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Exp Cell Res ; 382(1): 111467, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31202710

RESUMO

Hyperglycemia and hyperlipidemia (glycolipotoxicity)-triggered islet ß-cell dysfunction is known to drive the progression of obesity-related type 2 diabetes, however the underlying mechanisms have not been clearly elucidated. The current study aimed to investigate the role of mitogen-activated protein kinase phosphatase 5 (MKP-5) in islet cells under glucolipotoxic conditions. Using gene overexpression and knockdown approaches, we demonstrated that MKP-5 could alleviate glucolipotoxicity-induced apoptosis via the endoplasmic reticulum (ER) stress and mitochondrial apoptosis pathways owing to the altered regulation of caspase family members and ER stress-related molecules in MIN6 and primary islet cells. Overexpression of MKP-5 reversed the glucose and palmitic acid (GP)-induced impairment of insulin secretion as well as the abnormal decreases in the expression of islet functional genes, thereby maintaining the normal insulin secretory functionality, whereas the absence of MKP-5 aggravated islet cell dysfunction. In parallel, the production of ROS and increased inflammation-associated genes in response to GP were also reduced upon MKP-5 overexpression. Further, inhibition of JNK or P38 MAPK pathways resisted to glucolipotoxicity observed in MKP-5 knockdown MIN6 cells. These findings indicate that MKP-5 is an important mediator for glucolipotoxicity-induced islet cell dysfunction and apoptosis, with JNK and P38 as the critical downstream pathways.


Assuntos
Apoptose/fisiologia , Fosfatases de Especificidade Dupla/fisiologia , Estresse do Retículo Endoplasmático/fisiologia , Glucose/toxicidade , Ilhotas Pancreáticas/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/fisiologia , Fosfatases da Proteína Quinase Ativada por Mitógeno/fisiologia , Palmitatos/toxicidade , Animais , Linhagem Celular Tumoral , Dieta Hiperlipídica/efeitos adversos , Fosfatases de Especificidade Dupla/genética , Técnicas de Silenciamento de Genes , Humanos , Insulina/metabolismo , Insulinoma/patologia , Ilhotas Pancreáticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Fosfatases da Proteína Quinase Ativada por Mitógeno/genética , Neoplasias Pancreáticas/patologia , Proteínas Recombinantes/metabolismo , Regulação para Cima
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