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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >Liver-specific beta-catenin knockout mice have bile canalicular abnormalities, bile secretory defect, and intrahepatic cholestasis.
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Liver-specific beta-catenin knockout mice have bile canalicular abnormalities, bile secretory defect, and intrahepatic cholestasis.

机译：肝脏特异性β-catenin敲除小鼠患有胆管小管异常，胆汁分泌缺陷和肝内胆汁淤积。

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摘要

Beta-catenin plays important roles in liver physiology and hepatocarcinogenesis. While studying the role of beta-catenin in diet-induced steatohepatitis, we recently found that liver-specific beta-catenin knockout (KO) mice exhibit intrahepatic cholestasis. This study was undertaken to further characterize the role of beta-catenin in biliary physiology. KO mice and wild-type (WT) littermates were fed standard chow or a diet supplemented with 0.5% cholic acid for 2 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 were similar, which 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 a 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. CONCLUSION: Liver-specific loss of beta-catenin leads to defective bile canalicular morphology, bile secretory defect, and intrahepatic cholestasis. Thus, our results establish a critical role for beta-catenin in biliary physiology.
机译：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基因敲除（KO）小鼠表现出肝内胆汁淤积。进行该研究以进一步表征β-catenin在胆汁生理中的作用。给KO小鼠和野生型（WT）同窝仔喂标准食物或补充0.5％胆酸的饮食2周。饲喂KO的小鼠的血清和肝脏总胆汁酸水平高于WT小鼠，且胆汁流速较低。胆汁酸生物合成基因的表达水平较低，主要胆汁酸输出蛋白的水平相似，因此不能解释KO表型。尽管丧失了紧密连接蛋白claudin-2，KO小鼠仍保留了紧密连接的功能完整性。 KO小鼠胆汁小管形态异常，通过F-肌动蛋白和透明带闭合染色证实。电子显微镜显示KO肝中胆管小管弯曲和曲折，同时小管和正弦微绒毛减少。胆酸饮食的KO小鼠肝和血清胆汁酸水平较高，胆管反应，细胞周围纤维化增加，胆管小管畸形。在KO肝脏中发现了几种胆汁酸转运蛋白和调节基因的表达水平的代偿性变化。结论：β-catenin的肝脏特异性丢失导致胆管形态缺陷，胆汁分泌缺陷和肝内胆汁淤积。因此，我们的结果确立了β-catenin在胆汁生理中的关键作用。

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