在肝脏疾病包括囊性纤维化(CF)中观察到导管反应(DR)期间胆管上皮细胞(BECs)的扩增,并与炎症和纤维化有关,尽管对潜在机制没有完全理解。使用两种不同的β-catenin基因敲除小鼠,β-连环蛋白丢失的一个是肝细胞和BECs(KO1),和另一个只有肝细胞(KO2)的损失,我们证明了2周胆碱缺乏乙硫氨酸补充饮食在初次损伤后不同的长期修复。KO2显示BEC衍生的β-连环蛋白阳性肝细胞的逐渐肝再增殖和损伤的解决。KO1显示β-连环蛋白持续丢失,NF-κB在BECs中的激活,进行性DR和纤维化,让人想起CF组织学。我们确定了β-连环蛋白的相互作用,NFκB,和BECs中的CF跨膜电导调节剂(CFTR)。CFTR或β-catenin的缺失导致NF-κB激活,DR,和炎症。因此,我们报道了一种新的BECsβ-catenin-NFκB-CFTR相互作用组,其破坏可能与CF的肝脏病理有关。
肝脏具有令人难以置信的自我修复或“再生”能力——也就是说,它具有用新组织替换受损组织的能力。为了做到这一点,该器官依赖于肝细胞(形成肝脏的细胞)和胆管细胞(形成胆管的细胞)分裂和转化为彼此修复和替换受损组织,以防侮辱是可怕的。在长期或慢性肝损伤期间,胆管细胞经历一个叫做“导管反应”的过程,导致细胞繁殖并产生刺激炎症的蛋白质,并可能导致肝脏疤痕(纤维化)。导管反应是严重肝病的标志,不同的疾病表现出不同特征的导管反应。例如,在囊性纤维化中,一种独特类型的导管反应发生在后期,同时伴有炎症和纤维化。尽管导管反应在肝脏疾病中起作用,它是如何在分子水平上工作的还不是很清楚。胡等人。着手研究一种称为β-连环蛋白的蛋白质——它可以导致许多类型的细胞增殖——是如何参与导管反应的。他们在实验中使用了三种类型的小鼠:野生型小鼠,没有转基因;和两株转基因小鼠。其中一只突变小鼠在胆管细胞中不产生β-catenin,而另一种在胆管细胞和肝细胞中均缺乏β-catenin。短暂的肝损伤后-Hu等人。通过给小鼠喂食特定的饮食引起的-野生型小鼠能够再生和修复肝脏而不表现出任何导管反应。肝细胞中缺乏β-连环蛋白的突变小鼠表现出暂时的导管反应,并最终通过将胆管细胞转化为肝细胞来修复他们的肝脏。另一方面,在肝细胞和胆管细胞中缺乏β-catenin的突变小鼠表现出持续的导管反应,炎症和纤维化,这看起来像在与囊性纤维化相关的肝病患者中看到的。进一步的探测表明,β-连环蛋白与一种称为CTFR的蛋白质相互作用,与囊性纤维化有关。当胆管细胞缺乏这些蛋白质时,另一种叫做NF-B的蛋白质被激活,导致导管反应,导致炎症和纤维化。胡等人的发现。阐明β-连环蛋白在导管反应中的作用。Further,结果表明,β-catenin之间存在先前未知的相互作用,CTFR和NF-B,这可能会导致更好的治疗囊性纤维化的未来。
Expansion of biliary epithelial cells (BECs) during ductular reaction (DR) is observed in liver diseases including cystic fibrosis (CF), and associated with inflammation and fibrosis, albeit without complete understanding of underlying mechanism. Using two different genetic mouse knockouts of β-catenin, one with β-catenin loss is hepatocytes and BECs (KO1), and another with loss in only hepatocytes (KO2), we demonstrate disparate long-term repair after an initial injury by 2-week choline-deficient ethionine-supplemented diet. KO2 show gradual liver repopulation with BEC-derived β-catenin-positive hepatocytes and resolution of injury. KO1 showed persistent loss of β-catenin, NF-κB activation in BECs, progressive DR and fibrosis, reminiscent of CF histology. We identify interactions of β-catenin, NFκB, and CF transmembranous conductance regulator (CFTR) in BECs. Loss of CFTR or β-catenin led to NF-κB activation, DR, and inflammation. Thus, we report a novel β-catenin-NFκB-CFTR interactome in BECs, and its disruption may contribute to hepatic pathology of CF.
The liver has an incredible capacity to repair itself or ‘regenerate’ – that is, it has the ability to replace damaged tissue with new tissue. In order to do this, the organ relies on hepatocytes (the cells that form the liver) and bile duct cells (the cells that form the biliary ducts) dividing and transforming into each other to repair and replace damaged tissue, in case the insult is dire. During long-lasting or chronic liver injury, bile duct cells undergo a process called ‘ductular reaction’, which causes the cells to multiply and produce proteins that stimulate inflammation, and can lead to liver scarring (fibrosis). Ductular reaction is a hallmark of severe liver disease, and different diseases exhibit ductular reactions with distinct features. For example, in cystic fibrosis, a unique type of ductular reaction occurs at late stages, accompanied by both inflammation and fibrosis. Despite the role that ductular reaction plays in liver disease, it is not well understood how it works at the molecular level. Hu et al. set out to investigate how a protein called β-catenin – which can cause many types of cells to proliferate – is involved in ductular reaction. They used three types of mice for their experiments: wild-type mice, which were not genetically modified; and two strains of genetically modified mice. One of these mutant mice did not produce β-catenin in biliary duct cells, while the other lacked β-catenin both in biliary duct cells and in hepatocytes. After a short liver injury – which Hu et al. caused by feeding the mice a specific diet – the wild-type mice were able to regenerate and repair the liver without exhibiting any ductular reaction. The mutant mice that lacked β-catenin in hepatocytes showed a temporary ductular reaction, and ultimately repaired their livers by turning bile duct cells into hepatocytes. On the other hand, the mutant mice lacking β-catenin in both hepatocytes and bile duct cells displayed sustained ductular reactions, inflammation and fibrosis, which looked like that seen in patients with liver disease associated to cystic fibrosis. Further probing showed that β-catenin interacts with a protein called CTFR, which is involved in cystic fibrosis. When bile duct cells lack either of these proteins, another protein called NF-B gets activated, which causes the ductular reaction, leading to inflammation and fibrosis. The findings of Hu et al. shed light on the role of β-catenin in ductular reaction. Further, the results show a previously unknown interaction between β-catenin, CTFR and NF-B, which could lead to better treatments for cystic fibrosis in the future.