通过转录协活性剂PGC-1控制肝脏葡萄糖生成
J C Yoon1, P Puigserver, G Chen
1Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nature
|September 15, 2001
概括
转录协激活剂PGC-1在禁食和糖尿病期间在肝脏中被诱导. PGC-1激活了生产葡萄糖的关键酶,突出了它在调节血糖中的作用.
科学领域:
- 代谢过程中的代谢.
- 分子生物学分子生物学
- 内分泌学 在内分泌学.
背景情况:
- 血糖平衡依赖于肝脏的葡萄糖生产和外围吸收.
- 葡萄糖生成,在肝脏中合成葡萄糖的过程,在禁食期间至关重要,在糖尿病中失调.
- 特定的转录协激活剂在调节葡萄糖生成中的作用是一个活跃的研究领域.
研究的目的:
- 为了研究转录协激活剂PGC-1在肝脏葡萄糖生成中的作用.
- 确定PGC-1表达的调节及其对葡萄糖生成酶活性的影响.
- 阐明PGC-1在响应代谢线索时调节葡萄糖生成的分子机制.
主要方法:
- 在禁食和胰岛素缺乏症的小鼠模型中研究了PGC-1诱导 (链毒素诱导的糖尿病,产后/产后,肝脏胰岛素受体淘汰).
- 在使用循环AMP和葡萄皮质皮质激素的初级肝培养中研究了PGC-1诱导.
- 在肝细胞中利用腺病毒介导的PGC-1表达 (体外和体内) 来评估其对PEPCK和葡萄糖-6-酸酶等葡萄糖生成酶的影响.
- 分析了PEPCK促进体的转录激活,检查了葡萄糖皮质体受体和HNF-4alpha的作用.
主要成果:
- 在禁食期间和在多种胰岛素抵抗模型中,PGC-1在肝脏中被显著诱导.
- 循环AMP和肝细胞中的葡萄皮质类药物协同增强了PGC-1表达.
- 腺病毒输送PGC-1强烈激活关键的葡萄糖生成酶 (PEPCK,葡萄糖-6-酸酶),增加肝脏葡萄糖输出.
- 通过PGC-1完全激活PEPCK转录,需要同时激活葡萄糖皮质体受体和HNF-4alpha.
结论:
- PGC-1是肝脏葡萄糖生成的关键调节剂.
- 在肝脏内,PGC-1 作为胰岛素-cAMP 信号轴中的中央调解器.
- 这些发现确定了PGC-1作为一种潜在的治疗点,用于表现为异常葡萄糖生产的代谢障碍.
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