肌肉心脏转动剂介导的日常新陈代谢节奏和肥胖悖论
Shiyang Song1,2, Chih-Liang Tien3, Hao Cui4
1Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism (S.S., P.B., N.Z., Y.G., W. Li, Y.X., R.C., W.Z., V.M., Z.S.), Baylor College of Medicine, Houston, TX.
Rev-erbα/β核受体对心脏功能和昼夜节律至关重要. 它们的干扰会导致心力衰竭, 但肥胖会通过改变新陈代谢来保护,
科学领域:
- 心血管生物学
- 时间生物学
- 分子新陈代谢
背景情况:
- 核受体Rev-erbα/β是生物钟的关键组成部分,被认为是心脏病的药物点.
- 心脏Rev- erb的体内功能及其在人类心脏病进展中的作用尚未研究.
- 心脏衰竭中的肥胖悖论缺乏机械的理解.
研究的目的:
- 研究心脏Rev-erbα/β在心脏功能和疾病中的作用.
- 解释心力衰竭中肥胖悖论的机制.
- 探索心脏时钟功能障碍与人体扩张性心肌病之间的联系.
主要方法:
- 产生心脏特异性的Rev-erbα/β淘汰 (KO) 鼠标模型 (构成性和诱导性).
- 进行多组分分析 (RNA-seq,ChIP-seq,蛋白质组分,代谢组分) 和饮食/药物救援实验.
- 心脏时钟基因表达模式与人类扩张性心肌病的严重程度相关.
主要成果:
- 心脏Rev- erbα/ βKO诱发了渐进式扩张性心肌病和心力衰竭.
- 脂肪酸氧化受损和碳水化合物利用增加之前的收缩功能障碍.
- 肥胖症通过增加脂质供应改善了心脏功能障碍,拯救了脂质氧化基因表达.
结论:
- 生物节律与营养代谢之间的时间协调对于心肌功能至关重要.
- 肥胖悖论是通过增强脂肪溶解和心脏脂质供应来解释的.
- 心脏分子时间型和Rev-erb调节的心肌生物能是心力衰竭的潜在时间治疗点.
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