胆管上皮细胞
胆汁淤积
肝损伤
蛋白激酶B
熊去氧胆酸
1-磷酸鞘氨醇
信号转导
癌症研究
生物
脂质信号
胆汁酸
鞘氨醇
内科学
内分泌学
细胞生物学
生物化学
受体
医学
作者
Yongqing Wang,Hiroaki Aoki,Jing Yang,Kesong Peng,Runping Liu,Xiaojiaoyang Li,Xiaoyan Qiang,Lixin Sun,Emily C. Gurley,Guan‐Hua Lai,Luyong Zhang,Guang Liang,Masayuki Nagahashi,Kazuaki Takabe,William M. Pandak,Phillip B. Hylemon,Huiping Zhou
出处
期刊:Hepatology
[Wiley]
日期:2017-01-25
卷期号:65 (6): 2005-2018
被引量:174
摘要
Bile duct obstruction is a potent stimulus for cholangiocyte proliferation, especially for large cholangiocytes. Our previous studies reported that conjugated bile acids (CBAs) activate the protein kinase B (AKT) and extracellular signal-regulated kinase 1 and 2 (ERK1/2) signaling pathways through sphingosine 1-phosphate receptor (S1PR) 2 in hepatocytes and cholangiocarcinoma cells. It also has been reported that taurocholate (TCA) promotes large cholangiocyte proliferation and protects cholangiocytes from bile duct ligation (BDL)-induced apoptosis. However, the role of S1PR2 in bile-acid-mediated cholangiocyte proliferation and cholestatic liver injury has not been elucidated. Here, we report that S1PR2 is the predominant S1PR expressed in cholangiocytes. Both TCA- and sphingosine-1-phosphate (S1P)-induced activation of ERK1/2 and AKT were inhibited by JTE-013, a specific antagonist of S1PR2, in cholangiocytes. In addition, TCA- and S1P-induced cell proliferation and migration were inhibited by JTE-013 and a specific short hairpin RNA of S1PR2, as well as chemical inhibitors of ERK1/2 and AKT in mouse cholangiocytes. In BDL mice, expression of S1PR2 was up-regulated in whole liver and cholangiocytes. S1PR2 deficiency significantly reduced BDL-induced cholangiocyte proliferation and cholestatic injury, as indicated by significant reductions in inflammation and liver fibrosis in S1PR2 knockout mice. Treatment of BDL mice with JTE-013 significantly reduced total bile acid levels in serum and cholestatic liver injury.This study suggests that CBA-induced activation of S1PR2-mediated signaling pathways plays a critical role in obstructive cholestasis and may represent a novel therapeutic target for cholestatic liver diseases. (Hepatology 2017;65:2005-2018).
科研通智能强力驱动
Strongly Powered by AbleSci AI