The zonula occludens protein family regulates the hepatic barrier system in the murine liver
The zonula occludens protein family regulates the hepatic barrier system in the murine liver
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DOI：
10.1016/j.bbadis.2020.165994
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发表时间：
2021-01-01
影响因子：
6.2
通讯作者：
Sugimoto, Hiroyuki
中科院分区：
文献类型：
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作者：
Itoh, Masahiko;Terada, Misao;Sugimoto, Hiroyuki
肝屏障对于肝脏的生理功能是不可缺少的，并且在各种病理条件下受损。据报道，紧密连接在肝屏障调节中发挥核心作用;然而，支持这一观察结果的直接证据有限，迄今为止，几乎没有体内模型或确认所涉及的分子机制。我们在小鼠肝脏中灭活了紧密连接组分基因Tjp 2/ZO-2和相关分子Tjp 1/ZO-1。在人类中，TJP 2/ZO-2突变与人类进行性家族性肝内胆汁淤积4（PFIC 4）的发生有关。肝脏中ZO-1或ZO-2缺陷的小鼠未表现出重大异常。然而，这两种分子的消融损害了肝细胞紧密连接的分子结构以及结构和功能，这破坏了肝屏障，并在6周龄时对小鼠致命。在突变小鼠中，胆小管形成和细胞极性受损;此外，转运蛋白表达和定位失调。此外，典型的肝分区和胆管形成受到抑制，窦血管紊乱。这些发现阐明了紧密连接和极性在肝屏障中的作用，以及它们的破坏对肝组织的影响。这些观察结果还表明，肝脏特异性ZO-1（-/-）和ZO-2（-/-）小鼠可用作PFIC 4的模型，这将为肝脏病理生理学和临床应用提供新的见解。
The hepatic barrier is indispensable for the physiological functions of the liver and is impaired under various pathological conditions. Tight junctions reportedly play a central role in hepatic barrier regulation; however, there is limited direct evidence supporting this observation, with few in vivo models or confirmations of the implicated molecular mechanisms presented to date. We inactivated the tight junction component gene, Tjp2/ZO-2, and the related molecule, Tjp1/ZO-1, in mouse livers. In humans, TJP2/ZO-2 mutations have been implicated in the development of human progressive familial intrahepatic cholestasis 4 (PFIC4). The mice deficient in either ZO-1 or ZO-2 in the liver did not exhibit major abnormalities. However, the ablation of both molecules impaired the molecular architecture as well as the structure and function of hepatocyte tight junctions, which disrupted the hepatic barrier and was lethal to the mice by 6 weeks of age. In mutant mice, bile canaliculus formation and cellular polarity were compromised; also, transporter expression and localization were deregulated. Moreover, typical hepatic zonation and bile duct formation were inhibited, and sinusoidal vessels were disorganized. These findings clarify the role of tight junctions and polarity in the hepatic barrier as well as the effect that their disruption has on liver tissue. The observations also suggest that liver-specific ZO-1(-/- )and ZO-2(-/-) mice could be used as models for PFIC4, and this will provide new insights into liver pathophysiology and clinical applications.