饮食诱导的循环增强重塑同步对抗肝脂代谢过程
Dongyin Guan1, Ying Xiong1, Patricia C Borck1
1Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Cell
|July 31, 2018
概括
过度营养会通过改变昼夜基因活动来破坏新陈代谢节奏. 这项研究揭示了饮食诱导的肥胖如何导致脂肪酸合成和氧化的高幅节奏,提供了新的时代药物策略.
科学领域:
- 代谢调节
- 时间生物学
- 分子生物学
背景情况:
- 营养过度会通过不明确的机制扰乱昼夜代谢节奏.
- 饮食引起的肥胖 (DIO) 显著影响代谢途径和基因表达.
- 了解这些干扰对于解决代谢障碍至关重要.
研究的目的:
- 研究DIO如何重塑肝脏中的昼夜增强剂活性.
- 阐明过度营养与脂肪酸代谢的昼夜节律相关的机制.
- 探索对代谢疾病的时间药理干预的潜力.
主要方法:
- 在DIO小鼠肝脏模型中分析昼夜增强剂活性.
- 测量脂肪酸合成和氧化节奏.
- 研究醇调控元素结合蛋白 (SREBP) 和过氧体增殖器激活受体α (PPARα) 的表达和功能.
- PPARα的药理活性.
主要成果:
- 在小鼠肝脏中,DIO在脂肪酸合成和氧化过程中诱导了同步的,高幅度的昼夜节律.
- 通过DIO,SREBP表达成为节律诱导,驱动昼夜脂肪酸合成和氧化.
- DIO还导致PPARα的高幅度昼夜节律,这对脂肪酸氧化至关重要.
- 药理学剂的PPARα激活降低了SREBP对脂肪酸氧化的需求,这表明SREBP通过PPARα连接体的间接作用.
- 高幅度的PPARα节律显示了对降脂药物的日时依赖性反应.
结论:
- 通过DIO, 营养过度会重塑生理节律增强器的活性,
- 在非核心时钟组件 (PPARα和SREBP1) 中获得节律性对于过度营养的代谢基因转录变化至关重要.
- 这些发现允许通过针对日间时间的药物反应来管理代谢障碍的时代药物学方法.
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