The Ceramide-centric Universe of Lipid-mediated Cell Regulation: Stress Encounters of the Lipid Kind
Year: 2002
Type: article
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 ceramide in mediating/regulating many key and specific cellular responses. A major biochemical breakthrough in the past few years centered on the identification of the genes for all known enzymes of sphingolipid metabolism in the yeast Saccharomyces cerevisiae (1Hannun Y.A. Luberto C. Argraves K.M. Biochemistry. 2001; 40: 4893-4903Crossref PubMed Scopus (443) Google Scholar, 6Dickson R.C. Lester R.L. Biochim. Biophys. Acta. 1999; 1426: 347-357Crossref PubMed Scopus (171) Google Scholar). Importantly, most of these enzymes have either homologues or orthologues in mammalian species (1Hannun Y.A. Luberto C. Argraves K.M. Biochemistry. 2001; 40: 4893-4903Crossref PubMed Scopus (443) Google Scholar), and this is already paying dividends in the identification of mammalian counterparts (7Mao C.G., Xu, R.J. Szulc Z.M. Bielawska A. Galadari S.H. Obeid L.M. J. Biol. Chem. 2001; 276: 26577-26588Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar). The diacylglycerol kinase assay for ceramide quantitation has emerged as the workhorse for quantitative analysis of this lipid, and some shortfalls in its application (especially poor attention to quantitative conversion of ceramide) have recently been identified and clarified (8Perry D.K. Bielawska A. Hannun Y.A. Methods Enzymol. 2000; 312: 22-31Crossref PubMed Google Scholar). Also quite promising are various newly developed mass spectroscopy-based assays for qualitative and semi-quantitative analysis of ceramide and its molecular species that may allow dissection of specific pathways of ceramide metabolism and/or function (9Sullards M.C. Methods Enzymol. 2000; 312: 32-45Crossref PubMed Google Scholar, 10Kroesen B.J. Pettus B. Luberto C. Busman M. Sietsma H., De Leij L. Hannun Y.A. J. Biol. Chem. 2001; 276: 13606-13614Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar). The first decade of investigation on ceramide biology relied heavily on the use of short chain soluble ceramides such as C2- and C6-ceramide. Although this approach suffers the usual limitations that arise from the use of lipid reagents (11Ghidoni R. Sala G. Giuliani A. Biochim. Biophys. Acta. 1999; 1439: 17-39Crossref PubMed Scopus (40) Google Scholar), its utility has been reinforced by the determination of the specificity of action of these molecules (especially the lack of activity of dihydroceramide, the metabolic precursor of ceramide) (12Bielawska A. Crane H.M. Liotta D. Obeid L.M. Hannun Y.A. J. Biol. Chem. 1993; 268: 26226-26232Abstract Full Text PDF PubMed Google Scholar). Results using these reagents have led to the generation of several hypotheses on the roles of ceramide in mediating specific effects in apoptosis and stress responses (1Hannun Y.A. Luberto C. Argraves K.M. Biochemistry. 2001; 40: 4893-4903Crossref PubMed Scopus (443) Google Scholar). The availability of specific pharmacologic inhibitors of some enzymes of ceramide metabolism (e.g. glucosylceramide synthase (GCS) and CDases) and the ongoing molecular cloning of some of the key enzymes of ceramide formation (SMases and serine palmitoyltransferase (SPT)) have allowed the examination of the cellular consequences of inducing levels of endogenous ceramide, and the results, for the most part, have agreed with those obtained with exogenous ceramides. For example, inhibitors of GCS and of CDases have been shown to induce increases in ceramide levels and cause apoptosis and/or cell cycle arrest, especially of cancer cells, and overexpression of bacterial SMase has been shown to induce apoptosis and cell cycle arrest (1Hannun Y.A. Luberto C. Argraves K.M. Biochemistry. 2001; 40: 4893-4903Crossref PubMed Scopus (443) Google Scholar). The cloning of enzymes that clear ceramide such as GCS and CDases (1Hannun Y.A. Luberto C. Argraves K.M. Biochemistry. 2001; 40: 4893-4903Crossref PubMed Scopus (443) Google Scholar, 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), the generation of knock-out mice in acid SMase (13Horinouchi K. Erlich S. Perl D.P. Ferlinz K. Bisgaier C.L. Sandhoff K. Desnick R.J. Stewart C.L. Schuchman E.H. Nat. Genet. 1995; 10: 288-293Crossref PubMed Scopus (418) Google Scholar), and the development/discovery of specific inhibitors of enzymes of ceramide generation (myriocin/ISP1 for SPT and fumonisin B1 for ceramide synthase) (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) have begun to provide substantial evidence on the roles of ceramide in mediating key cellular activities. For example, fumonisin B1 has been shown to inhibit various aspects of apoptosis in response to many agents (e.g. angiotensin II (14Lehtonen J.Y.A. Horiuchi M. Daviet L. Akishita M. Dzau V.J. J. Biol. Chem. 1999; 274: 16901-16906Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar), anti-IgM (10Kroesen B.J. Pettus B. Luberto C. Busman M. Sietsma H., De Leij L. Hannun Y.A. J. Biol. Chem. 2001; 276: 13606-13614Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar), and some cancer chemotherapy agents (5Perry D.K. Ann. N. Y. Acad. Sci. 2000; 905: 91-96Crossref PubMed Scopus (37) Google Scholar)). The