通过调节SREBP1,CREB联合激活剂CRTC2控制肝脂代谢
Jinbo Han1, Erwei Li1, Liqun Chen1
1MOE Key Laboratory of Bioinformatics, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
Nature
|July 7, 2015
概括
克雷布调控转录协活性剂2 (CRTC2) 通过调节醇调控元素结合蛋白1 (SREBP1) 运输,影响脂质代谢. 这一发现为治疗非酒精性脂肪肝病和胰岛素抵抗提供了新的见解.
科学领域:
- 代谢性疾病是一种代谢性疾病.
- 分子生物学分子生物学
- 脂质平衡是脂质的平衡.
背景情况:
- 非酒精性脂肪性肝病 (NAFLD) 和胰岛素抵抗与异常的肝脏甘油三积累和增加的新生脂质生成有关.
- 固醇调节元件结合蛋白1 (SREBP1) 是脂质生成的关键转录调节器,在内分泌网膜 (ER) 中合成为非活性前体.
- 胰岛素信号通常促进SREBP1从ER转移到Golgi进行处理和核转移,但肥胖和糖尿病的机制尚不清楚.
研究的目的:
- 调查CREB调节转录协激剂2 (CRTC2) 在调节SREBP1处理及其与mTOR信号的连接中的作用.
- 在肥胖和胰岛素抵抗的背景下,阐明CRTC2影响COPII依赖的SREBP1传输和成熟的机制.
主要方法:
- 使用的小鼠模型,包括肥胖的小鼠,肝脏过度表达了mTOR缺陷的CRTC2突变.
- 研究了CRTC2,mTOR信号传输和COPII复合组件 (Sec23A和Sec31A) 之间的相互作用.
- 评估了CRTC2调制对SREBP1处理,脂原基因表达和胰岛素敏感性的影响.
主要成果:
- 证明CRTC2在调节COPII依赖的SREBP1处理中作为mTOR信号的调解者.
- 显示CRTC2与Sec23A竞争与Sec31A结合,从而破坏了SREBP1的传输.
- 发现在养过程中,mTOR可酸化CRTC2,减少其对SREBP1成熟的抑制作用.
- 观察到肥胖小鼠中mTOR缺陷的CRTC2突变体的肝脏过度表达改善了脂原计划和胰岛素敏感性.
结论:
- 在被养状态和肥胖时,CRTC2在调节mTOR介导的脂质平衡中发挥着至关重要的作用.
- CRTC2与COPII机制之间的相互作用是SREBP1处理的关键监管点.
- 针对CRTC2-mTOR-SREBP1通路可能为NAFLD和胰岛素抵抗提供治疗策略.
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