AMPK通过加密染色体酸化和降解来调节昼夜时钟
Katja A Lamia1, Uma M Sachdeva, Luciano DiTacchio
1Gene Expression Laboratory, the Salk Institute, La Jolla, CA 92037, USA.
Science (New York, N.Y.)
|October 17, 2009
概括
具有营养反应的腺单酸盐激活蛋白激酶 (AMPK) 化并破坏了密码色素1 (CRY1) 的稳定,这是一个关键的时钟组件. 这种机制有助于外周器官,如肝脏,同步他们的昼夜节律与营养的可用性.
科学领域:
- 时间生物学 时间生物学
- 分子生物学分子生物学
- 代谢过程中的代谢.
背景情况:
- 循环时钟调节行为和生理学的日常节奏,由大脑中的光和外周器官的营养可用性同步.
- 周围的昼夜时钟,如肝脏时钟,受到营养信号的精确机制在很大程度上是未知的.
- 加密染色体1 (CRY1) 是基底生日节律的分子时钟的关键组成部分.
研究的目的:
- 研究营养响应信号通路在调节外周生理时钟中的作用.
- 为了阐明分子机制,通过营养的可用性 entrains 外围器官节拍器.
- 确定腺单酸激活蛋白激酶 (AMPK) 是否影响昼夜时钟组成部分CRY1.1的稳定性和功能.
主要方法:
- 利用小鼠纤维细胞来研究AMPK和CRY1.1之间的相互作用.
- 研究了小鼠肝脏中的节奏AMPK活性和CRY1核丰度.
- 在小鼠中使用AMPK通路的遗传干扰来评估其对外围时钟的影响.
- 刺激AMPK活动,观察其对加密色素稳定性和昼夜节律的影响.
主要成果:
- 证明AMPK在小鼠纤维细胞中酸化和破坏CRY1的稳定性.
- 观察到节律性AMPK活性和与老鼠肝脏中核CRY1丰度的反相关性.
- 表明AMPK刺激会破坏加密染色体的稳定,并破坏昼夜节律.
- 发现AMPK途径的遗传干扰导致小鼠的外周时钟功能发生改变.
结论:
- 通过AMPK介导的CRY1酸化作为转导营养信号到哺乳动物外围昼夜钟的关键机制.
- 这一途径突出显示了细胞能量状态与外周器官中昼夜时间调节之间的直接联系.
- 了解这种营养时钟相互作用对于理解代谢健康和与生理节律中断相关的疾病至关重要.
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