J Hepatology: 肝细胞β-连环蛋白的丧失可以保护小鼠免于实验性卟啉症相关的肝损伤

2018-12-17 MedSci MedSci原创

卟啉症(Porphyrias)是由血红素生物合成酶的异常引起的,它可导致肝硬化和肝细胞癌。在小鼠中,这种疾病可以通过给予含有3,5-二乙氧基羰基-1,4-二氢可乐定(DDC)的饮食来进行模型制作,该饮食引起卟啉中间体的积累,导致肝胆损伤。目前有文献表明Wnt /β-连环蛋白信号传导是胆道损伤模型中的可调节靶标; 因此,研究人员希望探明它在DDC驱动的损伤中的作用。

背景与目的
卟啉症(Porphyrias)是由血红素生物合成酶的异常引起的,它可导致肝硬化和肝细胞癌。在小鼠中,这种疾病可以通过给予含有3,5-二乙氧基羰基-1,4-二氢可乐定(DDC)的饮食来进行模型制作,该饮食引起卟啉中间体的积累,导致肝胆损伤。目前有文献表明Wnt /β-连环蛋白信号传导是胆道损伤模型中的可调节靶标; 因此,研究人员希望探明它在DDC驱动的损伤中的作用。

方法
研究人员将β-连环蛋白(Ctnnb1)敲除(KO)小鼠,Wnt共受体KO小鼠和同窝对照饲喂DDC饮食2周。通过在DDC饮食后给小鼠施用与脂质纳米颗粒缀合的β-连环蛋白二聚体 - 底物RNA(DsiRNA),然后每周一次,持续4周,在肝细胞中外源性抑制β-连环蛋白,在进行试验的同时研究人员收集小鼠的血清和肝脏; 通过组织学,蛋白质印迹和实时PCR分析肝脏组织学情况。通过荧光,偏振光图像和液相色谱 - 质谱法测量卟啉含量。

结果
与对照相比,缺乏β-连环蛋白或Wnt信号传导的DDC喂养的小鼠肝损伤是减少的。与接受脂质纳米颗粒的对照小鼠相比,在DDC喂养期间经历DsiRNA抑制β-连环蛋白的外源小鼠也显示出较少的损伤。对照组中肝脏含有广泛的卟啉沉积物,其在缺乏β-连环蛋白信号传导的小鼠中基本上不存在。值得注意的是,研究人员确定了一个关键的血红素生物合成酶网络,这些酶在没有β-连环蛋白的情况下会被抑制,从而防止有毒原卟啉的积累。另外,缺乏β-连环蛋白的小鼠表现出较少的蛋白质聚集体,改善的蛋白酶体活性和减少的自噬诱导,所有这些都有助于保护免受损伤。

结论
β-连环蛋白通过其对代谢,细胞应激和自噬的多效性抑制作用,为卟啉症患者提供了一种新的治疗方法。

原始出处:

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    2019-02-03 lujian
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    2019-09-01 xjy02
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    2018-12-19 gwc384

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