Insulin inhibits hepatocellular glucose production by utilizing liver-enriched transcriptional inhibitory protein to disrupt the association of CREB-binding protein and RNA polymerase II with the phosphoenolpyruvate carboxykinase gene promoter
Insulin inhibits hepatocellular glucose production by utilizing liver-enriched transcriptional inhibitory protein to disrupt the association of CREB-binding protein and RNA polymerase II with the phosphoenolpyruvate carboxykinase gene promoter
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DOI：
10.1074/jbc.m204873200
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发表时间：
2002-08-30
影响因子：
4.8
通讯作者：
Granner, DK
中科院分区：
文献类型：
--
作者：
Duong, DT;Waltner-Law, ME;Granner, DK
激素调节葡萄糖稳态，部分是通过控制促葡萄糖生成酶的表达，如磷酸烯醇丙酮酸羧激酶（PEPCK）。胰岛素和糖皮质激素主要在基因转录水平相互调节PEPCK表达。我们在这里证明，糖皮质激素促进，而胰岛素破坏，CREB结合蛋白（CBP）和RNA聚合酶II与肝脏PEPCK基因启动子在体内的协会。我们还表明，辅助因子，如CCAAT/增强子结合蛋白β（C/EBP β），可以招募CBP驱动转录。胰岛素以磷脂酰肌醇3-激酶依赖性方式增加肝脏富集转录抑制蛋白（LIP）的蛋白水平，LIP是C/EBP β的抑制形式。LIP同时取代PEPCK基因启动子上的肝脏富集的转录激活蛋白，这可以消除CBP和聚合酶II的募集，最终导致PEPCK表达的抑制和肝细胞葡萄糖产生的衰减。
Hormones regulate glucose homeostasis, in part, by controlling the expression of gluconeogenic enzymes, such as phosphoenolpyruvate carboxykinase (PEPCK). Insulin and glucocorticoids reciprocally regulate PEPCK expression primarily at the level of gene transcription. We demonstrate here that glucocorticoids promote, whereas insulin disrupts, the association of CREB-binding protein (CBP) and RNA polymerase II with the hepatic PEPCK gene promoter in vivo. We also show that accessory factors, such as CCAAT/enhancer-binding protein beta (C/EBPbeta), can recruit CBP to drive transcription. Insulin increases protein levels of liver-enriched transcriptional inhibitory protein (LIP), an inhibitory form of C/EBPbeta, in a phosphatidylinositol 3-kinase-dependent manner. LIP concomitantly replaces liver-enriched transcriptional activator protein on the PEPCK gene promoter, which can abrogate the recruitment of CBP and polymerase II, culminating in the repression of PEPCK expression and the attenuation of hepatocellular glucose production.