蛋白酸酶6通过mTORC1通路调节与代谢功能障碍相关的脂肪肝炎
Zhengshuai Liu1, Shuang Wei1, Yang Jiang2
1CAS Key Laboratory of Nutrition and Metabolism, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Journal of hepatology
|February 13, 2025
概括
纤维细胞生长因子21 (FGF21) 向蛋白酸酶PPPP6C,用于治疗与代谢功能障碍相关的脂肪肝炎 (MASH). 减少的PPP6C加速MASH,而FGF21通过脱化TSC2来增强它,提供新的治疗途径.
科学领域:
- 肝病学和代谢疾病研究.
- 肝病进展的分子机制.
- 药理学向肝脏病理的药理学向.
背景情况:
- 代谢功能障碍相关的脂肪肝炎 (MASH) 是一种严重的肝病,治疗选择有限.
- 纤维细胞生长因子21 (FGF21) 类似物对MASH有希望,但它们的机制尚不清楚.
研究的目的:
- 阐明FGF21在治疗MASH中的作用机制.
- 在肝细胞中识别FGF21的下游标.
- 评估针对MASH的FGF21-PPP6C相互作用的治疗潜力.
主要方法:
- 在MASH诱导饮食中利用肝脏特异性PPPP6C和βKlotho淘汰赛小鼠模型.
- 管理了复合FGF21并分析了它对MASH进展的影响.
- 采用质谱和体外酸酶试验来识别和描述FGF21的标,包括PPPP6C及其与βKlotho和TSC2的相互作用.
主要成果:
- 确定了氨酸/氨酸酸酶PPPP6C作为FGF21的直接标和肝细胞中的关键介质.
- 证明肝脏PPPP6C缺乏症会加剧MASH,阻断FGF21的治疗作用.
- 显示的FGF21治疗增加了PPPP6C活性,导致TSC2脱,mTORC1抑制,并促进TFE3/Lipin1核进入. 在人类MASH肝脏中,PPPP6C降低,TSC2酸化增加.
结论:
- PPPP6C是肝细胞中FGF21信号传递的关键下游媒介,对其抗MASH作用至关重要.
- 用FGF21准PPP6C代表了人类MASH的潜在治疗策略.
- 了解FGF21-PPP6C-TSC2轴,可以了解MASH的发病和治疗.
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