葡萄糖通过Golgi PtdIns4P介导的ATGL调节来控制脂解
Lianggong Ding1, Florian Huwyler2, Fen Long1
1Institute of Food, Nutrition and Health, ETH Zürich, Schwerzenbach, Switzerland.
Nature cell biology
|April 1, 2024
概括
一个新的细胞内在机制将葡萄糖感应与脂解联系起来,调节脂肪酸的释放. 这一途径涉及Golgi PtdIns4P和CUL7FBXW8复合体,影响脂肪甘油三酸脂酶 (ATGL) 活性,并显示出治疗肝硬化症的前景.
科学领域:
- 代谢调节 代谢调节 代谢调节
- 蜂信号传输是如何进行的
- 脂质代谢 脂质代谢 是一种
背景情况:
- 系统代谢平衡依赖于营养杂交,葡萄糖和脂肪酸 (FA) 协调对于预防糖尿病和代谢功能障碍相关的脂肪肝炎 (MASH) 等疾病至关重要.
- 通过胰岛素,甲醇胺和葡萄糖调节的荷尔蒙主要控制脂解,以应对血糖波动.
- 通过葡萄糖传感直接调节脂解的细胞内在机制的存在仍然在很大程度上未被探索.
研究的目的:
- 通过细胞内葡萄糖传感直接调节脂解的细胞内在机制的识别和描述.
- 为了阐明参与Golgi PtdIns4P介导的脂肪甘油三酸脂酶 (ATGL) 驱动脂解的分子参与者.
主要方法:
- 研究了细胞内葡萄糖水平在调节Golgi PtdIns4P.中的作用.
- 研究了高尔基器官中E3结合酶复合体CUL7FBXW8的组合和功能.
- 评估了葡萄糖耗尽对ATGL多基化和脂解的影响.
- 使用肝硬化和MASH的小鼠模型,以及ex vivo人肝 perfusion,以测试针对已识别的途径的治疗干预措施.
主要成果:
- 细胞内葡萄糖的耗尽导致Golgi PtdIns4P水平下降,损害了CUL7FBXW8复合体的组合.
- 降低的CUL7FBXW8复合物水平通过降低ATGL多基提化来增强ATGL驱动的脂解.
- 这种内在机制调节细胞内FA池和细胞外释放,这在禁食和葡萄糖剥夺期间至关重要.
- 针对Golgi PtdIns4P-CUL7FBXW8-ATGL轴改善了小鼠模型和人类肝脏移植中的肥胖症.
结论:
- 确定了一种新的细胞内在机制,其中葡萄糖感知通过Golgi PtdIns4P和CUL7FBXW8-ATGL轴调节脂解.
- 这一途径在管理细胞内脂肪酸动态和基质可用性方面发挥着关键作用.
- 戈尔吉PtdIns4P-CUL7FBXW8-ATGL通路代表了与代谢功能障碍相关的脂肪性肝病和MASH的潜在治疗标.
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