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

Abstract

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).

• Authors: Yongqing Wang, Hiroaki Aoki, Jing Yang, Kesong Peng, Runping Liu, Xiaojiaoyang Li, Xiaoyan Qiang, Lixin Sun, Emily C Gurley, Guanhua Lai, Luyong Zhang, Guang Liang, Masayuki Nagahashi, Kazuaki Takabe, William M Pandak, Phillip B Hylemon, Huiping Zhou
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 65 Issue 6 Pg. 2005-2018 (06 2017) ISSN: 1527-3350 [Electronic] United States
• PMID: 28120434 (Publication Type: Journal Article)
• Copyright: © 2017 by the American Association for the Study of Liver Diseases.

Chemical References

• Bile Acids and Salts
• Lysophospholipids
• Receptors, Lysosphingolipid
• Sphingosine-1-Phosphate Receptors
• sphingosine-1-phosphate receptor-2, mouse
• sphingosine 1-phosphate
• Mapk1 protein, mouse
• Mitogen-Activated Protein Kinase 1
• Sphingosine

Topics

• Analysis of Variance
• Animals
• Bile Acids and Salts (pharmacology)
• Bile Duct Neoplasms (metabolism, pathology)
• Bile Ducts (surgery)
• Cell Proliferation (drug effects, physiology)
• Cholangiocarcinoma (metabolism, pathology)
• Cholangitis, Sclerosing (metabolism, pathology)
• Cholestasis (complications, pathology)
• Disease Models, Animal
• Ligation
• Liver (injuries, pathology)
• Liver Cirrhosis (metabolism, pathology)
• Lysophospholipids (metabolism)
• Male
• Mice
• Mice, Inbred CBA
• Mice, Knockout
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Random Allocation
• Receptors, Lysosphingolipid (metabolism)
• Role
• Signal Transduction
• Sphingosine (analogs & derivatives, metabolism)
• Sphingosine-1-Phosphate Receptors
• Up-Regulation