循环时钟反循环通过NAMPT介导的NAD+生物合成
Kathryn Moynihan Ramsey1, Jun Yoshino, Cynthia S Brace
1Department of Medicine, Northwestern University Feinberg School of Medicine, 2200 Campus Drive, Evanston, IL 60208-3500, USA.
概括
小鼠表现出尼古丁胺氨酸二核酸 (NAD+) 生物合成酶NAMPT和NAD+水平的每日节律. 这一发现揭示了连接NAMPT/NAD+和SIRT1/CLOCK:BMAL1的反循环,影响着昼夜钟调节.
科学领域:
- 时间生物学 时间生物学
- 代谢过程中的代谢.
- 分子生物学分子生物学
背景情况:
- 昼夜时钟通过转录-翻译反循环将生理过程与每日光暗周期同步.
- 尼古丁胺胺氨基二核酸 (NAD+) 是一个关键的代谢物,参与能量代谢和细胞过程.
- 酶NAMPT限制了哺乳动物中NAD+生物合成的速度.
研究的目的:
- 为了研究昼夜时钟机制对NAMPT和NAD+水平的调节.
- 阐明涉及NAMPT/NAD+和核心时钟组件的反机制.
主要方法:
- 利用小鼠模型研究昼夜振荡.
- 使用NAMPT的遗传和药理抑制.
- 分析了时钟基因 (例如Per2) 和蛋白质复合体 (例如CLOCK:BMAL1,SIRT1) 的表达.
主要成果:
- 证明NAMPT和NAD+水平在小鼠中表现出昼夜振荡,由核心时钟组件调节.
- 表明NAMPT抑制通过释放CLOCK:BMAL1从SIRT1介导的抑制来增强Per2振荡.
- 确定转录因子CLOCK调节Nampt表达,建立一个反循环.
结论:
- NAMPT/NAD+通路集成到哺乳动物的昼夜钟中.
- 在NAMPT/NAD+和SIRT1/CLOCK:BMAL1复合体之间存在一种新的反循环,影响昼夜节律.
- 这种相互作用提供了新陈代谢和昼夜时间之间的分子联系.
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