Cell:治疗代谢综合征的新思路——利用生物钟
创作:女巫 审核:mildbreeze 2018年09月01日
  • 饮食诱导的肥胖(DIO)大幅改变小鼠肝脏中生理节律相关的基因增强子活性,重塑脂肪代谢生物钟;
  • 具体表现:脂肪酸(FA)合成和氧化这两个相反的脂代谢通路活性的生理节律,变得同步、振幅剧增,下午5点左右达到峰值;
  • 转录因子SREBP和PPARα分别促进FA合成和氧化,DIO诱导二者的同步高振幅节律性表达;
  • SREBP的节律不仅引起节律性的FA合成,还通过促进PPARα活性诱导FA氧化的生理节律;
  • DIO小鼠中,药物降脂在PPARα表达最高时更有效。
主编推荐语
mildbreeze
营养过度可打破代谢节律,但机制不清。Cell上周发表研究,在小鼠中发现饮食诱导的肥胖可改变脂代谢生物钟,揭示了背后的分子机制,并用小鼠实验表明,按脂代谢的节律服用降脂药,效果更好。这些发现为治疗代谢类疾病带来启示,提示利用生物钟在正确的时间服药,可使疗效最大化。
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Cell [IF:38.637]

Diet-Induced Circadian Enhancer Remodeling Synchronizes Opposing Hepatic Lipid Metabolic Processes

饮食诱导的生理节奏增强子重塑,同步相反的肝脏脂质代谢过程

10.1016/j.cell.2018.06.031

2018-07-26, Article

Abstract & Authors:展开

Abstract:收起
Overnutrition disrupts circadian metabolic rhythms by mechanisms that are not well understood. Here, we show that diet-induced obesity (DIO) causes massive remodeling of circadian enhancer activity in mouse liver, triggering synchronous high-amplitude circadian rhythms of both fatty acid (FA) synthesis and oxidation. SREBP expression was rhythmically induced by DIO, leading to circadian FA synthesis and, surprisingly, FA oxidation (FAO). DIO similarly caused a high-amplitude circadian rhythm of PPARα, which was also required for FAO. Provision of a pharmacological activator of PPARα abrogated the requirement of SREBP for FAO (but not FA synthesis), suggesting that SREBP indirectly controls FAO via production of endogenous PPARα ligands. The high-amplitude rhythm of PPARα imparted time-of-day-dependent responsiveness to lipid-lowering drugs. Thus, acquisition of rhythmicity for non-core clock components PPARα and SREBP1 remodels metabolic gene transcription in response to overnutrition and enables a chronopharmacological approach to metabolic disorders.

First Authors:
Dongyin Guan

Correspondence Authors:
Mitchell A Lazar

All Authors:
Dongyin Guan,Ying Xiong,Patricia C Borck,Cholsoon Jang,Paschalis-Thomas Doulias,Romeo Papazyan,Bin Fang,Chunjie Jiang,Yuxiang Zhang,Erika R Briggs,Wenxiang Hu,David Steger,Harry Ischiropoulos,Joshua D Rabinowitz,Mitchell A Lazar

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