sphingosine-1-phosphate and Syndrome

Sphingosine-1-phosphate lyase (SPL) is an intracellular enzyme that controls the final step in the sphingolipid degradative pathway, the only biochemical pathway for removal of sphingolipids. Specifically, SPL catalyzes the cleavage of sphingosine 1-phosphate (S1P) at the C2-3 carbon bond, resulting in its irreversible degradation to phosphoethanolamine (PE) and hexadecenal. The substrate of the reaction, S1P, is a bioactive sphingolipid metabolite that signals through a family of five G protein-coupled S1P receptors (S1PRs) to mediate biological activities including cell migration, cell survival/death/proliferation and cell extrusion, thereby contributing to development, physiological functions and - when improperly regulated - the pathophysiology of disease. In 2017, several groups including ours reported a novel childhood syndrome that featured a wide range of presentations including fetal hydrops, steroid-resistant nephrotic syndrome (SRNS), primary adrenal insufficiency (PAI), rapid or insidious neurological deterioration, immunodeficiency, acanthosis and endocrine abnormalities. In all cases, the disease was attributed to recessive mutations in the human SPL gene, SGPL1. We now refer to this condition as SPL Insufficiency Syndrome, or SPLIS. Some features of this new sphingolipidosis were predicted by the reported phenotypes of Sgpl1 homozygous null mice that serve as vertebrate SPLIS disease models. However, other SPLIS features reveal previously unrecognized roles for SPL in human physiology. In this review, we briefly summarize the biochemistry, functions and regulation of SPL, the main clinical and biochemical features of SPLIS and what is known about the pathophysiology of this condition from murine and cell models. Lastly, we consider potential therapeutic strategies for the treatment of SPLIS patients.

Topics: Aldehyde-Lyases; Animals; Cell Movement; Disease Models, Animal; Humans; Lipid Metabolism, Inborn Errors; Lysophospholipids; Mice; Mice, Mutant Strains; Sphingosine; Syndrome

A previous in vitro study showed that sphingosine-1-phosphate (S1P), a ceramide antagonist, preserved endothelial cells in culture from radiation-induced apoptosis. We proposed to validate the role of S1P in tissue radioprotection by inhibiting acute gastrointestinal (GI) syndrome induced by endothelial cell apoptosis after high dose of radiation. Retro-orbital S1P was injected in mice exposed to 15 Gy, a dose-inducing GI syndrome within 10 days. Overall survival and apoptosis on intestines sections were studied. Intestinal cell type targeted by S1P and early molecular survival pathways were researched using irradiated in vitro cell models and in vivo mouse models. We showed that retro-orbital S1P injection before irradiation prevented GI syndrome by inhibiting endothelium collapse. We defined endothelium as a specific therapeutic target because only these cells and not intestinal epithelial cells, or B and T lymphocytes, were protected. Pharmacologic approaches using AKT inhibitor and pertussis toxin established that S1P affords endothelial cell protection in vitro and in vivo through a mechanism involving AKT and 7-pass transmembrane receptors coupled to Gi proteins. Our results provide strong pharmacologic and mechanistic proofs that S1P protects endothelial cells against acute radiation enteropathy.

Topics: Animals; Apoptosis; Blotting, Western; Bone Marrow; Cell Line; Cells, Cultured; Endothelial Cells; Gastrointestinal Tract; Humans; Immunohistochemistry; Intestine, Small; Lymphoid Tissue; Lysophospholipids; Male; Mice; Mice, Inbred C57BL; Phosphorylation; Proto-Oncogene Proteins c-akt; Radiation Injuries, Experimental; Signal Transduction; Sphingosine; Syndrome