The ultimate goal of our work is to understand how sphingolipid metabolism and signaling are regulated during normal biology and in disease.
Sphingolipids are a diverse family of cellular lipids whose structure is based on a sphingoid (long-chain base) backbone. A well-known function for sphingolipid metabolism is the generation of lipids for the formation and function of biological membranes. For the most part, these are complex sphingolipids, such as sphingomyelin and glycosphingolipids, and represent the most abundant forms of sphingolipids in cells. They contain ceramide as a lipid anchor attached to hydrophilic head groups consisting of either phosphorylcholine (to form sphingomyelin) or carbohydrate (to form glycosphingolipids). Complex sphingolipids are believed to drive the formation of plasma membrane microdomains that serve as platforms for cell signaling and endocytosis.
Sphingolipids also directly function as signaling molecules. These include the metabolic intermediates ceramide, sphingosine, and sphingosine-1-phosphate (S1P), which have been found to regulate basic cell activities, including proliferation, apoptosis, and movement by binding to and regulating intracellular enzymes and plasma membrane receptors. S1P in particular has come to the fore as a central regulator of several biological processes, with both intracellular and extracellular signaling roles. It is generated after the liberation of sphingosine by ceramidases through the action of sphingosine kinases. S1P levels are also controlled by different types of degradative enzymes. S1P can be produced by all cells and its concentration is elevated—in the high-nanomolar to low-micromolar range—in blood and other physiologic fluids. The five high-affinity G-protein-coupled receptors (GPCRs) for S1P (S1PR1-S1PR5) are among the most highly and widely expressed of the GPCR superfamily. S1P extracellular signaling through its receptors underlies basic functions in the vascular, nervous, and immune systems. The profound impact of S1P receptor signaling on mammalian biology may be a consequence of the abundance and ubiquity of receptors and their ligand. The system is a model for understanding the interactions of cell metabolism and signaling.
Sphingolipid metabolism is directly involved in human disease. This is most clearly seen in the sphingolipidoses, a family of inherited metabolic diseases where blocks in the degradation of sphingolipids cause serious and, in many cases, lethal disorders. Tay-Sachs, Sandhoff, Niemann-Pick, and Gaucher diseases are prominent examples. Over the past few years, substantial evidence has emerged that implicates sphingolipid metabolism and signaling in more prominent pathologies, such as autoimmune disease, atherosclerosis, cancer, and diabetes. In 2010, the U.S. Food and Drug Administration approved FTY720 (fingolimod), a sphingosine analogue that is active on S1P receptors, as a first-line, oral multiple-sclerosis treatment that has been shown to significantly reduce relapses and delay disability progression.
In our lab, we attempt to delineate the functions of sphingolipids in normal biology and in disease using mouse models as a major research tool. Through this effort we have established several models of the sphingolipid storage disorders that have helped illuminate their pathogenesis pathways and identify new potential therapies. We have identified functions of the glycosphingolipids in development and disease, and more recently discovered functions of sphingosine-1-phosphate signaling in vivo.
Our current research focuses on identifying mechanisms underlying the regulation of sphingolipid metabolism and signaling. Some specific questions that we are trying to answer include the following:
- How do animals maintain precise levels of sphingolipids in their cells?
- How is sphingosine-1-phosphate signaling regulated in vivo where the lipid is made by virtually all cells and the receptors are ubiquitously expressed?
Applying our Research
Great advances in the understanding of sphingolipid metabolism and signaling have been made as the result of efforts on many fronts—in biochemistry, cell biology, genetics, and physiology. The scope of the impact of the system on biology has proven to be extensive, and its role in human disease is only beginning to be appreciated. A deeper understanding of the system holds potential for the development of additional novel therapies for human disease.
Need for Further Study
How are sphingolipid levels maintained in cells? How is sphingolipid signaling controlled?