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TM7SF3控制TEAD1拼接,以防止MASH诱导的肝纤维化

Roi Isaac¹, Gautam Bandyopadhyay¹, Theresa V Rohm¹

¹Division of Endocrinology & Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.

Cell metabolism

|April 26, 2024

概括

TM7SF3蛋白缺失通过促进肝星细胞 (HSC) 激活来加速肝纤维化. 抑制TEAD1的替代拼接与反感性寡合物 (ASO) 减少纤维化,提供一个潜在的治疗策略.

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
细胞生物学细胞生物学

背景情况:

驱动肝星细胞 (HSC) 激活和肝纤维化的精确机制仍未完全阐明.
了解这些过程对于开发有效的肝脏疾病治疗方法至关重要,例如代谢功能障碍相关的脂肪肝炎 (MASH).

研究的目的:

研究核膜蛋白TM7SF3在HSC激活和肝纤维化中的作用.
确定MASH相关肝纤维化治疗干预的分子标.

主要方法:

使用肝脏器官,人类初级HSC和体内MASH小鼠模型.
研究了TM7SF3删除/抑制对HSC激活和纤维基因基因表达的影响.
分析了Hippo通路转录因子TEAD1的替代拼接,重点关注异质核核核糖核蛋白U (hnRNPU) 的作用.
在体外和体内使用反感性寡合体 (ASOs) 抑制TEAD1的替代拼接.

主要成果:

在各种模型中,TM7SF3删除加速了HSC激活,纤维化程序激活和HSC扩散.
TM7SF3的淘汰通过抑制hNRNPU促进了TEAD1的替代拼接,从而排除了抑制性外子5并产生了更活跃的TEAD1.
使用ASO抑制TEAD1替代拼接,在实验室中禁用了HSC,并在MASH小鼠中改善了肝纤维化.

结论:

TM7SF3通过调节TEAD1替代拼接,在抑制HSC激活和MASH相关的肝纤维化方面发挥着关键作用.
准TEAD1替代拼接是一种有前途的治疗策略,用于管理MASH中的肝纤维化.

关键词:

在ASO的基础上,ASO是ASO.河马的路径河马的路径马什 (MASH) 是一个非常重要的产品.纳什·纳什 (Nash Nash) 是一个名为纳什的城市.我们的 TEAD1 团队.TM7SF3SF3 在线观看替代性拼接是一种替代性的拼接.纤维化纤维化肝脏的恒星细胞.

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