肝损伤
肝细胞
胆管上皮细胞
胆汁淤积
Wnt信号通路
基因剔除小鼠
纤维化
熊去氧胆酸
化学
炎症
癌症研究
内分泌学
氧化应激
内科学
胆管
医学
胆汁酸
连环蛋白
连环素
细胞生物学
生物
条件基因敲除
信号转导
生物化学
体外
作者
Tirthadipa Pradhan-Sundd,Karis Kosar,Harvinder Saggi,Rong Zhang,Ravi Vats,Pamela Cornuet,Sydney Green,Sucha Singh,Gang Zeng,Prithu Sundd,Kari Nejak-Bowen
出处
期刊:Hepatology
[Wiley]
日期:2019-12-31
卷期号:71 (5): 1732-1749
被引量:18
摘要
Background and Aims The Wnt/β‐catenin signaling pathway has a well‐described role in liver pathobiology. Its suppression was recently shown to decrease bile acid (BA) synthesis, thus preventing the development of cholestatic liver injury and fibrosis after bile duct ligation (BDL). Approach and Results To generalize these observations, we suppressed β‐catenin in Mdr2 knockout (KO) mice, which develop sclerosing cholangitis due to regurgitation of BA from leaky ducts. When β‐catenin was knocked down (KD) in KO for 2 weeks, hepatic and biliary injury were exacerbated in comparison to KO given placebo, as shown by serum biochemistry, ductular reaction, inflammation, and fibrosis. Simultaneously, KO/KD livers displayed increased oxidative stress and senescence and an impaired regenerative response. Although the total liver BA levels were similar between KO/KD and KO, there was significant dysregulation of BA transporters and BA detoxification/synthesis enzymes in KO/KD compared with KO alone. Multiphoton intravital microscopy revealed a mixing of blood and bile in the sinusoids, and validated the presence of increased serum BA in KO/KD mice. Although hepatocyte junctions were intact, KO/KD livers had significant canalicular defects, which resulted from loss of hepatocyte polarity. Thus, in contrast to the protective effect of β‐catenin KD in BDL model, β‐catenin KD in Mdr2 KO aggravated rather than alleviated injury by interfering with expression of BA transporters, hepatocyte polarity, canalicular structure, and the regenerative response. Conclusions The resulting imbalance between ongoing injury and restitution led to worsening of the Mdr2 KO phenotype, suggesting caution in targeting β‐catenin globally for all cholestatic conditions.
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