The role of sphingosine 1‐phosphate receptor 2 in bile‐acid–induced cholangiocyte proliferation and cholestasis‐induced liver injury in mice

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 s...

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Published in:Hepatology (Baltimore, Md.) Md.), 2017-06, Vol.65 (6), p.2005-2018
Main Authors: Wang, Yongqing, Aoki, Hiroaki, Yang, Jing, Peng, Kesong, Liu, Runping, Li, Xiaojiaoyang, Qiang, Xiaoyan, Sun, Lixin, Gurley, Emily C., Lai, Guanhua, Zhang, Luyong, Liang, Guang, Nagahashi, Masayuki, Takabe, Kazuaki, Pandak, William M., Hylemon, Phillip B., Zhou, Huiping
Format: Article
Language:English
Subjects:
AKT protein
Analysis of Variance
Animals
Apoptosis
Bile
Bile acids
Bile Acids and Salts - pharmacology
Bile Duct Neoplasms - metabolism
Bile Duct Neoplasms - pathology
Bile ducts
Bile Ducts - surgery
Cell proliferation
Cell Proliferation - drug effects
Cell Proliferation - physiology
Cholangiocarcinoma
Cholangiocarcinoma - metabolism
Cholangiocarcinoma - pathology
Cholangitis, Sclerosing - metabolism
Cholangitis, Sclerosing - pathology
Cholestasis
Cholestasis - complications
Cholestasis - pathology
Disease Models, Animal
Extracellular signal-regulated kinase
Fibrosis
Hepatocytes
Hepatology
Kinases
Ligation
Liver
Liver - injuries
Liver - pathology
Liver Cirrhosis - metabolism
Liver Cirrhosis - pathology
Liver diseases
Lysophospholipids - metabolism
Male
Mice
Mice, Inbred CBA
Mice, Knockout
Mitogen-Activated Protein Kinase 1 - metabolism
Random Allocation
Receptors, Lysosphingolipid - metabolism
Ribonucleic acid
RNA
Rodents
Role
Signal Transduction
Sphingosine - analogs & derivatives
Sphingosine - metabolism
Sphingosine 1-phosphate
Sphingosine-1-Phosphate Receptors
Up-Regulation
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Summary: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. Conclusion: 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).
ISSN:0270-9139
1527-3350
DOI:10.1002/hep.29076