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NADPH氧化酶4-SH3域含有YSC84-like 1复合物参与肝炎和纤维化

Yeo Kyu Hur¹, Hye Eun Lee², Jung-Yeon Yoo¹

¹Department of Life Sciences, Ewha Womans University, 52 Ewhayeodae-Gil, Seodaemoon-Gu, Seoul, 03760, South Korea.

Free radical biology & medicine

|December 7, 2024

概括

含有SH3域的Ysc84-like 1 (SH3YL1) 蛋白调节NADPH氧化酶4 (Nox4) 的活性,有助于在代谢功能障碍相关的脂肪肝炎 (MASH) 中导致肝炎和纤维化. 针对这个Nox4-SH3YL1轴可能会提供新的MASH疗法.

科学领域:

肝病学肝病学是一种肝病学.
分子生物学分子生物学
生物化学生物化学

背景情况:

代谢功能障碍相关的脂肪肝炎 (MASH) 涉及肝脏炎症和纤维化.
肝细胞中的NADPH氧化酶4 (Nox4) 与MASH病变发生有关.
在MASH中Nox4的调节和具体作用尚不清楚.

研究的目的:

调查SH3域含Ysc84-like 1 (SH3YL1) 在MASH期间肝炎和纤维化中的作用.
为了确定SH3YL1是否在MASH的背景下调节Nox4活动.
探索针对Nox4-SH3YL1轴的治疗潜力.

主要方法:

生成全身SH3YL1淘汰赛 (SH3YL1-/-),Nox4淘汰赛 (Nox4-/-),以及肝细胞特异性SH3YL1条件淘汰赛 (Alb-Cre/SH3YL1fl/fl) 的小鼠.
使用甲素/胆缺乏 (MCD) 饮食诱导的MASH.
评估了肝炎,纤维化,肝细胞亡和氧化应激标志物 (3-尼托铁,4-氨).
在小鼠肝脏和人类MASH患者肝脏活检中检查了SH3YL1蛋白质表达.

主要成果:

在MCD饮食小鼠中,SH3YL1和Nox4缺乏明显减少肝炎,肝细胞亡和纤维化.
在Palmitate刺激后,SH3YL1和Nox4缺乏的肝细胞和HSCs没有显示H2O2的产生.
在接受MCD饮食养的WT小鼠和MASH患者的肝细胞中观察到SH3YL1蛋白表达升高.
肝细胞中的Nox4-SH3YL1复合体增加了H2O2的产生,促进了MASH特征.

结论:

在MASH中,SH3YL1在促进肝炎,肝细胞亡和纤维化方面发挥着关键作用.
诺克斯4-SH3YL1复合体是MASH中氧化应激和肝损伤的关键媒介.
Nox4-SH3YL1轴代表了人类MASH的潜在治疗标.

关键词:

纤维化纤维化纤维化与代谢功能障碍相关的脂肪肝炎.第4号x4号有反应性氧物种的反应性氧物种.这就是SH3YL1的意思.

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