Liver-specific β-catenin knockout mice have bile canalicular abnormalities, bile secretory defect, and intrahepatic cholestasis.
Liver-specific β-catenin knockout mice have bile canalicular abnormalities, bile secretory defect, and intrahepatic cholestasis.
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DOI：
10.1002/hep.23801
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发表时间：
2010-10
期刊：
影响因子：
13.5
通讯作者：
Behari, Jaideep
中科院分区：
文献类型：
--
作者：
Yeh, Tzu-Hsuan;Krauland, Lindsay;Singh, Vijay;Zou, Baobo;Devaraj, Prathab;Stolz, Donna B.;Franks, Jonathan;Monga, Satdarshan P. S.;Sasatomi, Eizaburo;Behari, Jaideep
β-Catenin在肝脏生理和肝癌发生中起重要作用。在研究β-catenin在饮食诱导的脂肪性肝炎中的作用时，我们最近发现肝脏特异性β-catenin敲除（KO）小鼠表现出肝内胆汁淤积。本研究旨在进一步表征β-连环蛋白在胆道生理学中的作用。KO小鼠和野生型（WT）同窝出生的小鼠喂食标准食物或补充0.5%胆酸的饮食两周。与WT小鼠相比，Chow喂养的KO小鼠具有更高的血清和肝脏总胆汁酸水平和更低的胆汁流速。胆汁酸生物合成基因的表达水平较低，主要胆汁酸输出者的水平相似，因此无法解释KO表型。尽管紧密连接蛋白claudin-2丢失，KO小鼠保留了紧密连接的功能完整性。KO小鼠具有胆小管形态异常，如通过F-肌动蛋白和闭合性胆固醇1染色所证明的。电子显微镜检查显示KO肝脏中胆管扩张和迂曲沿着小管和窦状微绒毛减少。接受胆酸饲料的KO小鼠具有较高的肝脏和血清胆汁酸水平、胆管反应、细胞周围纤维化增加以及扩张、畸形的胆小管。在KO肝脏中发现了几种胆汁酸转运蛋白和调控基因表达水平的补偿性变化。总之，肝脏特异性β-连环蛋白缺失导致有缺陷的胆小管形态、胆汁分泌缺陷和肝内胆汁淤积。因此，我们的研究结果确立了β-连环蛋白在胆道生理学中的关键作用。
β-Catenin plays important roles in liver physiology and hepatocarcinogenesis. While studying the role of β-catenin in diet-induced steatohepatitis, we recently found that liver-specific β-catenin knockout (KO) mice exhibit intrahepatic cholestasis. This study was undertaken to further characterize the role of β-catenin in biliary physiology. KO mice and wild type (WT) littermates were fed standard chow or 0.5% cholic acid supplemented diet for two weeks. Chow-fed KO mice had higher serum and hepatic total bile acid levels and lower bile flow rate than WT mice. Expression levels of bile acid biosynthetic genes were lower and levels of major bile acid exporters similar and, therefore, could not explain the KO phenotype. Despite loss of the tight junction protein claudin-2, KO mice had preserved functional integrity of tight junctions. KO mice had bile canalicular morphologic abnormalities as evidenced by staining for F-actin and zona occludens 1. Electron microscopy revealed dilated and tortuous bile canaliculi in KO livers along with decreased canalicular and sinusoidal microvilli. KO mice on cholic acid diet had higher hepatic and serum bile acid levels, bile ductular reaction, increased pericellular fibrosis, and dilated, misshapen bile canaliculi. Compensatory changes in expression levels of several bile acid transporters and regulatory genes were found in KO livers. In conclusion, liver-specific loss of β-catenin leads to defective bile canalicular morphology, bile secretory defect, and intrahepatic cholestasis. Thus, our results establish a critical role for β-catenin in biliary physiology.
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影响因子：
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作者：
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