ReviewCeramide/sphingosine/sphingosine 1-phosphate metabolism on the cell surface and in the extracellular space
Introduction
Sphingolipids are major components of the eukaryotic plasma membrane. These compounds have numerous roles, such as regulating signal transduction pathways, directing protein sorting, and mediating cell-to-cell interactions and recognition [1], [2]. Recent studies have also demonstrated that sphingolipids dynamically cluster with sterols to form lipid microdomains or rafts, which function as platforms for effective signal transduction and protein sorting [3].
Over the past decade, sphingolipid metabolites including ceramide (N-acylsphingosine, Cer), sphingosine (Sph), and sphingosine 1-phosphate (S1P) have emerged as a new class of lipid biomodulators of various cell functions [4], [5], [6]. Cer has been shown to mediate many cellular events including growth arrest, differentiation, and apoptosis [4]. Sph, the N-deacylated product of Cer, is also capable of inducing apoptosis [4], [5]. In contrast to Cer and Sph, however, S1P has been implicated in mediating cell proliferation and antagonizing Cer-mediated apoptosis [6]. A model has been proposed in which the balance between the intracellular levels of Cer and S1P, i.e. the ‘Cer/S1P rheostat’, could determine whether a cell survives or dies [6].
Some studies have suggested that Cer, Sph, and S1P function as second messengers by binding to specific intracellular protein targets [4], [5], [6], although this idea remains somewhat controversial. Other studies have focused on the functions of these sphingolipid metabolites in the extracellular space, including the outer leaflet of the plasma membrane. S1P, for instance, is considered to function not only intracellularly, but also as an extracellular messenger that regulates cell motility and morphology. In particular, S1P is a known ligand for five G protein-coupled receptors, the endothelial differentiation gene receptors S1P1–5 [7]. With such multiple and pleiotropic extracellular targets, S1P influences numerous physiologic functions, including vascular maturation during development [8], heart rate [9], and lymphocyte recirculation [10]. In addition, Cer is known to function within the cell membrane in both microdomain coalescence and receptor clustering [11].
Sphingomyelin (SM) degradation is a major pathway involved in producing these lipid messengers (Fig. 1). SM in the exoplasmic side of the plasma membrane is broken down by signal-activated sphingomyelinases (SMases) leading to the formation of Cer [4]. Subsequently, Cer is deacylated by ceramidase (CDase) to generate Sph [5]. Sph is considered to be exclusively generated from Cer through the action of CDase, and de novo synthesis of Sph has been ruled out since delta 4 desaturase specifically acts on dihydroCer and not on dihydroSph [12]. In the next step, which occurs mainly in the cytoplasmic region of the cells, Sph is phosphorylated by Sph kinase into S1P [6]. In most cells, generated S1P is rapidly degraded either by lyase, to hexadecenal and phosphoethanolamine, or by phosphohydrolase to Sph [6].
Recent studies have shown that sphingolipid-metabolizing enzymes function not only in intracellular organelles but also in the extracellular spaces, including the outer leaflet of the plasma membrane (Fig. 2). In the present review, we highlight the metabolic enzymes that are involved in the production of these sphingolipid metabolites in these extracellular spaces.
Section snippets
Cer production in the extracellular space and at the plasma membrane by acid SMase
Three groups of SMases, acid, neutral, and alkaline, have been cloned [13], [14], [15], [16], [17]. These groups are distinguished by their catalytic pH optimum, primary structure and localization. Mammalian neutral SMase was first cloned using its homology to bacterial SMase, and until recently two forms of the enzyme (neutral SMase 1 and 2) were known [14], [15]. Very recently neutral SMase 3, which was purified from bovine brain, was also cloned [16]. These enzymes may regulate levels of
Involvement of neutral ceramidase in Cer metabolism at the plasma membrane and in extracellular space
Ceramidases (CDases) have been classified into three groups, acid, neutral, and alkaline, distinguished by their catalytic pH optimum, primary structure and localization [42]. Acid CDase is a lysosomal enzyme that contributes to the catabolism of Cer [43] and its genetic mutation causes Farber’s disease, a disorder in which Cer accumulates in lysosomes [44]. The biological importance of neutral and alkaline CDases is far less understood, although accumulating evidence now suggests that these
Physiological functions and the generation of extracellular S1P
The bioactive lipid molecule S1P regulates several cellular processes such as cell proliferation, cell migration, and differentiation, through binding to its cell surface receptors (S1P1–5) [6], [7] S1P is abundant in plasma and is physiologically important, especially in the vascular and immune systems [7], [61]. Disruption of the zebrafish gene miles apart, which encodes a homologue of mammalian S1P2, resulted in the defective migration of myocardial cells during heart development [64].
Mechanisms of Sph and S1P generation in platelets
Platelets, which are large cell fragments derived from megakaryocytes, have unique sphingolipid metabolism properties. Generally, S1P levels are low in cells because of degradation by S1P lyase [6]. However, platelets lack S1P lyase activity and have highly active Sph kinases, so they accumulate high concentrations of S1P [84], [85]. In fact, multiple forms of Sph kinase exist in platelets [89] and depletion assays using antibodies against Sph kinase 1 and 2 revealed additional unidentified Sph
Digestion of dietary SM by alkaline SMase and neutral CDase in the small intestine
Dietary products contain sphingolipids. Humans on an ordinary Western diet ingest 0.3–0.4 g of sphingolipids per day, of which SM (from meat, milk, egg products, and fish) is a large part [92]. Generally, SM in foods is sequentially hydrolyzed to Cer, Sph, and fatty acids in the lumen side of the small intestine, and the metabolites are subsequently incorporated into mucosal cells via the brush border. Although there is no evidence that dietary SM and Cer are directly absorbed into these cells,
Conclusion
Recent studies described in this review suggest the presence of one or more metabolic pathways from SM to S1P in the extracellular space, and accentuate its physiological importance (Fig. 2). However some questions remain, such as how the extracellular localization of the sphingolipid metabolic enzymes is regulated. For example, more information is needed in regards to the retention of acid SMase in plasma membranes and the secretion mechanism of the generally cytosolic Sph kinase. In addition,
Acknowledgements
Research in our laboratory is supported in part by Grants-in-aid for Scientific Research on Priority Areas (B) (12140201 for YI and 12140204 for MI), and Basic Research (B) (17380068 for MI) from the Ministry of Education, Culture, Sports, Science and Technology, of the Japanese Government.
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2022, Biochimica et Biophysica Acta - Reviews on CancerCitation Excerpt :Relevant to this point, sphingolipid metabolites and sphingolipid-metabolizing enzymes may function not only at the intracellular level but also on the cell surface and in the extracellular microenvironment [37]. For instance, extracellular acid sphingomyelinase retains a significant, albeit decreased enzymatic activity at neutral pH when compared to optimal pH 5.5 and can catalyze the hydrolysis of sphingomyelin present in lipid rafts when localized in the outer leaflet of the plasma membrane [37]. Of note, GalCer is abundant at the extracellular surface of the multilayered myelin sheath and it is present in the outer layer of the cell membrane, contributing to its nanomechanical properties (see [38] and references therein).