Knockdown of ezrin causes intrahepatic cholestasis by the dysregulation of bile fluidity in the bile duct epithelium in mice.
Knockdown of ezrin causes intrahepatic cholestasis by the dysregulation of bile fluidity in the bile duct epithelium in mice.
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DOI：
10.1002/hep.27565
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发表时间：
2015-05
期刊：
影响因子：
--
通讯作者：
Asano S
中科院分区：
文献类型：
--
作者：
Hatano R;Akiyama K;Tamura A;Hosogi S;Marunaka Y;Caplan MJ;Ueno Y;Tsukita S;Asano S
胆管疾病有共同的特征，包括胆管增生、门静脉周围纤维化和肝内胆汁淤积。自身免疫性疾病、病毒感染、毒性化合物和发育异常引起的胆管上皮损伤导致严重的进行性肝脏疾病，导致高死亡率。然而，这些胆汁淤积性疾病的病因仍然不清楚，因为没有可用的模型来研究致病机制。在本研究中，我们发现ezrin敲低（Vil 2kd/kd）小鼠发生严重的肝内胆汁淤积，其特征是广泛的胆管增生，管周纤维化，肝内胆汁酸积累，而胆管形态发育缺陷和炎性细胞浸润。Ezrin是一种膜细胞骨架交联蛋白，已知其与质膜上的转运蛋白、支架蛋白和肌动蛋白细胞骨架相互作用。我们发现Vil 2kd/kd小鼠胆管中几种转运蛋白包括囊性纤维化跨膜传导调节因子（CFTR）、阴离子交换因子2（AE-2）、水通道蛋白1（AQP 1）和Na+/H+交换调节因子的正常顶膜定位受到干扰。在永生化小鼠胆管细胞中稳定表达显性负性形式的ezrin也导致CFTR，AE-2和AQP 1的表面表达减少。这些转运蛋白的表面表达减少伴随着功能表达减少，这一点可以通过这些细胞表现出CFTR介导的Cl−外排活性降低来证明。此外，Vil 2kd/kd小鼠的胆汁流量和胆汁HCO 3 −浓度也显著降低。结论：埃兹蛋白功能障碍模仿负责胆管疾病的病理机制的重要方面。Vil 2kd/kd小鼠可能是开发和测试胆管病潜在疗法的有用模型。
Cholangiopathies share common features, including bile duct proliferation, periportal fibrosis, and intrahepatic cholestasis. Damage of biliary epithelium by autoimunne disorder, virus infection, toxic compounds, and developmental abnormalities causes severe progressive hepatic disorders responsible for high mortality. However, the etiologies of these cholestatic diseases remain unclear because useful models to study the pathogenic mechanisms are not available. In the present study, we have found that ezrin knockdown (Vil2kd/kd) mice develop severe intrahepatic cholestasis characterized by extensive bile duct proliferation, periductular fibrosis, and intrahepatic bile acid accumulation without developmental defects of bile duct morphology and infiltration of inflammatory cells. Ezrin is a membrane cytoskeletal cross-linker protein, which is known to interact with transporters, scaffold proteins, and actin cytoskeleton at the plasma membrane. We found that the normal apical membrane localizations of several transport proteins including cystic fibrosis transmembrane conductance regulator (CFTR), anion exchanger 2 (AE-2), aquaporin 1 (AQP1), and Na+/H+ exchanger regulatory factor were disturbed in bile ducts of Vil2kd/kd mice. Stable expression of a dominant negative form of ezrin in immortalized mouse cholangiocytes also led to the reduction of the surface expression of CFTR, AE-2, and AQP1. Reduced surface expression of these transport proteins was accompanied by reduced functional expression, as evidenced by the fact these cells exhibited decreased CFTR-mediated Cl− efflux activity. Furthermore, bile flow and biliary HCO3− concentration were also significantly reduced in Vil2kd/kd mice. Conclusion: Dysfunction of ezrin mimics important aspects of the pathological mechanisms responsible for cholangiopathies. The Vil2kd/kd mouse may be a useful model to exploit in the development and testing of potential therapies for cholangiopathies.
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影响因子：
29.4
作者：
Salas, January T.;Banales, Jesus M.;Medina, Juan F.
通讯作者：
Medina, Juan F.
影响因子：
3.7
作者：
Hayashi H;Tamura A;Krishnan D;Tsukita S;Suzuki Y;Kocinsky HS;Aronson PS;Orlowski J;Grinstein S;Alexander RT
通讯作者：
Alexander RT
影响因子：
11.4
作者：
Dransfield, DT;Bradford, AJ;Goldenring, JR
通讯作者：
Goldenring, JR
DOI：
10.1083/jcb.200410083
发表时间：
2005-04-11
期刊：
The Journal of cell biology
影响因子：
--
作者：
Tamura A;Kikuchi S;Hata M;Katsuno T;Matsui T;Hayashi H;Suzuki Y;Noda T;Tsukita S;Tsukita S
通讯作者：
Tsukita S
DOI：
10.1073/pnas.0135434100
发表时间：
2003-01-07
影响因子：
11.1
作者：
Naren, AP;Cobb, B;Clancy, JP
通讯作者：
Clancy, JP