福克斯O1-zDHHC4-CD36 S-转化轴驱动糖尿病中的代谢功能障碍
Kaitlyn M J H Dennis1, Keshav Gopal2, Claudia N Montes Aparicio1
1Department of Physiology, Anatomy and Genetics (K.M.J.H.D., C.N.M.A., J.A.Z., M.C.-G., T.N., R.M.D., R.D.C., U.P., C.A.C., G.S., E.K.G., P.S., S.D.V., L.C.H.), University of Oxford, United Kingdom.
Circulation research
|May 13, 2025
概括
由FoxO1-zDHHC4信号驱动的CD36 S-化增加,在2型糖尿病中损害心脏功能. 准这种途径可以改善糖尿病患者的心脏代谢和收缩能力.
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
- 分子心脏病学分子心脏病学
背景情况:
- CD36是心脏中的关键脂肪酸 (FA) 载体,调节心脏FA代谢.
- 偏好的CD36局部化至肉膜是胰岛素抵抗和2型糖尿病心脏病的早期事件.
- 翻译后的S-化会影响蛋白质的运输和功能.
研究的目的:
- 调查CD36S-化在糖尿病心肌病发展中的作用.
- 阐明调节糖尿病心脏中CD36 S-化过程的分子机制.
- 为了确定是否向CD36 S-化可以改善2型糖尿病的心脏功能障碍.
主要方法:
- 在大鼠中,通过高脂肪饮食和链毒素诱导了2型糖尿病.
- 评估了FoxO1对zDHHC4的转录调节,使用ChIP测序和光酶试验.
- 使用siRNA和shRNA用于基因沉默,以及药理抑制剂用于酶调节.
主要成果:
- 2型糖尿病增加了心脏CD36的S-化,sarcolemmal定位,FA氧化和三糖储存跨物种.
- 在糖尿病心脏中,负责CD36S-化的酶zDHHC4被FoxO1上调.
- 抑制zDHHC酶通过降低CD36 S-化和改善FA代谢,改善了糖尿病模型中的心脏功能.
结论:
- 在2型糖尿病心脏中,FoxO1-zDHHC4-CD36 S-化轴被激活.
- 这种激活驱动了糖尿病心肌病的代谢和收缩功能障碍的特征.
- 针对这一轴为糖尿病心脏病提供了潜在的治疗策略.
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