肝脏视网甲缺乏症通过增强PCK1-和G6PC介导的葡萄糖生成,与糖尿病恶化有关
Hanyu Yang1,2, Mengxiang Su3, Ming Liu2
1State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
Acta pharmaceutica Sinica. B
|September 18, 2023
概括
肝脏视网甲 (Rald) 缺乏与2型糖尿病 (T2D) 的进展有关. 恢复Rald水平或抑制视网甲脱酶1 (RALDH1) 改善葡萄糖代谢,降低糖尿病模型中的血糖.
科学领域:
- 生物化学 生化学
- 内分泌学 在内分泌学.
- 代谢过程中的代谢.
背景情况:
- 2型糖尿病 (T2D) 与视网膜甲脱酶1 (RALDH1) 表达的增加以及肝脏视网膜甲 (Rald) 水平的降低有关.
- 肝脏拉尔德缺陷在T2D病原体中的特定作用仍然在很大程度上是未知的.
研究的目的:
- 调查肝脏拉尔德缺陷在T2D进展中的功能作用.
- 探索针对RALDH1进行T2D治疗的潜力.
主要方法:
- 使用糖尿病db/db小鼠和高脂肪饮食诱导的肥胖小鼠模型.
- 服用拉尔德或治疗,并使用肝脏特定的Raldh1静音.
- 进行了对人类原发性肝细胞和HepG2细胞的实验.
- 进行了 luciferase 记者测定和分子对接,以阐明机制.
主要成果:
- 在糖尿病小鼠中,逆转肝脏拉尔德缺陷或静止Raldh1显著降低了禁食血糖,并抑制了肝脏葡萄糖生成.
- 在恢复Rald水平或Raldh1抑制的情况下,观察到基酸碳动酶1 (PCK1) 和葡萄糖-6-酸酶 (G6PC) 表达的下调.
- 肝脏Rald水平与禁食血糖和PCK1/G6PC表达有负相关性.
- 发现Rald可以对抗视网体X受体α (RXRα),从而降低PCK1和G6PC的表达.
结论:
- 肝脏拉尔德缺乏症有助于葡萄糖双相稳定和T2D进展.
- 恢复肝脏Rald水平或抑制RALDH1表明T2D的治疗潜力.
- RALDH1成为治疗2型糖尿病的有希望的治疗点.
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