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

TLDR

Bile duct obstruction drives proliferation of large cholangiocytes, and conjugated bile acids activate AKT and ERK1/2 signaling through S1PR2, while taurocholate promotes proliferation and protects against BDL‑induced apoptosis. The study aimed to determine the role of S1PR2 in bile‑acid‑mediated cholangiocyte proliferation and cholestatic liver injury. S1PR2 is the predominant receptor in cholangiocytes, and its activation by taurocholate or S1P drives ERK1/2 and AKT signaling, proliferation, and migration, all of which are blocked by the antagonist JTE‑013 or S1PR2 knockdown; in bile‑duct‑ligated mice, S1PR2 is up‑regulated, and its deficiency or pharmacologic inhibition markedly reduces cholangiocyte proliferation, inflammation, fibrosis, and serum bile acid levels, indicating that S1PR2‑mediated signaling is a key driver of obstructive cholestasis and a potential therapeutic target. Hepatology 2017;65:2005‑2018.

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).