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J. Biol. Chem., Vol. 277, Issue 29, 25847-25850, July 19, 2002

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

Yusuf A. Hannun and Lina M. Obeid^§¶

From the Department of Biochemistry and Molecular Biology and the ^§ Ralph H. Johnson Veterans Affairs Medical Center and Department of Medicine, Medical University of South Carolina, Charleston, South Carolina 29425

	INTRODUCTION

TOP INTRODUCTION Summary of the Ceramide-centric... Recent Advances in the... Organizing Principles Future Directions/Goals Conclusions REFERENCES

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 (1).

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.

	Summary of the Ceramide-centric View of Universe

TOP INTRODUCTION Summary of the Ceramide-centric... Recent Advances in the... Organizing Principles Future Directions/Goals Conclusions REFERENCES

Ceramide is at the hub of sphingolipid metabolism, and it serves as the first point of significant accumulation of sphingolipids in the de novo pathway (see minireview by Merrill (55)). 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. (56)). 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. 1 and 2).

View larger version (26K): [in this window] [in a new window]   Fig. 1.   Basic pathways of ceramide metabolism and interrelationship of regulatory pathways mediated by bioactive lipids. Ceramide can be formed de novo or from hydrolysis of SM or complex glycolipids (horizontal plane in diagram). In turn, ceramide may be converted to sphingosine (Sph) or serve as a substrate for SM synthesis (generating DAG) or glycolipids. Each of the major bioactive lipids is then capable of interacting with specific targets leading to specific responses (vertical plane). PalCoA, palmitoyl-CoA; DHS, dihydrosphingosine; DHCer, dihydroceramide; SK, sphingosine kinase; PC, phosphatidylcholine; PA, phosphatidic acid; SMS, SM synthase; DGK, DAG kinase; SL, sphingolipid.

Functionally, ceramide has been proposed as a "coordinator" of eukaryotic stress responses (3). 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 (4) or the de novo pathway (5) 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.

	Recent Advances in the Study of Ceramide Metabolism and Function

TOP INTRODUCTION Summary of the Ceramide-centric... Recent Advances in the... Organizing Principles Future Directions/Goals Conclusions REFERENCES

Yeast and Molecular Identification of Enzymes of Sphingolipid Metabolism-- 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 (1, 6). Importantly, most of these enzymes have either homologues or orthologues in mammalian species (1), and this is already paying dividends in the identification of mammalian counterparts (7).

Improved Methods for Quantitation of Ceramide-- 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 (8). 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 (9, 10).

Probing for Functions of Endogenous Ceramide-- 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 (11), 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) (12). 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 (1).

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 (1).

Determination of Necessary Roles for Ceramide in Key Cellular Events-- The cloning of enzymes that clear ceramide such as GCS and CDases (1, 2), the generation of knock-out mice in acid SMase (13), and the development/discovery of specific inhibitors of enzymes of ceramide generation (myriocin/ISP1 for SPT and fumonisin B1 for ceramide synthase) (2) 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 (14), anti-IgM (10), and some cancer chemotherapy agents (5)). The overexpression of GCS (15) or CDase (16) 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.

Mechanisms of Action of Ceramide: Phosphatases, Proteases, and Kinases-- 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 PKC, Akt/PKB, c-Jun, and Bcl-2 (17).

Cathepsin D was discovered as a ceramide-binding protein, and evidence has been provided that ceramide activates this lysosomal protease in cells (18).

Kinase suppressor of Ras has been advanced as a mediator of the effects of ceramide on Ras, Raf, and ERKs (extracellular signal-regulated kinases) (19). Similarly, it has been shown that ceramide activates PKC and that this may couple the action of ceramide to activation of the transcription factor NF-B and the activation of the stress-activated kinases (20, 21).

Oxidation and Neutral SMases-- Numerous studies point to a role for changes in intracellular redox in regulation of neutral SMase (4). 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 (4).

The Mitochondrion: a Novel Compartment for Ceramide Metabolism and Action-- A novel CDase has been localized to mitochondria, demonstrating unequivocally the existence of a mitochondrial pathway of ceramide metabolism (22). Ceramide levels have been detected in mitochondria (23), and TNF was shown to induce accumulation of ceramide in the heavy membrane compartment (10,000 × g pellet) (24). The addition of exogenous ceramide to purified mitochondria results in inhibition of the respiratory chain, the generation of reactive oxygen species, and the release of cytochrome c (24-27). The expression of bacterial SMase in mitochondria, but not other subcellular compartments, resulted in induction of apoptosis (28), suggesting a role for endogenous mitochondrial ceramide in regulating apoptosis.

