卡林3环E3酶不活化会导致NRF2依赖的NADH减小压力,肝脂,以及全身胰岛素抵抗
Lijie Gu1, Yanhong Du1, Jianglei Chen1
1Harold Hamm Diabetes Center, Department of Biochemistry and Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104.
概括
库林3 (Cul3) E3酶调节肝脏的新陈代谢. 在肝细胞中删除Cul3可以防止脂肪的积累,但会通过NRF2激活引起全身性问题,导致胰岛素抵抗.
科学领域:
- 肝病学 肝病学是一种肝病学.
- 代谢调节 代谢调节 代谢调节
- 分子生物学分子生物学
背景情况:
- 卡林环E3酶 (CRL) 在疾病途径和药物开发中至关重要.
- 含Cullin3 (Cul3) 的CRL (CRL3) 影响肝脏胰岛素和氧化应激信号.
- 在肝病中CRL3的确切作用尚不清楚.
研究的目的:
- 为了研究CRL3在肝脏病理生理学中的功能.
- 了解CRL3在肝细胞中失活的代谢后果.
- 阐明将CRL3与代谢功能障碍联系起来的下游机制.
主要方法:
- 使用了肝细胞特异的Cul3淘汰赛小鼠模型.
- 进行了肝脏转录学和全球代谢学.
- 用NRF2和Keap1淘汰赛小鼠来验证这些发现.
主要成果:
- 肝细胞Cul3淘汰赛在肥胖小鼠中迅速解决了肥胖症,但引起了全身代谢障碍.
- CRL3的失活导致了持续的NRF2激活,阻止了甘油三储存和重编程脂质代谢.
- Nrf2的激活诱导了消耗NADH的酶,导致NADH降解性压力,抑制糖解,并恶化胰岛素抵抗.
结论:
- CRL3在调节肝脏新陈代谢方面发挥着至关重要的作用.
- 由于CRL3损失导致下游NRF2过度激活,导致肝脏代谢不适应.
- 准CRL3-NRF2轴可能为肥胖和胰岛素抵抗提供治疗策略.
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