基蛋白4是TGFβ1诱导的肝星细胞激活的关键分子驱动因素
Feifan Xu1, Sidan Lu1, Nachuan Pan2
1Department of Biochemistry & Molecular Biology, Medical School, Nantong University, Qi xiou Road 19, Nantong 226001, Jiangsu, China.
Biochimica et biophysica acta. Molecular cell research
|August 19, 2023
概括
原蛋白4 (BrD4) 通过调节肝星细胞激活来驱动肝纤维化. 向BrD4可以减少肝损伤和纤维化,为肝病提供潜在的治疗策略.
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
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
背景情况:
- 肝纤维化涉及过度的细胞外基质沉积,主要是由激活的肝星细胞 (HSC) 驱动的.
- 转化生长因子β1 (TGFβ1) 是纤维生成中的一个关键细胞因子.
- 基因蛋白4 (BrD4) 通过基因素乙化调节基因表达.
研究的目的:
- 研究BrD4在TGFβ1依赖性HSC激活和肝纤维化中的作用.
- 阐明BrD4影响纤维细胞通路的分子机制.
主要方法:
- 使用异性TGFβ1淘汰小鼠和BrD4淘汰模型 (体内和体外).
- 分析了纤维化标记物的蛋白质水平,信号通路组件 (Smad3,Stat3,Akt) 和表观遗传调节剂 (p300,NFkB p65).
- 从四化碳诱导的肝损伤模型和人类肝硬化样本中检查了HSC和肝脏组织中的蛋白质相互作用.
主要成果:
- 在HSC中,TGFβ1上调了BrD4蛋白水平.
- BrD4倒置显著降低了TGFβ1诱导的HSC激活和肝纤维化.
- BrD4调解了TGFβ1对PDGFβ受体,Smad3,Stat3和Akt通路的影响.
- BrD4调节的TGFβ1诱导的p300,NFkB p65和TIMP1的增加,并降低了Caspase-3.
- 在HSC和肝损伤模型中证明了BrD4和NFkB p65之间的相互作用.
- 在人类肝硬化患者中观察到BrD4和NFkB p65的并行增加.
结论:
- BrD4是TGFβ1诱导的HSC激活和肝纤维化的关键媒介.
- BrD4在纤维化过程中起到关键的分子驱动作用.
- 准BrD4为肝纤维化提供了潜在的治疗途径.
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