Diseases Related to Disturbances in Ceramide Metabolism: Neuropathies, Diabetes, Cancer, and Aging-- One of the most exciting areas of development in sphingolipid biology has been the increasing evidence pointing to roles for these pathways in disease pathogenesis. For example, the primary mutation responsible for hereditary neuropathy has been mapped to the LCB1 subunit of SPT, and it was suggested to induce apoptosis of susceptible sensory neurons (29, 30). Ceramide levels have been shown to be elevated in a number of neurodegenerative disorders such as Batten's disease, and two of the genes responsible for subtypes of this disorder, CLN3 and protein palmitoyl thioesterase, have been shown to attenuate ceramide levels in response to apoptotic stimuli, suggesting a role for the ceramide pathway in mediating cell dysfunction and death in these disorders (31, 32).

A flurry of recent studies have begun to implicate ceramide and sphingolipid metabolism in the pathogenesis of diabetes and its complications. Ceramide has been shown to induce dephosphorylation and inactivation of the Akt/PKB protein kinases which play key roles in insulin action (33). Unger and co-workers (34) have proposed that conditions of free fatty acid overload (especially palmitate), as would occur in obesity or diabetes, drive the de novo pathway of ceramide synthesis leading to induction of ceramide-mediated responses (e.g. dysfunction and death of islet cells).

The emerging intimate role for ceramide in regulating stress responses and apoptosis has led to implicating this lipid in mediating the apoptotic and cytotoxic actions of various chemotherapeutic agents (35). Moreover, it has been shown that drug resistance often involves up-regulation of GCS and the failure to sustain an accumulation of ceramide in response to chemotherapy agents (15, 36). Deficiency in acid SMase has also been shown to diminish the response of endothelial and neuronal cells to radiation-induced apoptosis (37).

The results demonstrating causative roles for oxidative stress in activating SMases begin to point to important coupling of oxidative stress to ceramide signaling. This is of particular importance to aging biology as the aging of many tissues as well as animal models has been closely related to accumulative oxidant stress (38). In addition, a strong case has been provided for an important role for ceramide in regulating the senescence of fibroblasts, endothelial cells, and neuronal cells, tissue culture models that recapitulate several aspects of in vivo aging (39). For example, ceramide was found to inhibit mitogenic signaling by inhibiting PKC activation of phospholipase D and subsequent AP1-mediated transcription. Ceramide also causes dephosphorylation of the retinoblastoma gene product, resulting in cell cycle arrest (40), and more recently, ceramide has been shown to inhibit telomerase, thus linking these two regulators of cell senescence (41).

Very recently, two genes encoding for ceramide synthase (or essential regulatory subunits) have been identified (42, 43). These genes had been previously discovered in S. cerevisiae as longevity assurance genes (lag1 and the homologous lac1), and deletion of these genes extended yeast life span by 50%, thus suggesting a role for ceramide in yeast longevity/aging.

	Organizing Principles

TOP INTRODUCTION Summary of the Ceramide-centric... Recent Advances in the... Organizing Principles Future Directions/Goals Conclusions REFERENCES

Yeast as a Model for Investigating Sphingolipid Action-- Studies in S. cerevisiae have provided substantial evidence for a basic conservation of ceramide and sphingolipid metabolism (noted above) and function. For example, heat stress in S. cerevisiae activates SPT and induces accumulation of sphingoid bases, their phosphates, and ceramides over a time frame of 10-120 min (44). Evidence has been provided for a necessary role for this pathway in inducing the transient cell cycle arrest and the down-regulation of nutrient permeases seen in response to heat stress (45, 46). Thus, strong parallels are emerging on the function of bioactive sphingolipids between mammals and yeast, and this promises significant insight generated from the combined use of genetics and biochemistry in probing the mechanisms of these pathways and their function.

Focusing on Specific Pathways of Ceramide Metabolism: Modules in Signal Transduction-- A major principle in understanding ceramide metabolism (which applies to all other bioactive lipids) stipulates that individual enzymes function as modules in cell regulation (Fig. 1) that transduce an input (the activating mechanism) to an output (the response to the changes in the product). It has thus become obvious that "the study of ceramide" should be attempted at the level of individual pathways and modules.

