Sphingosine-1-phosphate signaling and the gut-liver axis in liver diseases

The liver is the central organ involved in lipid metabolism and the gastrointestinal (GI) tract is responsible for nutrient absorption and partitioning. Obesity, dyslipidemia and metabolic disorders are of increasing public health concern worldwide, and novel therapeutics that target both the liver and the GI tract (gut-liver axis) are much needed. In addition to aiding fat digestion, bile acids act as important signaling molecules that regulate lipid, glucose and energy metabolism via activating nuclear receptor, G protein-coupled receptors (GPCRs), Takeda G protein receptor 5 (TGR5) and sphingosine-1-phosphate receptor 2 (S1PR2). Sphingosine-1-phosphate (S1P) is synthesized by two sphingosine kinase isoforms and is a potent signaling molecule that plays a critical role in various diseases such as fatty liver, inflammatory bowel disease (IBD) and colorectal cancer. In this review, we will focus on recent findings related to the role of S1P-mediated signaling pathways in the gut-liver axis.