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首页> 外文期刊>Nature >Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1 alpha interaction
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Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1 alpha interaction

机译：通过FOXO1-PGC-1α相互作用的胰岛素调节肝糖异生

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Hepatic gluconeogenesis is absolutely required for survival during prolonged fasting or starvation, but is inappropriately activated in diabetes mellitus. Glucocorticoids and glucagon have strong gluconeogenic actions on the liver. In contrast, insulin suppresses hepatic gluconeogenesis(1-3). Two components known to have important physiological roles in this process are the forkhead transcription factor FOXO1 (also known as FKHR) and peroxisome proliferative activated receptor-gamma co-activator 1 (PGC-1alpha; also known as PPARGC1), a transcriptional co-activator; whether and how these factors collaborate has not been clear. Using wild-type and mutant alleles of FOXO1, here we show that PGC-1alpha binds and co-activates FOXO1 in a manner inhibited by Akt-mediated phosphorylation. Furthermore, FOXO1 function is required for the robust activation of gluconeogenic gene expression in hepatic cells and in mouse liver by PGC-1alpha. Insulin suppresses gluconeogenesis stimulated by PGC-1alpha but co-expression of a mutant allele of FOXO1 insensitive to insulin completely reverses this suppression in hepatocytes or transgenic mice. We conclude that FOXO1 and PGC-1alpha interact in the execution of a programme of powerful, insulin-regulated gluconeogenesis. [References: 22]
机译：长期禁食或饥饿期间生存绝对需要肝糖异生，但在糖尿病中不适当地激活。糖皮质激素和胰高血糖素对肝脏具有很强的糖异生作用。相反，胰岛素抑制肝糖异生（1-3）。已知在此过程中具有重要生理作用的两个组件是叉头转录因子FOXO1（也称为FKHR）和过氧化物酶体增殖激活受体-γ共激活因子1（PGC-1alpha；也称为PPARGC1），一种转录共激活因子。 ;这些因素是否以及如何协作尚不清楚。使用FOXO1的野生型和突变等位基因，我们在这里显示PGC-1alpha以受Akt介导的磷酸化抑制的方式结合并共激活FOXO1。此外，FOXO1功能是PGC-1alpha能够强烈激活肝细胞和小鼠肝脏中糖异生基因表达的必需条件。胰岛素抑制PGC-1alpha刺激的糖原异生，但对胰岛素不敏感的FOXO1突变等位基因的共表达完全逆转了肝细胞或转基因小鼠中的这种抑制作用。我们得出结论，FOXO1和PGC-1alpha在执行功能强大的胰岛素调节的糖异生的程序中相互作用。 [参考：22]

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