Sphingosine kinase and sphingosine-1-phosphate in liver pathobiology

Abstract

Over 20 years ago, sphingosine-1-phosphate (S1P) was discovered to be a bioactive signaling molecule. Subsequent studies later identified two related kinases, sphingosine kinase 1 and 2, which are responsible for the phosphorylation of sphingosine to S1P. Many stimuli increase sphingosine kinase activity and S1P production and secretion. Outside the cell, S1P can bind to and activate five S1P-specific G protein-coupled receptors (S1PR1–5) to regulate many important cellular and physiological processes in an autocrine or paracrine manner. S1P is found in high concentrations in the blood where it functions to control vascular integrity and trafficking of lymphocytes. Obesity increases blood S1P levels in humans and mice. With the world wide increase in obesity linked to consumption of high-fat, high-sugar diets, S1P is emerging as an accomplice in liver pathobiology, including acute liver failure, metabolic syndrome, control of blood lipid and glucose homeostasis, nonalcoholic fatty liver disease, and liver fibrosis. Here, we review recent research on the importance of sphingosine kinases, S1P, and S1PRs in liver pathobiology, with a focus on exciting insights for new therapeutic modalities that target S1P signaling axes for a variety of liver diseases.

Keywords:

• Metabolic syndrome
• nonalcoholic fatty liver disease
• sphingosine-1-phosphate
• acute liver failure
• steatosis

Disclosure statement

The authors declare that they have no conflicts of interest with the contents of this article.

Additional information

Funding

This work was supported by National Institutes of Health grant No. R01GM043880 to S.S. T.R. was supported by T32 training grant in Digestive Disease and Liver Disease 5T32DK007150–39.