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1.
Theranostics ; 10(9): 4233-4249, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32226550

RESUMO

Rationale: Subjects unable to sustain ß-cell compensation develop type 2 diabetes. Early growth response-1 protein (EGR-1), implicated in the regulation of cell differentiation, proliferation, and apoptosis, is induced by diverse metabolic challenges, such as glucose or other nutrients. Therefore, we hypothesized that deficiency of EGR-1 might influence ß-cell compensation in response to metabolic overload. Methods: Mice deficient in EGR-1 (Egr1-/-) were used to investigate the in vivo roles of EGR-1 in regulation of glucose homeostasis and beta-cell compensatory responses. Results: In response to a high-fat diet, Egr1-/- mice failed to secrete sufficient insulin to clear glucose, which was associated with lower insulin content and attenuated hypertrophic response of islets. High-fat feeding caused a dramatic impairment in glucose-stimulated insulin secretion and downregulated the expression of genes encoding glucose sensing proteins. The cells co-expressing both insulin and glucagon were dramatically upregulated in islets of high-fat-fed Egr1-/- mice. EGR-1-deficient islets failed to maintain the transcriptional network for ß-cell compensatory response. In human pancreatic tissues, EGR1 expression correlated with the expression of ß-cell compensatory genes in the non-diabetic group, but not in the diabetic group. Conclusion: These results suggest that EGR-1 couples the transcriptional network to compensation for the loss of ß-cell function and identity. Thus, our study highlights the early stress coupler EGR-1 as a critical factor in the development of pancreatic islet failure.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Proteína 1 de Resposta de Crescimento Precoce/fisiologia , Glucose/metabolismo , Células Secretoras de Insulina/metabolismo , Animais , Linhagem Celular Tumoral , Glucagon/metabolismo , Insulina/metabolismo , Células Secretoras de Insulina/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
2.
J Mol Med (Berl) ; 93(7): 807-18, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25737480

RESUMO

UNLABELLED: Pancreatic ß-cells are particularly susceptible to fatty-acid-induced endoplasmic reticulum (ER) stress and apoptosis. To understand how ß-cells sense fatty acid stimuli and translate into a long-term adaptive response, we investigated whether palmitic acid (PA) regulates early growth response-1 (Egr-1), an immediate-early transcription factor, which is induced by many environmental stimuli and implicated in cell proliferation, differentiation, and apoptosis. We found that Egr-1 was rapidly and transiently induced by PA in MIN6 insulinoma cells, which was accompanied by calcium influx and ERK1/2 phosphorylation. Calcium chelation and MEK1/2 inhibition blocked PA-induced Egr-1 upregulation, suggesting that PA induces Egr-1 expression through a calcium influx-MEK1/2-ERK1/2 cascade. Knockdown of Egr-1 increased PA-induced caspase-3 activation and ER stress markers and decreased PA-induced Akt phosphorylation and insulin secretion and signaling. Akt replenishment and insulin supplementation rescued PA-induced apoptosis in Egr-1 knockdown cells. These results suggest that the absence of Egr-1 loses its ability to couple the short-term insulin/Akt pathway to long-term survival adaptation. Finally, Egr-1-deficient mouse islets are more susceptible to ex vivo stimuli of apoptosis. In human pancreatic tissues, EGR1 expression correlated with expression of ER stress markers and anti-apoptotic gene. In conclusion, Egr-1 is induced by PA and further attempts to rescue ß-cells from ER stress and apoptosis through improving insulin/Akt signaling. Our study underscores Egr-1 as a critical early sensor in pancreatic ß-cells to translate fatty acid stimuli into a cellular adaptation mechanism. KEY MESSAGE: PA stimulates Egr-1 expression via a calcium influx-MEK1/2-ERK1/2-Elk-1 cascade. Egr-1 attenuates PA-induced ER stress and apoptosis. Egr-1 maintains Akt survival pathway to protect ß-cells from PA-induced apoptosis. Egr-1-deficient islets are prone to ex vivo stimuli of apoptosis. Human EGR1 expression correlates with genes for ER stress and anti-apoptosis.


Assuntos
Apoptose/genética , Proteína 1 de Resposta de Crescimento Precoce/genética , Estresse do Retículo Endoplasmático/genética , Células Secretoras de Insulina/patologia , Ácido Palmítico/farmacologia , Animais , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Caspase 3/metabolismo , Linhagem Celular , Retículo Endoplasmático/patologia , Estresse do Retículo Endoplasmático/fisiologia , Ativação Enzimática , Fator de Iniciação 2 em Eucariotos/metabolismo , Humanos , Insulina/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , MAP Quinase Quinase 1/antagonistas & inibidores , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Palmitatos , Fosforilação/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , RNA Interferente Pequeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
3.
Mol Cell Biol ; 32(2): 309-19, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22083962

RESUMO

Mitochondrial dysfunction in skeletal muscle has been implicated in the development of insulin resistance and type 2 diabetes. Considering the importance of mitochondrial dynamics in mitochondrial and cellular functions, we hypothesized that obesity and excess energy intake shift the balance of mitochondrial dynamics, further contributing to mitochondrial dysfunction and metabolic deterioration in skeletal muscle. First, we revealed that excess palmitate (PA), but not hyperglycemia, hyperinsulinemia, or elevated tumor necrosis factor alpha, induced mitochondrial fragmentation and increased mitochondrion-associated Drp1 and Fis1 in differentiated C2C12 muscle cells. This fragmentation was associated with increased oxidative stress, mitochondrial depolarization, loss of ATP production, and reduced insulin-stimulated glucose uptake. Both genetic and pharmacological inhibition of Drp1 attenuated PA-induced mitochondrial fragmentation, mitochondrial depolarization, and insulin resistance in C2C12 cells. Furthermore, we found smaller and shorter mitochondria and increased mitochondrial fission machinery in the skeletal muscle of mice with genetic obesity and those with diet-induced obesity. Inhibition of mitochondrial fission improved the muscle insulin signaling and systemic insulin sensitivity of obese mice. Our findings indicated that aberrant mitochondrial fission is causally associated with mitochondrial dysfunction and insulin resistance in skeletal muscle. Thus, disruption of mitochondrial dynamics may underlie the pathogenesis of muscle insulin resistance in obesity and type 2 diabetes.


Assuntos
Resistência à Insulina , Mitocôndrias Musculares/metabolismo , Mitocôndrias Musculares/patologia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Obesidade/metabolismo , Obesidade/patologia , Animais , Linhagem Celular , Dinaminas/metabolismo , Ácidos Graxos/metabolismo , Glucose/metabolismo , Camundongos , Mitocôndrias Musculares/química , Proteínas Mitocondriais/metabolismo , Ácido Palmítico/metabolismo , Proteínas Quinases/metabolismo , Espécies Reativas de Oxigênio/metabolismo
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