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除了水果分解之外:基托赫索基纳酶在营养压力肝细胞中协调ER蛋白质稳定

Salaheldeen Elsaid¹, Xiangdong Wu¹, Junkai Hu¹

¹Radiology Department, University of Maryland, Baltimore, Maryland, United States.

American journal of physiology. Gastrointestinal and liver physiology

|October 25, 2025

概括

凯托赫索基纳酶 (KHK) 通过在高果糖和脂肪饮食期间管理内质网膜 (ER) 压力来维持肝细胞的健康. 这种酶是这种酶.

科学领域:

肝病学肝病学是一种肝病学.
细胞应激反应的应激反应
代谢障碍代谢障碍代谢障碍

背景情况:

过多的果糖和脂肪摄入会破坏肝细胞的功能,导致内分泌网膜 (ER) 应激和与代谢功能障碍相关的脂肪肝炎 (MASLD).
对于果糖代谢至关重要的基托赫索基纳斯 (KHK) 已被认为具有非代谢作用,但其在营养压力下的ER蛋白质稳定中的功能尚不清楚.

研究的目的:

研究KHK在稳定性条件下调节ER蛋白质稳定性中的作用.
阐明在营养过载期间参与肝细胞存活的KHK介导信号通路.

主要方法:

利用了来自GAN饮食小鼠的HepG2细胞,初级肝细胞和来自MASLD患者的肝脏活检.
进行了KHK淘汰实验,并分析了展开的蛋白质响应 (UPR) 信号通路 (IRE1α-XBP1,PERK-CHOP).
评估了蛋白质聚合,无处不在和亡标志物.

主要成果:

稳态性条件诱导了KHK的表达,并激活了适应性IRE1α-XBP1 UPR轴,在物种中保存.
通过PERK-CHOP信号传递,KHK的淘汰导致了蛋白质错误折叠,积累,蛋白质毒性压力和亡的增加.
尽管KHK缺乏导致肥胖症,但它破坏了ER蛋白质稳定.

结论:

KHK作为一种双重功能酶,调节果糖代谢和ER蛋白质稳定.
KHK-IRE1α轴是肝细胞面临营养压力的保存生存途径.
选择性抑制KHK酶活性可能是MASLD/MASH的治疗策略,而不会破坏ER功能.

关键词:

压力ERER压力ERER压力马什 (MASH) 是一个非常重要的产品.灭症 (apoptosis) 是一种死亡的过程.基托赫克索基纳酶 (Ketohexokinase) 是一种展开的蛋白质反应 (UPR)

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