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翻译后的修改驱动了HMGB1在与酒精有关的肝病中的作用

Xiaodong Ge¹, Nithyananthan Subramaniyam¹, Zhuolun Song¹

¹Department of Pathology, University of Illinois Chicago, Chicago, Illinois, USA.

Hepatology communications

|January 6, 2025

概括

氧化高流动性组盒-1 (HMGB1) 驱动酒精相关性肝病 (AALD) 通过激活骨髓细胞通过RAGE. 乙化HMGB1可以抵消这些有害影响,为AALD提供潜在的治疗点.

科学领域:

肝病学肝病学是一种肝病学.
免疫学免疫学免疫学
分子生物学分子生物学

背景情况:

酒精消费增加高流动性组框-1 (HMGB1) 和其翻译后修改 (PTMs).
肝细胞和髓质细胞中的特定HMGB1 PTM被假设驱动酒精相关肝病 (AALD).

研究的目的:

研究特定HMGB1 PTMs (减少[H],氧化[O],乙化[Ac]) 在AALD病变发生过程中的作用.
确定HMGB1及其PTM在肝细胞和髓状细胞中的细胞特异性贡献.
阐明参与HMGB1介导的肝损伤的受体机制 (RAGE,TLR4).

主要方法:

使用了利伯-德卡利 (LD) 酒精诱导的肝损伤模型.
采用病毒载体和遗传方法来以细胞特异的方式操纵HMGB1,其PTM和受体 (RAGE,TLR4).
在肝细胞和骨髓细胞中分析了HMGB1 PTM,并在转基因小鼠中评估了AALD表型.

主要成果:

在对AALD部分受保护的肝细胞或骨髓细胞中切除HMGB1;联合切除可以预防肝损伤,脂肪和炎症.
肝细胞是[O]和[Ac]HMGB1的主要来源,而髓状细胞则产生[H]和[Ac]HMGB1.
氧化HMGB1 ([O] HMGB1) 通过激活骨髓细胞通过RAGE加剧了AALD,导致IL1B的产生和炎症;乙化HMGB1 ([Ac] HMGB1) 赋予了保护.

结论:

来自肝细胞的氧化HMGB1作为RAGE信号传递在骨髓细胞中的配体,驱动AALD病原体.
针对[O] HMGB1及其与RAGE的相互作用,为AALD提供了一个潜在的治疗策略.
乙化HMGB1 ([Ac] HMGB1) 通过抵消AALD中[O] HMGB1的有害影响,显示出具有保护作用.

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