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BBAMCB-57537; No. of pages: 10; 4C: 2 Biochimica et Biophysica Acta xxx (2013) xxx–xxx Contents lists available at ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbalip Review Sphingolipid homeostasis in the web of metabolic routes☆ Auxiliadora Aguilera-Romero 1, Charlotte Gehin 1, Howard Riezman ⁎ Department of Biochemistry and NCCR Chemical Biology, University of Geneva, CH-1211 Geneva 4, Switzerland a r t i c l e i n f o Article history: Received 15 August 2013 Received in revised form 17 October 2013 Accepted 19 October 2013 Available online xxxx Keywords: Sphingolipid Homeostasis Metabolism Eucaryote a b s t r a c t Sphingolipids play a key role in cells as structural components of membrane lipid bilayers and signaling molecules implicated in important physiological and pathological processes. Their metabolism is tightly regulated. Mechanisms controlling sphingolipid metabolism are far from being completely understood. However, they already reveal the integration of sphingolipids in the whole metabolic network as signaling devices that coordinate different metabolic pathways. A picture of sphingolipids integrated into metabolic networks might help to understand sphingolipid homeostasis. This review describes recent advances in the regulation of de novo sphingolipid synthesis with a focus on the bridges that exist with other metabolic pathways and the importance of this crosstalk in the control of sphingolipid homeostasis. This article is part of a Special Issue entitled New frontiers in sphingolipid biology. © 2013 Elsevier B.V. All rights reserved. 1. Introduction Sphingolipids (SLs) are essential structural components of membranes and critical signaling molecules whose levels must be tightly regulated. Most sphingolipids contain a ceramide i.e. a long chain sphingoid base attached to a fatty acid through an amide linkage. Ceramides are the simplest sphingolipids and the precursor onto which different head groups can be added to form either phospho- or glycosphingolipids [1]. Regulation of SL homeostasis is of fundamental importance for cells and, to a larger extent, for multicellular organisms. Indeed, many biosynthetic intermediates, in addition to the SL end products, are bioactive molecules whose accumulation or absence can severely influence cell functions [1–3]. As a consequence, several mechanisms contribute to the control of enzymes at different steps of SL synthesis and breakdown. Recently, an interesting review extensively summarized these mechanisms [4]. Some of these mechanisms operate by the sensing of nonsphingolipid metabolites that are functionally or metabolically coupled to SL biosynthesis [4]. Indeed, SL synthesis is strongly influenced by substrate availability and therefore coupled to other metabolic routes. Coordination of metabolic routes is particularly observable when cells Abbreviations: CPE, Ceramidephosphoethanolamine; DG, Diacylglycerol; ER, Endoplasmic reticulum; EtnP, Phosphoethanolamine; FA, Fatty acid; GPL, Glycerophospholipid; LCB, Long chain base; LCB-P, Long chain base phosphate; LCFA, Long chain fatty acid; LD, Lipid droplet; PA, Phosphatidic acid; PC, Phosphatidylcholine; PE, Phosphatidylethanolamine; PI, Phosphatidylinositol; SL, Sphingolipid; SM, Sphingomyelin; SPL, Sphingosine-1-phosphate lyase; SPT, Serine palmitoyltransferase; TG, Triacyglycerol; VLCFA, Very long chain fatty acids ☆ This article is part of a Special Issue entitled New frontiers in sphingolipid biology. ⁎ Corresponding author. E-mail addresses: [email protected] (A. Aguilera-Romero), [email protected] (C. Gehin), [email protected] (H. Riezman). 1 The authors contributed equally to this work. undergo differentiation, for example, a shift between stationary to proliferative phase in yeast [5], transformation into cancer cells in mammals [6] or during development. This coupling and its importance in the control of SL balance is increasingly highlighted in recent studies. For instance, during the heat stress response Chen and coworkers describe concomitant changes between SL concentrations and the activity of all enzymes participating in SL metabolism [7]. In this review, we provide an overview of the regulation of SL homeostasis. We focus particularly on bridges that exist between the de novo SL synthesis pathway and other metabolic routes, and how they are coupled. 