在钟表突变小鼠中,降低胆固醇代谢和增强动脉样硬化
Xiaoyue Pan1, Xian-Cheng Jiang, M Mahmood Hussain
1Departments of Cell Biology and Pediatrics, SUNY Downstate Medical Center, Brooklyn, NY.
Circulation
|September 10, 2013
概括
循环时钟活动影响胆固醇水平和动脉样硬化. 一种主导负的时钟突变蛋白增加了血胆固醇,并通过影响肠道吸收和巨细胞功能,在小鼠中加剧了动脉样硬化.
科学领域:
- 心血管生物学 心血管生物学
- 时间生物学 时间生物学
- 代谢性疾病 代谢性疾病
背景情况:
- 昼夜钟是调节昼夜节律的关键转录因子.
- 时钟在血胆固醇平衡和动脉样硬化中的作用仍未研究.
研究的目的:
- 研究时钟蛋白在调节血胆固醇水平中的作用.
- 为了确定时钟对动脉样硬化发展的影响.
- 阐明钟表对脂质新陈代谢和动脉生成的影响的分子机制.
主要方法:
- 使用了三种不同的小鼠模型,其中有一种主导负的时钟突变蛋白 (Clock ((Δ19/Δ19)).
- 对血脂质,脂蛋白组成和肠道和巨细胞中的基因表达进行了详细的生理和分子分析.
- 研究了胆固醇的吸收,脂蛋白组合,巨食者受体表达和胆固醇的排泄.
主要成果:
- 时钟(Δ19/Δ19) 的小鼠表现出显著升高的血胆固醇,这是由于阿波利波蛋白B48含有脂蛋白的增加.
- 强化肠道胆固醇吸收,主要基因 (NPC1L1,ACAT1,MTP) 的上调表达表明,有助于高胆固醇血症.
- 巨细胞功能障碍,其特征是改性脂蛋白吸收增加和胆固醇排泄受损 (由于ABCA1表达低),进一步促进了动脉样硬化.
结论:
- 主导-负 时钟蛋白通过增加肠道胆固醇吸收和损害巨细胞胆固醇处理来加剧动脉样硬化.
- 循环时钟活动对于维持低血胆固醇和预防小鼠动脉动脉生成至关重要.
- 时钟通过上游转录因子2 (UTF2) 调节巨细胞ABCA1的表达.
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