The Ceramide-centric Universe of Lipid-mediated Cell Regulation: Stress Encounters of the Lipid Kind

Abstract

sphingosine 1-phosphate sphingomyelin sphingomyelinase ceramidase tumor necrosis factor glucosylceramide synthase serine palmitoyltransferase protein kinase C interleukin-1 diacylglycerol neutral sphingomyelinase Whereas regulated turnover of glycerolipids has been observed and studied for more than six decades, dogma has held sphingolipids to be mostly structural molecules with inert metabolism. If anything, investigation over the past 15 years or so has taught us that sphingolipid metabolism comprises a set of highly regulated pathways that serve to control the levels of individual molecules, their interconversions, and their function. Most notable of these bioactive molecules are the sphingoid bases, ceramide, and sphingosine 1-phosphate (S1P)1; other emerging bioactive sphingolipids include sphingosylphosphorylcholine, psychosine, lactosylceramide, and cerebroside (1Hannun Y.A. Luberto C. Argraves K.M. Biochemistry. 2001; 40: 4893-4903Crossref PubMed Scopus (443) Google Scholar). Much attention in the last decade has focused on ceramide metabolism and function because of the increased appreciation of the involvement of pathways involving this lipid in regulating key biologic responses such as stress responses, cell senescence, and apoptosis. Indeed, there have been more than 5000 publications on the biochemistry and cellular activities of ceramide during this period. The excitement and anticipation of rapid progress in elucidating the molecular/biochemical mechanisms of these pathways and their specific contributions to emerging fields of cell biology have been tempered by the serious lag in studies on sphingolipids when compared with other fields of biochemical study. Most of the key enzymes regulating ceramide metabolism have been poorly studied, and there has been a paucity of molecular and pharmacologic tools to probe these pathways and their functions. Luckily, there has been an advancing crescendo of studies that have begun to shed significant light on our understanding of ceramide metabolism and function. This minireview will highlight these major advances, elucidate organizing principles, and advance key questions for future research. By necessity, this minireview adopts a ceramide-centric view of sphingolipid metabolism and function. Borrowing from physics, it is easier to organize information and reconstruct pathways for a fixed observer with a fixed frame of reference. This does not change the validity of conclusions, only their relative perspective. Ceramide is at the hub of sphingolipid metabolism, and it serves as the first point of significant accumulation of sphingolipids in thede novo pathway (see minireview by Merrill (55Merrill A.H., Jr. J. Biol. Chem. 2002; 277: 25843-25846Abstract Full Text Full Text PDF PubMed Scopus (498) Google Scholar)). Ceramide then serves as the precursor for all major sphingolipids in eukaryotes (such as sphingomyelin (SM) or glucosylceramide) (Fig.1 and see minireview by Kolter et al. (56Kolter T. Proia R.L. Sandhoff K. J. Biol. Chem. 2002; 277: 25859-25862Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar)). The breakdown of complex sphingolipids results in the formation of ceramide through the action of either sphingomyelinases (SMases) or glycosidases. The breakdown of ceramide proceeds through the action of ceramidases (CDases), and the resulting sphingoid bases serve as substrates for sphingosine kinases to form S1P or are recycled into ceramide and complex sphingolipids through the action of ceramide synthases (for reviews see Refs. 1Hannun Y.A. Luberto C. Argraves K.M. Biochemistry. 2001; 40: 4893-4903Crossref PubMed Scopus (443) Google Scholar and 2Merrill A.H., Jr. Sullards M.C. Wang E. Voss K.A. Riley R.T. Environ. Health Perspect. 2001; 109: 283-289Crossref PubMed Scopus (334) Google Scholar). Functionally, ceramide has been proposed as a “coordinator” of eukaryotic stress responses (3Hannun Y.A. Science. 1996; 274: 1855-1859Crossref PubMed Scopus (1500) Google Scholar). This paradigm is supported by the repeated findings that many inducers of stress response (not limited to those inducing apoptosis) result in ceramide accumulation, usually as a result of activation of either SMases (4Andrieu-Abadie N. Gouazé V. Salvayre R. Levade T. Free Radic. Biol. Med. 2001; 31: 717-728Crossref PubMed Scopus (230) Google Scholar) or the de novo pathway (5Perry D.K. Ann. N. Y. Acad. Sci. 2000; 905: 91-96Crossref PubMed Scopus (37) Google Scholar) but sometimes as a result of inhibition of ceramide clearance (through SM synthase or CDases). These inducers include cytokines (TNF, Fas, nerve growth factor), “environmental” stresses (heat, UV radiation, hypoxia/reperfusion), chemotherapeutic agents (Ara-C, doxorubicin, etoposide, and many others), and other miscellaneous agents (dexamethasone, lipopolysaccharide, sitosterol, and B-cell receptor stimulation). Several lines of investigation (see next section) now support roles for endogenous cerami