2. Sphingolipid metabolism in eucaryotes: an overview 2.1. De novo sphingolipid synthesis The SL biosynthesis pathway shows elements of conservation in all eucaryotes. A complete description of the SL pathways in different organisms is not the scope of this review but the reader can find a detailed description in recent references [1,8–11]. An overview of the basic pathway is shown in Fig. 1. De novo SL synthesis begins in the endoplasmic reticulum (ER) with the condensation of serine and palmitoyl CoA into 3-ketodihydrosphingosine by serine palmitoyltransferase (SPT). This product is reduced to generate sphinganine, the precursor of long-chain bases (LCBs). LCBs vary in chain length, degree of unsaturation and hydroxylation. Combinations of these three parameters define the specific species of LCBs for each organism [12]. At the ER, LCBs can be phosphorylated by a kinase or condensed by a ceramide synthase with fatty acyl-CoA, giving dihydroceramides. The number of C atoms of the amide-linked fatty acid usually ranges from 14 to 26 and can extend to 36 carbons (Table 2). The very long chain fatty acids (VLCFA) are produced by specific enzymatic complexes called 1388-1981/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.bbalip.2013.10.014 Please cite this article as: A. Aguilera-Romero, et al., Sphingolipid homeostasis in the web of metabolic routes, Biochim. Biophys. Acta (2013), http://dx.doi.org/10.1016/j.bbalip.2013.10.014 2 A. Aguilera-Romero et al. / Biochimica et Biophysica Acta xxx (2013) xxx–xxx Fig. 1. Connection between de novo sphingolipid pathway and related metabolites. Several interconnected pathways link SL metabolism to other metabolisms. Main entries and exits of de novo pathway are shown. SL metabolites are highlighted in black. Red and blue arrows indicate the anabolic and catabolic SL pathways respectively. Dotted lines represent the connections with non-sphingolipid metabolites. elongases. In many species the dihydroceramide can be desaturated to form ceramide. The ceramides can then be modified in the ER to produce ceramide phosphoethanolamine or galactosylceramides, or travel to the Golgi through vesicular and non-vesicular transport routes. The mode of transport seems to determine the subsequent fate of the ceramide; conversion to glucosylceramide or sphingomyelin [13]. Once in the Golgi, diverse head groups are attached to the C-1 hydroxyl group of the ceramide backbone. The head group donor can be a glycerophospholipid (GPL) or nucleotide sugars to generate either phosphosphingolipids, with simultaneous release of diacylglycerol (DG), or glycosylsphingolipids with release of a nucleotide. The initial sugar of glycosphingolipids, usually glucose, can be extended to more complex glycan structures. Finally, complex SLs travel through the secretory pathway to the plasma membrane, endosomes and lysosomal/ vacuole system where their concentration is sensed and regulated. 2.2. Turnover and breakdown Many reactions of sphingolipid metabolism can be reversed allowing for the rapid interconversion of different metabolic intermediates (Fig. 1). Nonetheless, some steps are irreversible: the initial step catalyzed by SPT and the degradation of long chain base phosphates (LCB-P) by an ER-localized lyase to acyl aldehydes and phosphoethanolamine (EtnP). Deficiencies in both steps have severe consequences in SL metabolism [14]. Apart from these two reactions, there are several possible interconversions between SLs along their metabolic route. For instance, ceramidases regenerate LCBs from ceramides but they can also make ceramides through acylation of LCBs when ceramide synthase activity is compromised [15–17]. The activity of glycohydrolases or sphingomyelinases produces ceramides from complex SLs that can be recycled again into the sphingolipid pathway [18]. As in the anabolic pathway, enzymes responsible for SL turnover have an organelle-specific distribution in cells. For instance, in mammals, members of ceramidase and sphingomyelinase families localize in different cell compartments, such as mitochondria, ER, Golgi, lysosome/vacuole and plasma membrane [19]. In Saccharomyces cerevisiae, Isc1p, which removes inositol-containing head groups, changes its localization from ER to mitochondria depending on yeast growth phase [20]. Localization is thought to allow the production of local pools of bioactive SLs, such as ceramides, LCBs and their phospho-derivatives. Several interesting reviews highlight the importance of these degradative pathways in the production of bioactive lipids [18,21]. Sphingolipid turnover, named the salvage route, is also used to feed the sphingolipid synthesis pathway. In mammals, the salvage pathway can be responsible for 10% to 90% of sphingolipid synthesis [22]. In Leishmania parasites, it is essential to capture host SLs for infection [23,24]. Moreover, also in Leishmania this route can be used to compensate insufficiencies in SL biosynthesis. Similarly, in neurons deficient in sphingosine-1 phosphate lyase, complex SL production is mainly performed using products of the salvage pathway at the expense of de novo synthesis [25]. How cells coordinate de novo and salvage pathway to generate the proper amounts of bioactive or structural SLs is an interesting field of research. The complexity of the sphingolipidome might differentiate between these two functions. Growing evidence supports the importance of substrate specificity of enzymes belonging to the degradation pathway in production of bioactive SLs. Recent observations in S. cerevisiae support the role of a specific ceramide species generated by Isc1p (yeast ceramidase) in the