int J Mol Sci ; 24(4)2023 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-36835419

RESUMO

Estrogen-related receptor alpha (ERRα) plays an important role in endometrial cancer (EC) progression. However, the biological roles of ERRα in EC invasion and metastasis are not clear. This study aimed to investigate the role of ERRα and 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) in regulating intracellular cholesterol metabolism to promote EC progression. ERRα and HMGCS1 interactions were detected by co-immunoprecipitation, and the effects of ERRα/HMGCS1 on the metastasis of EC were investigated by wound-healing and transwell chamber invasion assays. Cellular cholesterol content was measured to verify the relationship between ERRα and cellular cholesterol metabolism. Additionally, immunohistochemistry was performed to confirm that ERRα and HMGCS1 were related to EC progression. Furthermore, the mechanism was investigated using loss-of-function and gain-of-function assays or treatment with simvastatin. High expression levels of ERRα and HMGCS1 promoted intracellular cholesterol metabolism for invadopodia formation. Moreover, inhibiting ERRα and HMGCS1 expression significantly weakened the malignant progression of EC in vitro and in vivo. Our functional analysis showed that ERRα promoted EC invasion and metastasis through the HMGCS1-mediated intracellular cholesterol metabolism pathway, which was dependent on the epithelial-mesenchymal transition pathway. Our findings suggest that ERRα and HMGCS1 are potential targets to suppress EC progression.


Assuntos
Neoplasias do Endométrio , Podossomos , Feminino , Humanos , Linhagem Celular Tumoral , Neoplasias do Endométrio/patologia , Hidroximetilglutaril-CoA Sintase , Podossomos/fisiologia , Receptores de Estrogênio/metabolismo , Invasividade Neoplásica , Metástase Neoplásica , Receptor ERRalfa Relacionado ao Estrogênio
17.
Int J Mol Sci ; 24(5)2023 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-36901694

RESUMO

Estrogen-related receptors (ERRα, ß and γ in mammals) are orphan members of the nuclear receptor superfamily acting as transcription factors. ERRs are expressed in several cell types and they display various functions in normal and pathological contexts. Amongst others, they are notably involved in bone homeostasis, energy metabolism and cancer progression. In contrast to other nuclear receptors, the activities of the ERRs are apparently not controlled by a natural ligand but they rely on other means such as the availability of transcriptional co-regulators. Here we focus on ERRα and review the variety of co-regulators that have been identified by various means for this receptor and their reported target genes. ERRα cooperates with distinct co-regulators to control the expression of distinct sets of target genes. This exemplifies the combinatorial specificity of transcriptional regulation that induces discrete cellular phenotypes depending on the selected coregulator. We finally propose an integrated view of the ERRα transcriptional network.


Assuntos
Redes Reguladoras de Genes , Receptores de Estrogênio , Animais , Regulação da Expressão Gênica , Mamíferos/metabolismo , Receptores de Estrogênio/metabolismo , Fatores de Transcrição/metabolismo , Humanos , Receptor ERRalfa Relacionado ao Estrogênio
18.
Int J Mol Sci ; 24(9)2023 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-37175690

RESUMO

Under low oxygen conditions (hypoxia), cells activate survival mechanisms including metabolic changes and angiogenesis, which are regulated by HIF-1. The estrogen-related receptor alpha (ERRα) is a transcription factor with important roles in the regulation of cellular metabolism that is overexpressed in hypoxia, suggesting that it plays a role in cell survival in this condition. This review enumerates and analyses the recent evidence that points to the role of ERRα as a regulator of hypoxic genes, both in cooperation with HIF-1 and through HIF-1- independent mechanisms, in invertebrate and vertebrate models and in physiological and pathological scenarios. ERRα's functions during hypoxia include two mechanisms: (1) direct ERRα/HIF-1 interaction, which enhances HIF-1's transcriptional activity; and (2) transcriptional activation by ERRα of genes that are classical HIF-1 targets, such as VEGF or glycolytic enzymes. ERRα is thus gaining recognition for its prominent role in the hypoxia response, both in the presence and absence of HIF-1. In some models, ERRα prepares cells for hypoxia, with important clinical/therapeutic implications.