Compartmentalization and Topology of Ceramide Metabolism-- Indeed, enzymes of ceramide metabolism show distinct subcellular localization and perhaps topology (see minireview by van Meer and Lisman (57)). (Fig. 2). (i) The plasma membrane harbors a fraction of acid SMase and possibly a caveolar-associated neutral SMase (4), and generation of ceramide at the plasma membrane exerts distinct and specific functions, such as inhibition of PKC translocation, inhibition of NF-B, and aggregation of the Fas receptor (1, 47) but not other effects mediated by endogenous ceramide (apoptosis, cell cycle arrest) (1). (ii) Lysosomal acid SMase may activate cathepsin D as a direct target for lysosomal ceramide (18). (iii) The endoplasmic reticulum (and possibly the Golgi, mitochondrial-associated membranes, and the nuclear membrane) is the primary site of de novo synthesis of ceramide, and several lines of evidence point to roles for this ceramide (inhibitable by fumonisin B) in mediating apoptosis. In a recent study, it was shown that de novo ceramide specifically induces dephosphorylation of nuclear SR proteins through activation of PP1 (17). (iv) As discussed above, recent evidence points to mitochondria as a major site for specific roles of ceramide in apoptosis. (v) The nucleus has also been implicated as a site of ceramide generation with possible roles in hepatocyte regeneration and apoptosis (48).

View larger version (49K): [in this window] [in a new window]   Fig. 2.   Compartmentalization of ceramide metabolism and function. Shown are several distinct compartments of ceramide metabolism and function (refer to text for discussion). Cer, ceramide; DHS, dihydrosphingosine; Cath D, cathepsin D; Sph, sphingosine; Sph-K, sphingosine kinase; Alk, alkaline; PalCoA, palmitoyl-CoA; SR, sarcoplasmic reticulum; dhCer, dihydroceramide; CerS, ceramide synthase; deSat, desaturase; PC, phosphatidylcholine; SMS, SM synthase.

Key Enzymes of Ceramide Metabolism as Switches in Cell Regulation-- Because of the intimate interconnections of lipid metabolism, many of the enzymes that regulate bioactive lipids also function as switches by regulating the levels of bioactive substrates and products. For example, ceramidases can regulate the levels of ceramide (substrate) and/or sphingosine and S1P (products), with S1P often exerting anti-apoptotic effects that antagonize ceramide-mediated responses (see minireview by Spiegel and Milstien (58)). TNF has been shown to activate CDases, and this was correlated with lack of accumulation of ceramide and absence of an apoptotic response. Also, the action of IL-1 was shown to induce activation of CDase especially at low concentrations of the cytokine, thus leading to sphingosine-mediated responses. At higher concentrations of IL-1, ceramide accumulates and mediates effects of IL-1 on expression of 1-acid glycoprotein (2). SM synthase (or inositol phosphoceramide synthase in yeast) regulates the levels of ceramide and DAG in a reciprocal manner. Indeed, evidence has been provided that active SM synthase can switch a signaling response from one mediated by ceramide (inhibition of NF-B) to one mediated by DAG (activation of NF-B) (49). Thus, many of the enzymes of sphingolipid metabolism are emerging as regulated switches controlling the relative levels of more than one bioactive lipid.

Integration of Ceramide Metabolism and Function: Concept of Lipidomics-- Although these switching functions may be confusing for the casual study of bioactive lipids, they do provide the cell with a very rich matrix for fine-tuning cell responses. As such, this interconnected network of bioactive lipids allows the titration of the levels of many lipids simultaneously whenever the existing steady state is perturbed at any of its enzymatic nodes (Fig. 1). For example, activation of SMase results in the accumulation of ceramide. However, the coupling of ceramide metabolism to that of sphingosine, DAG, S1P, and glucosylceramide (and other lipids) provides for an infinite number of permutations in the overall profiles of bioactive lipids. As each of these metabolites is recognized to exert its own direct actions, one could then appreciate the richness of responses mediated by the integration of these distinct pathways (Fig. 1).

As all bioactive lipids exert allosteric (read: non-genomic) effects on their direct targets, the consequences of changes in levels of bioactive lipids cannot be determined directly from genomic or proteomic profiles. Therefore, we propose that a more complete description of any given cell's configuration requires an assessment of the levels of its endogenous bioactive lipids (hence, the designation "lipidomics").

	Future Directions/Goals

TOP INTRODUCTION Summary of the Ceramide-centric... Recent Advances in the... Organizing Principles Future Directions/Goals Conclusions REFERENCES

Identifying the Few Missing Key Enzymes of Ceramide Metabolism-- There is a clear need for the molecular identification of sphingomyelinases, sphingomyelin synthases, and ceramide kinase, the remaining known enzymes of ceramide metabolism. Studies have reported on the cloning of two candidate neutral sphingomyelinases (nSMase 1 and nSMase 2) (50) although evidence was provided that nSMase 1, which localizes to the endoplasmic reticulum, probably functions as a lyso-PAF phospholipase C (51). nSMase 2 localizes to the Golgi, and its physiologic substrates have not been determined. Enzymatic and subfractionation studies suggest the presence of at least a plasma membrane and possibly mitochondrial SMases. Similarly, little is known concerning SM synthase, one of the most recalcitrant enzymes that has resisted efforts at purification and cloning.