resistance to hydroxyurea [26]. In mammals, bioactive sphingosine is mainly produced by ceramidase activity [21] and in plants, the alkaline ceramidase also presents a defined substrate selectivity [17]. Most of the enzymes of SL metabolism show specific subcellular localization. Therefore, spatial organization of the salvage pathway could be another discriminatory mechanism to differentiate between fates of products and to distinguish between structural and bioactive SLs. Interestingly, several enzymes of signaling pathways involved in SL metabolism are regulated by LCBs or ceramides [27,28]. This raises intriguing questions about the relative importance of the de novo and salvage pathways in the creation of bioactive sphingolipids to control their own synthesis. Indeed, the turnover of SLs in multicellular eucaryotes is vital for Please cite this article as: A. Aguilera-Romero, et al., Sphingolipid homeostasis in the web of metabolic routes, Biochim. Biophys. Acta (2013), http://dx.doi.org/10.1016/j.bbalip.2013.10.014 A. Aguilera-Romero et al. / Biochimica et Biophysica Acta xxx (2013) xxx–xxx survival as demonstrated by the existence of sphingolipidoses, human diseases generated by the defects in these pathways [3]. 2.3. Regulation of sphingolipid synthesis Although SLs are essential players in cell homeostasis the regulatory mechanisms controlling this pathway have only recently begun to emerge. The initial advances in the network of enzymatic control of this route brought to light transcriptional and posttranscriptional regulation, structural regulation through oligomer formation, and the role of several signaling pathways and of protein phosphorylation. There are excellent reviews about the regulation of the first steps in SL synthesis [4,29,30]. Below, we summarize the most recent advances in this field. 2.3.1. SPOTS complex, a key player in sphingolipid metabolism regulation The initial step of de novo SL biosynthesis has been uncovered as an important regulatory point of SL metabolism. The major advances have been made in S. cerevisiae where the discovery of the SPOTS complex led to a significant improvement in the understanding of SPT regulation. In yeast, this complex is formed by the SPT enzyme, the ER transmembrane proteins Orm1p and Orm2p, the regulatory subunit of SPT, Tsc3p, and the phosphoinositide 4-phosphatase, Sac1p [31]. Although functions of Orm proteins have been discovered in the last few years, a complete understanding of the role of this complex is still missing. Findings in yeast indicate that Orm proteins are key players in the SL pathway. These proteins directly inhibit SPT activity buffering the fluctuations in SL levels through the release of its inhibitory activity over the enzyme [31,32]. Additionally, Orm proteins are the target of two signaling pathways controlled by Target Of Rapamycin complexes, TORC1 and TORC2 working in an antagonistic way. While TORC2 plays a positive role in Orm inactivation, promoting SL synthesis, TORC1 is a negative regulator of the SL pathway. Briefly, the activity of Orm1p and Orm2p is controlled by TORC2 complex through the Kinase Ypk1p [33,34]. When SL levels drop, TORC2 is activated and Ypk1p is phosphorylated, which in turn phosphorylates Orm proteins that are inactivated, allowing the increase in SPT activity. The PP2A phosphatase is a candidate to counteract Ypk1p in controlling the Orm phosphorylation state [35]. Alternatively, during starvation, TORC1 inactivation promotes Npr1p kinase activation by means of the protein phosphatase Sit4p. Npr1p phosphorylates Orm proteins which changes the SL pattern, increasing the synthesis of complex SLs [36]. Although Orm proteins were initially only associated with SPT activity, recent data highlight a more complex role of these proteins in SL biosynthesis. Chang and coworkers describe an additional interaction between Orm proteins and the ceramide synthases [36], and Hall and coworkers show data that implicate Orm function in later steps of the route [37]. Moreover, TORC2 signaling has been previously associated with ceramide synthase activity [38]. Intriguingly, Orm response to TORC2 and TORC1 pathways is not the same. On one hand, TORC2 activation promotes Orm protein phosphorylation, inducing a change in SPOTS complex from an oligomeric to a more monomeric state, and Orm2p delocalization from the cortical ER to nuclear ER [31]. On the other hand, TORC1 inhibition increases Orm phosphorylation but doesn't affect the localization of Orm2p or the oligomeric state of SPOTS complexes [37]. The fact that Ypk1p and Npr1p specifically phosphorylate different residues is significant [37] and suggests that crosstalk between these two signaling pathways might improve the flexibility of the metabolic control. Moreover Orm regulation has been involved in stress responses including heat stress [35], unfolded protein response [32,37,39] or iron toxicity [40]. The above information raises the exciting possibility that Orm proteins may not only control SPT, but also