title: 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.
  
  
  
  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.affiliation: Research Division of Clinical Pharmacology, the First Affiliated Hospital and Department of Pharmacy, Jiangsu shengze Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.|Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA.
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University, Richmond, VA.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Aoki
authors.affiliation: Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA.|China Pharmaceutical University, Nanjing, Jiangsu, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA.|College of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Kesong
authors.initials: K
authors.lastname: Peng
authors.affiliation: Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA.
authors.forename: Runping
authors.initials: R
authors.lastname: Liu
authors.affiliation: Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA.|China Pharmaceutical University, Nanjing, Jiangsu, China.
authors.forename: Xiaojiaoyang
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA.|China Pharmaceutical University, Nanjing, Jiangsu, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Qiang
authors.affiliation: Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA.|China Pharmaceutical University, Nanjing, Jiangsu, China.
authors.forename: Lixin
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA.|McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, VA.
authors.forename: Emily C
authors.initials: EC
authors.lastname: Gurley
authors.affiliation: Department of Pathology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA.
authors.forename: Guanhua
authors.initials: G
authors.lastname: Lai
authors.affiliation: China Pharmaceutical University, Nanjing, Jiangsu, China.
authors.forename: Luyong
authors.initials: L
authors.lastname: Zhang
authors.affiliation: College of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Guang
authors.initials: G
authors.lastname: Liang
authors.affiliation: Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata City, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nagahashi
authors.affiliation: Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA.|Breast Surgery, Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Takabe
authors.affiliation: McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, VA.
authors.forename: William M
authors.initials: WM
authors.lastname: Pandak
authors.affiliation: Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA.|McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, VA.
authors.forename: Phillip B
authors.initials: PB
authors.lastname: Hylemon
authors.affiliation: Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA.|McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, VA.|College of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Huiping
authors.initials: H
authors.lastname: Zhou
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001647:Bile Acids and Salts / Q000494:pharmacology; D001650:Bile Duct Neoplasms / Q000378:metabolism / Q000473:pathology; D001652:Bile Ducts / Q000601:surgery; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D018281:Cholangiocarcinoma / Q000378:metabolism / Q000473:pathology*; D015209:Cholangitis, Sclerosing / Q000378:metabolism / Q000473:pathology*; D002779:Cholestasis / Q000150:complications / Q000473:pathology*; D004195:Disease Models, Animal; D008026:Ligation; D008099:Liver / Q000293:injuries / Q000473:pathology; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology*; D008246:Lysophospholipids / Q000378:metabolism; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D011897:Random Allocation; D049349:Receptors, Lysosphingolipid / Q000378:metabolism*; D012380:Role; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D000081025:Sphingosine-1-Phosphate Receptors; D015854:Up-Regulation
chemical_list: D001647:Bile Acids and Salts; D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; D000081025:Sphingosine-1-Phosphate Receptors; C533955:sphingosine-1-phosphate receptor-2, mouse; C060506:sphingosine 1-phosphate; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D013110:Sphingosine