sphingosine-1-phosphate and Disease

Sphingosine 1-phosphate (S1P) is an important bioactive sphingolipid metabolite that has been implicated in numerous physiological and cellular processes. Not only does S1P play a structural role in cells by defining the components of the plasma membrane, but in the last 20 years it has been implicated in various significant cell signaling pathways and physiological processes: for example, cell migration, survival and proliferation, cellular architecture, cell-cell contacts and adhesions, vascular development, atherosclerosis, acute pulmonary injury and respiratory distress, inflammation and immunity, and tumorogenesis and metastasis [1,2]. Given the wide variety of cellular and physiological processes in which S1P is involved, it is immediately obvious why the mechanisms governing S1P synthesis and degradation, and the manner in which these processes are regulated, are necessary to understand. In gaining more knowledge about regulation of the sphingosine kinase (SK)/S1P pathway, many potential therapeutic targets may be revealed. This review explores the roles of the SK/S1P pathway in disease, summarizes available SK enzyme inhibitors and examines their potential as therapeutic agents. This article is part of a Special Issue entitled Advances in Lysophospholipid Research.

Topics: Animals; Disease; Humans; Lysophospholipids; Molecular Targeted Therapy; Phosphotransferases (Alcohol Group Acceptor); Protein Kinase Inhibitors; Signal Transduction; Sphingosine

Simple bioactive sphingolipids include ceramide, sphingosine and their phosphorylated forms sphingosine 1-phosphate and ceramide 1-phosphate. These molecules are crucial regulators of cell functions. In particular, they play important roles in the regulation of angiogenesis, apoptosis, cell proliferation, differentiation, migration, and inflammation. Decoding the mechanisms by which these cellular functions are regulated requires detailed understanding of the signaling pathways that are implicated in these processes. Most importantly, the development of inhibitors of the enzymes involved in their metabolism may be crucial for establishing new therapeutic strategies for treatment of disease.

Topics: Animals; Ceramidases; Ceramides; Disease; Humans; Inflammation; Isoenzymes; Lysophospholipids; Macrophages; Molecular Structure; Phosphotransferases (Alcohol Group Acceptor); Signal Transduction; Sphingolipids; Sphingosine

The sphingolipid metabolite sphingosine-1-phosphate (S1P) and the kinases that produce it have emerged as critical regulators of numerous fundamental biological processes important for health and disease. Activation of sphingosine kinases (SphKs) by a variety of agonists increases intracellular S1P, which in turn can be secreted out of the cell and bind to and signal through S1P receptors (S1PRs) in an autocrine and/or paracrine manner. Recent studies suggest that this "inside-out" signaling by S1P may play a role in many human diseases. As the roles of the S1PRs in cell and organismal physiology are discussed elsewhere in this volume, we focus this review mainly on recent reports showing how SphKs are activated and S1P reaches its receptors, the role of SphKs and S1P in regulating sphingolipid homeostasis, and the potential importance of the SphK/S1P axis as a therapeutic target in human diseases.

Topics: Disease; Health; Humans; Lysophospholipids; Phosphotransferases (Alcohol Group Acceptor); Signal Transduction; Sphingolipids; Sphingosine

Sphingolipids are ubiquitous components of cell membranes and their metabolites ceramide (Cer), sphingosine (Sph), and sphingosine-1-phosphate (S1P) have important physiological functions, including regulation of cell growth and survival. Cer and Sph are associated with growth arrest and apoptosis. Many stress stimuli increase levels of Cer and Sph, whereas suppression of apoptosis is associated with increased intracellular levels of S1P. In addition, extracellular/secreted S1P regulates cellular processes by binding to five specific G protein coupled-receptors (GPCRs). S1P is generated by phosphorylation of Sph catalyzed by two isoforms of sphingosine kinases (SphK), type 1 and type 2, which are critical regulators of the "sphingolipid rheostat", producing pro-survival S1P and decreasing levels of pro-apoptotic Sph. Since sphingolipid metabolism is often dysregulated in many diseases, targeting SphKs is potentially clinically relevant. Here we review the growing recent literature on the regulation and the roles of SphKs and S1P in apoptosis and diseases.

Topics: Animals; Apoptosis; Disease; Enzyme Activation; Humans; Lysophospholipids; Phosphotransferases (Alcohol Group Acceptor); Sphingosine

Topics: Animals; Biopharmaceutics; Cadmium; Cation Transport Proteins; Disease; Ecotoxicology; Fatty Acids, Omega-3; Food; Food Analysis; Glutathione; Humans; Lysophospholipids; Manganese; Mice; Nutrients; Nutritional Sciences; Organoselenium Compounds; Preventive Medicine; Sphingosine; Trans Fatty Acids; Vitamin K; Vitamin K 2

Topics: Adherens Junctions; Animals; Capillary Permeability; Disease; Endothelium, Vascular; Health; Humans; Lysophospholipids; Models, Biological; Signal Transduction; Sphingosine; Thrombin; Tight Junctions