通过CREB调节的转录协激活剂2的林氧化控制肝脏葡萄糖代谢
Yaqian Xue1, Aoyuan Cui1, Shuang Wei1
1CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
概括
禁食诱导PHD3,它氧化CRTC2,促进葡萄糖的产生. 这种氧化在代谢性疾病中升高,这表明糖尿病和高血糖症的治疗点.
科学领域:
- 代谢调节 代谢调节 代谢调节
- 分子内分泌学分子内分泌学
- 蛋白质的氧化
背景情况:
- 酸酶域 (PHD) 酶调节基于氧气水平的HIF活性.
- 其他生理条件对PHD酶的调节还不清楚.
研究的目的:
- 研究PHD3在调节肝脏葡萄糖生成中的作用.
- 阐明PHD3控制葡萄糖生成的分子机制.
主要方法:
- 通过禁食来研究PHD3诱导.
- 通过PHD3.3分析了CRTC2的相互作用和基化.
- 使用肝脏特异性淘汰 (PHD3 LKO) 和淘汰 (PHD3 KI) 的小鼠.
- 在各种代谢功能障碍模型和人类糖尿病肝脏中检查了CRTC2氧化.
主要成果:
- PHD3是由禁食诱导的,并通过CRTC2氧化调节肝脏葡萄糖生成.
- 通过PHD3在Pro129和Pro615的CRTC2的基化对其与CREB的相互作用,核转位和加强与葡萄糖原基因促进体的结合至关重要.
- 在PHD3 LKO和PHD3 KI小鼠中,禁食葡萄糖生成和血糖降低.
- 在禁食小鼠,饮食引起的胰岛素抵抗,肥胖小鼠和患有糖尿病的人群中,PHD3的CRTC2氧化升高.
结论:
- 在禁食期间,PHD3介导的CRTC2氧化是肝脏葡萄糖生成的关键调节者.
- 这种途径在代谢疾病中失调,包括胰岛素抵抗和糖尿病.
- 向PHD3-CRTC2氧化可能为高血糖和2型糖尿病提供治疗策略.
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