Yes-associated protein regulates the hepatic response after bile duct ligation.
Yes-associated protein regulates the hepatic response after bile duct ligation.
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DOI：
10.1002/hep.25769
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发表时间：
2012-09
期刊：
影响因子：
13.5
通讯作者：
Anders, Robert A.
中科院分区：
文献类型：
--
作者：
Bai, Haibo;Zhang, Nailing;Xu, Yang;Chen, Qian;Khan, Mehtab;Potter, James J.;Nayar, Suresh K.;Cornish, Toby;Alpini, Gianfranco;Bronk, Steven;Pan, Duojia;Anders, Robert A.
人类慢性胆汁淤积性肝脏疾病的特征是胆管细胞增生、肝细胞损伤和纤维化。Yes相关蛋白（雅普）是Hippo肿瘤抑制通路的效应子，在胚胎肝脏发育和肝细胞癌变过程中，对促进胆管细胞和肝细胞的增殖和存活起重要作用。因此，本研究的目的是检查雅普是否参与胆汁淤积性损伤后的再生反应。首先，我们检查了慢性胆汁淤积患者的肝脏组织。我们发现在原发性硬化性胆管炎和原发性胆汁性肝硬化患者的肝脏样本中，胆管反应的核雅普更活跃。接下来，我们使用小鼠胆管结扎（BDL）模型诱导胆汁淤积性肝损伤。我们发现野生型小鼠BDL后雅普活性发生显著变化。用小鼠肝脏特异性雅普条件性缺失进一步评价雅普在BDL后肝脏反应中的功能。在小鼠肝脏中添加雅普不仅损害胆管增殖，而且在BDL后增强肝细胞坏死并抑制肝细胞增殖。此外，原代肝细胞和胆管细胞分离Yap缺陷的肝脏表现出减少增殖反应表皮生长因子在体外。最后，我们证明了雅普可能通过调节生存素表达来介导其生物学效应。结论：我们的数据表明，雅普促进胆管细胞和肝细胞增殖，并防止实质损伤后胆汁淤积性损伤小鼠，因此可能介导的反应胆汁淤积诱导的人类肝脏疾病。（肝病学2012;56：1097-1107）
Human chronic cholestatic liver diseases are characterized by cholangiocyte proliferation, hepatocyte injury, and fibrosis. Yes-associated protein (YAP), the effector of the Hippo tumor-suppressor pathway, has been shown to play a critical role in promoting cholangiocyte and hepatocyte proliferation and survival during embryonic liver development and hepatocellular carcinogenesis. Therefore, the aim of this study was to examine whether YAP participates in the regenerative response after cholestatic injury. First, we examined human liver tissue from patients with chronic cholestasis. We found more-active nuclear YAP in the bile ductular reactions of primary sclerosing cholangitis and primary biliary cirrhosis patient liver samples. Next, we used the murine bile duct ligation (BDL) model to induce cholestatic liver injury. We found significant changes in YAP activity after BDL in wild-type mice. The function of YAP in the hepatic response after BDL was further evaluated with liver-specific Yap conditional deletion in mice. Ablating Yap in the mouse liver not only compromised bile duct proliferation, but also enhanced hepatocyte necrosis and suppressed hepatocyte proliferation after BDL. Furthermore, primary hepatocytes and cholangiocytes isolated from Yap-deficient livers showed reduced proliferation in response to epidermal growth factor in vitro. Finally, we demonstrated that YAP likely mediates its biological effects through the modulation of Survivin expression. Conclusion: Our data suggest that YAP promotes cholangiocyte and hepatocyte proliferation and prevents parenchymal damage after cholestatic injury in mice and thus may mediate the response to cholestasis-induced human liver disease. (Hepatology 2012;56:1097–1107)
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影响因子：
64.5
作者：
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通讯作者：
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影响因子：
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作者：
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DOI：
10.1073/pnas.0911427107
发表时间：
2010-01-26
影响因子：
11.1
作者：
Lu, Li;Li, Ying;Johnson, Randy L.
通讯作者：
Johnson, Randy L.