RESUMO
O-GlcNAcylation, a nutritionally driven, post-translational modification of proteins, is gaining importance because of its health implications. Changes in O-GlcNAcylation are observed in various disease conditions. Changes in O-GlcNAcylation by diet that causes hypercholesterolemia are not critically looked into in the liver. To address it, both in vitro and in vivo approaches were employed. Hypercholesterolemia was induced individually by feeding cholesterol (H)/high-fat (HF) diet. Global O-GlcNAcylation levels and modulation of AMPK activation in both preventive and curative approaches were looked into. Diet-induced hypercholesterolemia resulted in decreased O-GlcNAcylation of liver proteins which was associated with decreased O-linked N-acetylglucosaminyltransferase (OGT) and Glutamine fructose-6-phosphate amidotransferase-1 (GFAT1). Activation of AMPK by metformin in preventive mode restored the O-GlcNAcylation levels; however, metformin treatment of HepG2 cells in curative mode restored O-GlcNAcylation levels in HF but failed to in H condition (at 24 h). Further, maternal faulty diet resulted in decreased O-GlcNAcylation in pup liver despite feeding normal diet till adulthood. A faulty diet modulates global O-GlcNAcylation of liver proteins which is accompanied by decreased AMPK activation which could exacerbate metabolic syndromes through fat accumulation in the liver. (AU)
Assuntos
Hipercolesterolemia , Doenças Metabólicas , Vias Biossintéticas , HexosaminasRESUMO
O-GlcNAcylation, a nutritionally driven, post-translational modification of proteins, is gaining importance because of its health implications. Changes in O-GlcNAcylation are observed in various disease conditions. Changes in O-GlcNAcylation by diet that causes hypercholesterolemia are not critically looked into in the liver. To address it, both in vitro and in vivo approaches were employed. Hypercholesterolemia was induced individually by feeding cholesterol (H)/high-fat (HF) diet. Global O-GlcNAcylation levels and modulation of AMPK activation in both preventive and curative approaches were looked into. Diet-induced hypercholesterolemia resulted in decreased O-GlcNAcylation of liver proteins which was associated with decreased O-linked N-acetylglucosaminyltransferase (OGT) and Glutamine fructose-6-phosphate amidotransferase-1 (GFAT1). Activation of AMPK by metformin in preventive mode restored the O-GlcNAcylation levels; however, metformin treatment of HepG2 cells in curative mode restored O-GlcNAcylation levels in HF but failed to in H condition (at 24 h). Further, maternal faulty diet resulted in decreased O-GlcNAcylation in pup liver despite feeding normal diet till adulthood. A faulty diet modulates global O-GlcNAcylation of liver proteins which is accompanied by decreased AMPK activation which could exacerbate metabolic syndromes through fat accumulation in the liver. (AU)
Assuntos
Hipercolesterolemia , Doenças Metabólicas , Vias Biossintéticas , HexosaminasRESUMO
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Assuntos
Humanos , Retinopatia Diabética/genética , MicroRNAs/genética , Neovascularização Patológica/genética , Glicemia/análise , Retinopatia Diabética/sangue , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/fisiopatologia , Regulação da Expressão Gênica/genética , Produtos Finais de Glicação Avançada/sangue , Hexosaminas/sangue , MicroRNAs/isolamento & purificação , Neovascularização Patológica/fisiopatologia , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Álcoois Açúcares/sangue , Lágrimas/química , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/fisiologiaRESUMO
Las incretinas son una serie de hormonas que tras una ingesta de alimentos son secretadas y liberadas al torrente sanguíneo por células enteroendocrinas del intestino, llegando al páncreas, donde producen un efecto potenciador en la liberación de insulina. El objetivo de este trabajo ha sido realizar una revisión sistemática de la modulación de la expresión génica de las incretinas mediada por nutrientes utilizando ecuaciones especificas de búsqueda en la base de datos PubMed. Las dos incretinas mas relevantes son el péptido análogo al glucagón 1 (GLP-1) y el péptido insulinotrópico dependiente de glucosa (GIP), que provienen de los precursores proglucagón y proGIP, respectivamente. GLP-1 es mayoritariamente sintetizado y secretado por las células L del ileon y del colon, a diferencia de GIP que lo hace por las células K de duodeno y yeyuno proximal. Se ha demostrado que la ruta canónica de señalización Wnt esta estrechamente relacionada con la producción de estas hormonas, ya que el factor de transcripción TCF7L2 influye en la expresión génica de proglucagón y proGIP en células enteroendocrinas L y K. Por otra parte, se ha demostrado que la ruta biosintetica de las hexosaminas es capaz de glicosilar la β-catenina, componente fundamental de la señalización canonica Wnt, lo que interfiere en la fosforilacion de esta proteína, impidiendo así su degradación en el proteasoma. El aumento de la concentración de glucosa incrementa la ruta de las hexosaminas y de esta manera la glicosilación de la β-catenina. Esto produce una acumulación de esta proteína en el citoplasma celular y permite su entrada al núcleo, donde ejerce su acción al unirse a una serie de moléculas y factores de transcripción, permitiendo de este modo que se expresen los genes diana, entre los que se encuentran los de las hormonas incretinas. También hay evidencias de que la glucosa, a través de la ruta de las hexosaminas, es capaz de inducir la activación autocrina de la ruta de señalización Wnt estimulando la secreción de proteínas Wnt (AU)
Incretins are a cluster of hormones which are secreted and released into the bloodstream after food intake by gutenteroendocrine cells, reaching to pancreas where produce a potentiating effect on insulin release. The aim of this study was to perform a systematic review of incretins gene expression mediated by nutrients using specific search equations in the Pub Med database. The two most relevant incretins are GLP-1 and GIP, which come from proglucagon and pro GIP precursor respectively. GLP-1is mainly synthesized and released by ileum and colon Lcells, in contrast to GIP which does it by K cells in duodenum and proximal jejunum. It has been shown that canonical Wnt signalling pathway is closely related to the production of these hormones, since transcription factorTCF7L2 affects proglucagon and proGIP gene expression in L and K enteroendocrine cells. On the other hand, it has been shown that the hexosamine biosynthetic pathway can produce N-linked glycosylation of -catenin, an essential component of canonical Wnt signalling. This process hinders β-catenin phosphorylation and, there by prevents proteasome degradation. Increasing glucose concentration enhances the hexosamine pathway and thusβ-catenin glycosylation. This causes a β-catenin cytoplasmic accumulation allowing entry into nucleus, where itexerts its action by binding to a clump of molecules andtranscription factors, allowing to express the target genes ,including the incretin hormones. There is also evidence that glucose, through the hexosamine pathway, can induces autocrine activation of Wnt signalling pathway by stimulating secretion of Wnt protein (AU)