overexpression of GCS (15Sanchenkov A. Litvak D.A. Cabot M.C. J. Natl. Cancer Inst. 2001; 93: 347-357Crossref PubMed Scopus (278) Google Scholar) or CDase (16Strelow A. Bernardo K. Adam-Klages S. Linke T. Sandhoff K. Krönke M. Adam D. J. Exp. Med. 2000; 192: 601-611Crossref PubMed Scopus (151) Google Scholar) has been shown to attenuate the induced levels of ceramide in response to TNF and other agents and to ameliorate the apoptotic response, thus providing substantial evidence for the role of endogenous ceramide in regulating apoptosis. Recent studies have begun to identify key direct targets for ceramide action. These include the ceramide-activated protein phosphatases PP1 and PP2A, which are activated by ceramide in vitro. Increasing evidence points to roles for these phosphatases in mediating many of the actions of ceramide in cells. For example, phosphatase inhibitors have been shown to inhibit the ability of ceramide (and agents that induce ceramide formation) to cause dephosphorylation of several cellular proteins including PKCα, Akt/PKB, c-Jun, and Bcl-2 (17Chalfant C.E. Hannun Y. Futerman A.H. Ceramide Signaling. Landes Bioscience, Austin, TX2002Google Scholar). Cathepsin D was discovered as a ceramide-binding protein, and evidence has been provided that ceramide activates this lysosomal protease in cells (18Heinrich M. Wickel M. Winoto-Morbach S. Schneider-Brachert W. Weber T. Brunner J. Saftig P. Peters C. Krönke M. Schütze S. Adv. Exp. Med. Biol. 2000; 477: 305-315Crossref PubMed Google Scholar). Kinase suppressor of Ras has been advanced as a mediator of the effects of ceramide on Ras, Raf, and ERKs (extracellular signal-regulated kinases) (19Xing H.R. Lozano J. Kolesnick R. J. Biol. Chem. 2000; 275: 17276-17280Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar). Similarly, it has been shown that ceramide activates PKCζ and that this may couple the action of ceramide to activation of the transcription factor NF-κB and the activation of the stress-activated kinases (20Lozano J. Berra E. Municio M.M. Diaz-Meco M.T. Dominguez I. Sanz L. Moscat J. J. Biol. Chem. 1994; 269: 19200-19202Abstract Full Text PDF PubMed Google Scholar, 21Bourbon N.A. Yun J. Kester M. J. Biol. Chem. 2000; 275: 35617-35623Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar). Numerous studies point to a role for changes in intracellular redox in regulation of neutral SMase (4Andrieu-Abadie N. Gouazé V. Salvayre R. Levade T. Free Radic. Biol. Med. 2001; 31: 717-728Crossref PubMed Scopus (230) Google Scholar). For example, it has been shown that the action of TNF in inducing apoptosis is closely related to intracellular oxidation and a drop in the levels of GSH. In turn, this has been demonstrated as a necessary condition for activation of SMase in response to TNF. Similarly, GSH may regulate activation of SMase in response to hypoxia, xenobiotics, and chemotherapeutic agents (4Andrieu-Abadie N. Gouazé V. Salvayre R. Levade T. Free Radic. Biol. Med. 2001; 31: 717-728Crossref PubMed Scopus (230) Google Scholar). A novel CDase has been localized to mitochondria, demonstrating unequivocally the existence of a mitochondrial pathway of ceramide metabolism (22El Bawab S. Roddy P. Qian T. Bielawska A. Lemasters J.J. Hannun Y.A. J. Biol. Chem. 2000; 275: 21508-21513Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar). Ceramide levels have been detected in mitochondria (23Ardail D. Popa I. Alcantara K. Pons A. Zanetta J.P. Louisot P. Thomas L. Portoukalian J. FEBS Lett. 2001; 488: 160-164Crossref PubMed Scopus (62) Google Scholar), and TNF was shown to induce accumulation of ceramide in the heavy membrane compartment (10,000 × g pellet) (24Garcı́a-Ruiz C. Colell A. Marı́ M. Morales A. Fernández-Checa J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The of exogenous ceramide to mitochondria results in inhibition of the the generation of and the of C. Colell A. Marı́ M. Morales A. Fernández-Checa J. Biol. Chem. 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For example, stress in S. cerevisiae activates SPT and accumulation of sphingoid bases, their and ceramides over a frame of R.C. Lester R.L. Biochim. Biophys. Acta. 1999; PubMed Scopus (130) Google Scholar). has been provided for a necessary role for this pathway in inducing the cell cycle arrest and the of in response to stress Hannun Y.A. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, N. G. Hannun Y.A. J. Obeid L.M. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). are emerging on the function of bioactive sphingolipids and and this significant from the use of and biochemistry in the mechanisms of these pathways and their function. A major in understanding ceramide metabolism to all other bioactive that individual enzymes function as in cell regulation that an to an response to the changes in the has thus that of be at the of individual pathways and Indeed, enzymes of ceramide metabolism and (see minireview by and G. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar)). The membrane a of acid SMase and a neutral SMase (4Andrieu-Abadie N. Gouazé V. Salvayre R. Levade T. Free Radic. Biol. Med. 2001; 31: 717-728Crossref PubMed Scopus (230) Google Scholar), and generation of ceramide at the membrane and specific such as inhibition of inhibition of and of the receptor (1Hannun Y.A. Luberto C. Argraves K.M. Biochemistry. 