Development of Pharmacologic Tools-- The study of ceramide and sphingolipid function has benefited significantly from the availability of myriocin/ISP1 and fumonisin B1 as specific inhibitors of SPT and ceramide synthase, respectively. These reagents have helped in establishing key roles for the de novo pathway of ceramide formation in apoptosis and agonist action (see above). Thus, there are important needs to define better inhibitors, especially for sphingomyelinases, SM synthase, and CDases.

Determination of Biochemical/Molecular Mechanisms of Regulation of Enzymes of Ceramide Metabolism-- The identification of these mechanisms (e.g. analogous to activation of phospholipase C by direct tyrosine phosphorylation) should define the specific biochemical inputs that are responsible for activation of each of these enzymes. As a rule in cell biology, these proximal mechanisms tend to be invariant and as such allow an advanced level of understanding of these pathways and the prediction of when they are to be activated.

Determination of Molecular Mechanisms of Action of Ceramide-- Similarly, defining the mechanisms of action of ceramide and related lipids should provide direct insight into the biochemical outputs of these specific pathways. Further studies are required to define which targets of ceramide are directly activated in cells and what specific functions they mediate.

Probing the Next Level of Cell Biology-- It is anticipated that specific and compartmentalized pathways of ceramide formation and clearance exert specific functions (such as the regulation of SR proteins in response to de novo generated ceramide, discussed above). Thus, the development of molecular and pharmacologic tools and the identification of direct cellular targets for ceramide (and related sphingolipids) should accelerate the delineation of specific functions for ceramide in response to individual agonists.

Exploring Other Layers of Sphingolipid Metabolism-- It is quite likely that the currently identified pathways of sphingolipid metabolism represent one layer with other layers to be determined. For example, recent studies have shown the presence of receptors for lyso-SM and psychosine, although little is known as to what enzymes regulate the metabolism of these molecules. It is conceivable that other "minor" pathways may exist that lead to novel metabolites.

Forging into Translational Research-- Ceramide analogs and inhibitors of ceramide metabolism are increasingly finding their way into translational research. Catheter balloon tips, coated with C₆-ceramide, exert significant anti-proliferative effects on endothelium and prevent coronary restenosis (52). Exogenous ceramides were shown to reduce infarct size in spontaneously hypertensive rats (53). B13, a ceramidase inhibitor, prevents metastasis of colon cancer to liver in a nude mouse model (54).

	Conclusions

TOP INTRODUCTION Summary of the Ceramide-centric... Recent Advances in the... Organizing Principles Future Directions/Goals Conclusions REFERENCES

Sphingolipid metabolism and function is not only an exciting and now rapidly developing field but is one of the few remaining "frontiers" in basic biochemistry, and delineation of its biochemical mechanisms and physiologic functions promises important rewards. It is our conjecture that one cannot understand key areas of cell biology (including apoptosis, senescence, vesicle sorting and trafficking, membrane organization, and stress responses) and disease pathobiology (cancer, diabetes, aging, and inflammation) without understanding sphingolipid metabolism.

	ACKNOWLEDGEMENTS

We thank Jeffrey Jones for providing Fig. 1. We apologize for not referring to the many outstanding studies that have propelled this field. These can be found cited in the several comprehensive reviews cited in this minireview.

	FOOTNOTES

^* This minireview will be reprinted in the 2002 Minireview Compendium, which will be available in December, 2002. This work was supported in part by National Institutes of Health Grants GM43285 and CA 87584 (to Y. A. H.) and AG 16583 and GM62887 (to L. M. O.). This is the second article of five in the "Sphingolipid Metabolism and Signaling Minireview Series."

To whom correspondence may be addressed. E-mail: hannun@musc.edu or obeidl{at}musc.edu.

^¶ Recipient of a Department of Veterans Affairs merit award.

Published, JBC Papers in Press, May 13, 2002, DOI 10.1074/jbc.R200008200

	ABBREVIATIONS

The abbreviations used are: S1P, sphingosine 1-phosphate; SM, sphingomyelin; SMase, sphingomyelinase; CDase, ceramidase; TNF, tumor necrosis factor; GCS, glucosylceramide synthase; SPT, serine palmitoyltransferase; PKC, protein kinase C; IL-1, interleukin-1; DAG, diacylglycerol; nSMase, neutral sphingomyelinase.

	REFERENCES

TOP INTRODUCTION Summary of the Ceramide-centric... Recent Advances in the... Organizing Principles Future Directions/Goals Conclusions REFERENCES

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