Targeting cholangiocyte sphingosine-1-phosphate (S1P) receptor 1 signaling alleviates cholestatic liver injury: Mechanistic insight into S1P/phosphorylated signal transducer and activator of transcription 3 axis.

Effective first-line treatments for cholestasis are limited, leading to poor outcomes and liver transplantation after ursodeoxycholic acid/obeticholic acid intolerance. We investigated the role of cholangiocyte sphingosine-1-phosphate receptor 1 (S1PR1) in cholestasis pathogenesis to identify new therapeutic targets. We generated cholangiocyte-specific S1pr1 knockout mice (S1pr1Δintrahepatic biliary epithelial cell). Cholestasis models included bile duct ligation (BDL) (14 days) and 0.5% cholic acid (CA) diet (4 months). The level of sphingosine-1-phosphate (S1P) and its receptor, especially S1PR1 in cholangiocytes were significantly increased in both BDL or 0.5% CA diet models. Sphingosine kinase 1-derived sphingosine-1-phosphate from hepatic stellate cells/endothelial cells activated cholangiocyte S1PR1, promoting signal transducer and activator of transcription 3 phosphorylation and releasing interleukin-6/C-C motif chemokine 7, which remodeled the inflammatory microenvironment and exacerbated liver injury. S1PR1 deletion significantly reduced liver injury, fibrosis, and inflammation. Likewise, treatment with a specific inhibitor of cholangiocyte S1PR1, W146, slightly improved liver injury induced by BDL. The functional effect of S1PR1 in cholangiocyte was further strengthened by our design of the nanoparticle-delivered W146. This demonstrated that cholangiocytes-specific deletion of S1PR1 can alleviate liver fibrosis and injury caused by biliary obstruction or chronic cholestasis, which helps to develop S1PR1 as a target for the treatment of liver fibrosis and cholestasis. SIGNIFICANCE STATEMENT: This study identifies elevated sphingosine-1-phosphate as a potential cholestasis biomarker. High sphingosine-1-phosphate binds sphingosine-1-phosphate receptor 1, activating signal transducer and activator of transcription 3 in cholangiocytes and creating proinflammatory microenvironment. Cholangiocyte-specific sphingosine-1-phosphate receptor 1 inhibition via nanocrystal agents alleviates cholestatic liver injury.