2001; 40: 4893-4903Crossref PubMed Scopus (443) Google Scholar, A. J. A. E. Kolesnick R. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar) but not other effects by endogenous ceramide cell cycle (1Hannun Y.A. Luberto C. Argraves K.M. Biochemistry. 2001; 40: 4893-4903Crossref PubMed Scopus (443) Google Scholar). acid SMase may D as a direct for lysosomal ceramide (18Heinrich M. Wickel M. Winoto-Morbach S. Schneider-Brachert W. Weber T. Brunner J. Saftig P. Peters C. Krönke M. Schütze S. Adv. Exp. Med. Biol. 2000; 477: 305-315Crossref PubMed Google Scholar). The (and the and the is the of de of ceramide, and several lines of evidence point to roles for this ceramide by fumonisin in mediating apoptosis. In a it was shown that de novo ceramide dephosphorylation of proteins through activation of PP1 (17Chalfant C.E. Hannun Y. Futerman A.H. Ceramide Signaling. Landes Bioscience, Austin, TX2002Google Scholar). evidence points to mitochondria as a major for specific roles of ceramide in apoptosis. The has been as a of ceramide generation with roles in and apoptosis A. S. 1995; PubMed Scopus Google Scholar). of the of lipid metabolism, many of the enzymes that regulate bioactive function as by regulating the levels of bioactive substrates and For example, ceramidases regulate the levels of ceramide and/or sphingosine and S1P with S1P effects that responses (see minireview by and S. S. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar)). TNF has been shown to and this was with lack of accumulation of ceramide and of an apoptotic the action of was shown to induce activation of CDase especially at of the thus to responses. of ceramide and effects of on of (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). SM synthase synthase in the levels of ceramide and in a Indeed, evidence has been provided that SM synthase a response from by ceramide of to by of C. Hannun Y.A. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). many of the enzymes of sphingolipid metabolism are emerging as regulated the relative levels of more than bioactive Although these may be for the of bioactive provide the cell with a for cell responses. this of bioactive the of the levels of many the is at of its For example, activation of SMase results in the accumulation of the of ceramide metabolism to that of and glucosylceramide (and other for an of in the of bioactive of these is to its direct then the of responses by the of these pathways all bioactive effects on their direct the consequences of changes in levels of bioactive be from or that a more of an of the levels of its endogenous bioactive the is a clear for the molecular identification of sphingomyelin and ceramide the known enzymes of ceramide metabolism. have on the cloning of neutral sphingomyelinases and K. S. G. W. Natl. Acad. Sci. S. A. 2000; PubMed Scopus Google Scholar) evidence was provided that which to the as a C N. N. Hannun Y.A. J. Biol. Chem. 1999; 274: Full Text Full Text PDF Scopus Google Scholar). to the and its substrates have not been and studies the of at a membrane and mitochondrial Similarly, is known SM of the most enzymes that has at and The of ceramide and sphingolipid function has from the availability of and fumonisin B1 as specific inhibitors of SPT and ceramide These reagents have in key roles for the de novo pathway of ceramide formation in apoptosis and action (see there are to especially for SM and The identification of these mechanisms (e.g. to activation of by direct the specific biochemical that are for activation of of these a in cell these mechanisms to be and as such allow an advanced of understanding of these pathways and the of when are to be Similarly, the mechanisms of action of ceramide and related provide direct into the biochemical of these specific studies are to which targets of ceramide are activated in cells and specific is that specific and pathways of ceramide formation and clearance specific (such as the regulation of proteins in response to de novo ceramide, the of molecular and pharmacologic tools and the identification of direct cellular targets for ceramide (and related the of specific for ceramide in response to individual is quite that the identified pathways of sphingolipid metabolism with other to be For example, studies have shown the of for and psychosine, is known as to enzymes regulate the metabolism of these is that other pathways may that to novel Ceramide and inhibitors of ceramide metabolism are their into research. with significant effects on and R. L. Yun J. N. R. Kester M. 2000; PubMed Scopus Google Scholar). ceramides shown to in K. I. Y. J. 2001; PubMed Scopus Google Scholar). a ceramidase of cancer to in a M. Bielawska A. D. Hannun Y.A. Cancer 2001; Google Scholar). metabolism and function is not only an and now but is of the few in and of its biochemical mechanisms and is our that key of cell biology senescence, and membrane and stress and and understanding sphingolipid metabolism.
Source: Journal of Biological Chemistry
Authors: Yusuf A. Hannun, Lina M. Obeid
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
OpenAlex ID: W1982533264