Assuntos
Neoplasias , Fatores de Transcrição , Humanos , Hipóxia Celular , Hipóxia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias/genética , Receptores de Estrogênio/metabolismo , Fatores de Transcrição/metabolismo , Receptor ERRalfa Relacionado ao Estrogênio
19.
J Biol Chem ; 297(1): 100825, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34029594

RESUMO

Normal contractile function of the heart depends on a constant and reliable production of ATP by cardiomyocytes. Dysregulation of cardiac energy metabolism can result in immature heart development and disrupt the ability of the adult myocardium to adapt to stress, potentially leading to heart failure. Further, restoration of abnormal mitochondrial function can have beneficial effects on cardiac dysfunction. Previously, we identified a novel protein termed Perm1 (PGC-1 and estrogen-related receptor (ERR)-induced regulator, muscle 1) that is enriched in skeletal and cardiac-muscle mitochondria and transcriptionally regulated by PGC-1 (peroxisome proliferator-activated receptor gamma coactivator 1) and ERR. The role of Perm1 in the heart is poorly understood and is studied here. We utilized cell culture, mouse models, and human tissue, to study its expression and transcriptional control, as well as its role in transcription of other factors. Critically, we tested Perm1's role in cardiomyocyte mitochondrial function and its ability to protect myocytes from stress-induced damage. Our studies show that Perm1 expression increases throughout mouse cardiogenesis, demonstrate that Perm1 interacts with PGC-1α and enhances activation of PGC-1 and ERR, increases mitochondrial DNA copy number, and augments oxidative capacity in cultured neonatal mouse cardiomyocytes. Moreover, we found that Perm1 reduced cellular damage produced as a result of hypoxia and reoxygenation-induced stress and mitigated cell death of cardiomyocytes. Taken together, our results show that Perm1 promotes mitochondrial biogenesis in mouse cardiomyocytes. Future studies can assess the potential of Perm1 to be used as a novel therapeutic to restore cardiac dysfunction induced by ischemic injury.


Assuntos
Mitocôndrias Cardíacas/metabolismo , Proteínas Musculares/metabolismo , Miócitos Cardíacos/metabolismo , Biogênese de Organelas , Oxigênio/metabolismo , Animais , Hipóxia Celular , DNA Mitocondrial/genética , Regulação para Baixo/genética , Coração/embriologia , Insuficiência Cardíaca/genética , Ventrículos do Coração/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos Endogâmicos C57BL , Proteínas Musculares/genética , Oxirredução , Fosforilação Oxidativa , Regiões Promotoras Genéticas/genética , Biossíntese de Proteínas , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Estrogênio/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcrição Gênica , Receptor ERRalfa Relacionado ao Estrogênio
20.
Mol Cancer ; 21(1): 77, 2022 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-35303882

RESUMO

BACKGROUND: The use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) brings remarkable benefits for the survival of patients with advanced NSCLC harboring EGFR mutations. Unfortunately, acquired resistance seems to be inevitable and limits the application of EGFR-TKIs in clinical practice. This study reported a common molecular mechanism sustaining resistance and potential treatment options to overcome EGFR-TKIs resistance. METHODS: EGFR-TKIs resistant NSCLC cells were established and confirmed by MTT assay. Cholesterol content was detected and the promotional function of cholesterol on NSCLC growth was determined in vivo. Then, we identified ERRα expression as the downstream factor of cholesterol-mediated drug resistance. To dissect the regulatory mechanism, we conducted experiments, including immunofluorescence, co-immunoprecipitation, luciferase reporter assay and chromatin immunoprecipitation assay. RESULTS: Long-term exposure to EGFR-TKIs generate drug resistance with the characteristic of cholesterol accumulation in lipid rafts, which promotes EGFR and Src to interact and lead EGFR/Src/Erk signaling reactivation-mediated SP1 nuclear translocation and ERRα re-expression. Further investigation identifies ERRα as a target gene of SP1. Functionally, re-expression of ERRα sustains cell proliferation by regulating ROS detoxification process. Lovastatin, a drug used to decrease cholesterol level, and XCT790, an inverse agonist of ERRα, overcome gefitinib and osimertinib resistance both in vitro and in vivo. CONCLUSIONS: Our study indicates that cholesterol/EGFR/Src/Erk/SP1 axis-induced ERRα re-expression promotes survival of gefitinib and osimertinib-resistant cancer cells. Besides, we demonstrate the potential of lowing cholesterol and downregulation of ERRα as effective adjuvant treatment of NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Colesterol/farmacologia , Colesterol/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/genética , Gefitinibe/farmacologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Receptores de Estrogênio , Fator de Transcrição Sp1/genética , Receptor ERRalfa Relacionado ao Estrogênio
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