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在肝纤维化期间,对低氧诱导因子转录活性进行UCHL1-依赖的控制

Amy Collins¹, Rebecca Scott¹, Caroline L Wilson¹

¹Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, U.K.

Bioscience reports

|May 29, 2024

概括

乌比奎丁C终端酶1 (UCHL1) 调节肝纤维化中缺氧诱导因子1 (HIF1) 的活性. 抑制UCHL1可降低亲纤维基因表达和细胞增殖,提供一种潜在的治疗策略.

科学领域:

细胞生物学细胞生物学
分子生物学分子生物学
胃肠病学胃肠病学

背景情况:

肝纤维化涉及过度的细胞外基质积累和肝星细胞 (HSC) 激活.
激活的HSCs由于基因表达的改变而表现出收缩性,增殖性和益菌性功能.
在HSC激活过程中,二基基酶泛基酸C终端酸酶1 (UCHL1) 的上调,但其点尚不清楚.

研究的目的:

为了研究UCHL1在调节低氧诱导因子1 (HIF1) 在HSC激活和肝纤维化期间的作用.
阐明UCHL1影响HIF1活动和益纤维细胞过程的机制.
评估UCHL1抑制在肝纤维化中的治疗潜力.

主要方法:

在HSC激活过程中与UCHL1mRNA和蛋白质水平相关联的HIF1α表达.
利用基因删除和UCHL1的化学抑制来评估其对HIF活动的影响.
进行机理学研究,以了解UCHL1对HIF1α的脱化活性.
在纤维化3D人肝切片模型中测试UCHL1抑制.

主要成果:

UCHL1通过控制HIF1α水平来调节HIF1的活动.
对UCHL1的遗传删除或化学抑制会降低HIF活性和HIF目标基因表达.
UCHL1通过切割无素链来促进亲纤维基因表达和增殖率.
在临床前的人类肝脏模型中,UCHL1抑制有效地抑制纤维生成.

结论:

UCHL1通过调节HIF1活动,在HSC激活和肝纤维化中发挥关键作用.
小分子抑制剂向duibiquitinases (DUBs),如UCHL1,可以在肝脏疾病中治疗调节HIF转录因子.
通过UCHL1抑制剂抑制HIF活性,为肝纤维化和其他与HIF相关的病理提供了潜在的治疗策略.

关键词:

在这里,dub,dub,dub,dub,dub,dub.在UCHL1上.没有二维基丁酶.缺氧诱导因素可以诱导缺氧.肝脏纤维化肝脏纤维化

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