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葡萄糖皮质体慢药学通过心肌细胞自主交换激活程序促进心脏中的葡萄糖代谢
Hima Bindu Durumutla1, Ashok Daniel Prabakaran1, Fadoua El Abdellaoui Soussi1
1Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, and.
JCI insight
|October 8, 2024
概括
葡萄糖皮质体受体 (GR) 和克鲁佩尔样因子15 (KLF15) 以昼夜依赖的方式控制心脏葡萄糖代谢. 准这个轴可以改善胰岛素抵抗中的心脏功能.
科学领域:
- 心血管生物学心血管生物学
- 代谢调节 代谢调节 代谢调节
- 时间生物学 时间生物学
背景情况:
- 葡萄糖皮质体受体 (GR) 和其辅因子克鲁佩尔样因子15 (KLF15) 对心脏功能和新陈代谢至关重要.
- 在心肌细胞中由GR/KLF15轴调节的特定代谢标尚未完全理解.
- 循环节的时间影响葡萄糖皮质激素的心脏保护作用.
研究的目的:
- 定义GR/KLF15轴的心肌细胞自主代谢标.
- 为了研究这个轴在指导心脏葡萄糖氧化过程中的作用,以昼夜依赖的方式.
- 探索代谢功能障碍的治疗潜力.
主要方法:
- 综合转录组学和表观组学.
- 特定于心肌细胞的GR或KLF15的诱导性除15.
- 在饮食诱导的肥胖和糖尿病小鼠模型 (db/db小鼠) 中给予普得尼松.
- 在体内消除GR和KLF15.
主要成果:
- GR和KLF15协同激活阿迪波涅克丁受体1 (Adipor1) 和线粒体的酸盐复合体 (Mpc1/2).
- 这种激活增强了胰岛素刺激的葡萄糖吸收和心肌细胞中的酸盐氧化.
- 在db/db小鼠中,轻相普得尼松的给药改善了心脏葡萄糖氧化和透缩功能.
- 这些改进被GR和KLF15淘汰.
结论:
- GR/KLF15轴在心脏中调节一个依赖于昼夜的葡萄糖氧化程序.
- 阿迪波涅克丁受体和线粒体的酸盐复合体是关键的目标.
- 循环定时的葡萄糖皮质类药物给药具有治疗心脏代谢功能障碍的潜力.
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