play a crucial role determining the subsequent fate of the sphingoid base. The sphingoid bases and their phosphates could be used as signaling molecules, for example in response to stress, whereas the complex sphingolipids are more likely used as structural components. The phosphorylation level of the phospho-sites, linked to changes in cell 3 distribution of Orm proteins, might be a powerful tool to regulate the production of sphingoid bases and SLs. The role that Sac1p plays as member of SPOTS complex is still unknown. Sac1p inhibits SPT activity but the mechanism of this inhibition remains unclear. Because Sac1p has been related with protein trafficking [41] it might be regulating the changes in Orm protein localization observed under myriocin treatment [31]. Furthermore, as mentioned before, these specific changes in enzyme localization could be another point of regulation, where changes in SPOTS complex distribution could control the destiny of the SPT products and promote local production of sphinganine corresponding to the needs of the cell. Orm proteins belong to ORMDL conserved family in eucaryotes [42]. There are three Orm homologues (ORMDL1/2/3) in mammals [42]. siRNA mediated knockdown of these genes increases ceramide synthesis [31] and ORMDLs are involved in the pathway used in controlling SLs levels [43]. Although the role of Orm proteins in controlling SL pathway is conserved in mammals, the precise mechanism remains unclear, because Orm phosphorylation sites modulated by Ypk1p and Npr1p kinases in yeast are not conserved [42]. Further research in this field should help to understand how mammals control ORMDL in SL regulation. Transcriptional control of ORM genes could be a possibility. In yeast, ORM2 is controlled at the transcriptional level in a calcineurindependent manner responding to different types of stress [44]. The study of ORMDL mammalian promoter shows a cooperative regulation by several transcription factors such as Ets-1, CREB and STAT-6 [45–47]. Furthermore, the regulation of one of these, CREB, has been linked to cAMP and PKA signaling pathways [48]. Therefore, one approach would be to determine transcriptional fluctuations of different ORMDLs in other organisms and the role of SLs in transcription control, as shown in regulation of others lipids as sterols [49]. Transcription levels of ceramide synthase and SPT genes are regulated in mammals. Changes in gene expression of the later enzymes of the route have also been found in plants [50], in several stress responses in yeast [51] and during the life cycle of trypanosomes [52]. 2.3.2. Other mechanisms of regulation In addition to the recent advances in regulation by Orm proteins, it is noteworthy that multiple enzymes of SL metabolism are controlled through phosphorylation of critical subunits. In yeast the activity of the LCB kinase, Lcb4p, changes during the growth phase and this is regulated by the kinase Pho85p [53]. Moreover, phosphorylation of the ceramide synthase has been found in phosphoproteomics studies [54]. In mammals the activity of CERT, responsible for non-vesicular transport of ceramides between ER and Golgi is regulated by two kinases PKD [55] and casein kinase I gamma 2 [56]. Interestingly, in yeast, a member of the casein kinase family, CKA2, has been also implicated in ceramide synthesis activity [57]. An additional mechanism of ceramide synthase regulation was recently described by Futerman and coworkers. Ceramide synthase is regulated by reversible dimerization. Modifications by phosphorylation or glycosylation allow ceramide synthases to form homo- or heterodimers, a process that regulates their activities [58]. In S. cerevisiae, ceramide synthases Lag1p and Lac1p associate with the regulatory subunit Lip1p [59]. Regulation by oligomeric state is also found at SPT level. In yeast SPT interacts with the regulatory subunit, Tsc3p [60], and in mammals and Drosophila SPT interacts with a regulatory subunit named small subunit of SPT (ssSPT) [61,62]. Finally, the transport of SL intermediates between cell organelles is becoming an important issue in the control of SL homeostasis. In metazoan animals, the ceramide transport protein (CERT) involved in nonvesicular transport of ceramides between ER and the Golgi complex, plays a central role in SM synthesis [13]. In vertebrates, the fourphosphate adaptor protein 2 (FAPP2) responsible for non-vesicular transport of glucosylceramides has been shown to control the Please cite this article as: A. Aguilera-Romero, et al., Sphingolipid homeostasis in the web of metabolic routes, Biochim. Biophys. Acta (2013), http://dx.doi.org/10.1016/j.bbalip.2013.10.014 4 A. Aguilera-Romero et al. / Biochimica et Biophysica Acta xxx (2013) xxx–xxx subcellular distribution of glucosylceramide and to promote the synthesis of glycosphingolipids at the Golgi complex [63,64]. 3. Crosstalk between sphingolipid biosynthesis and other metabolic pathways As described in the first section, enzymes involved in de novo SL synthesis are tightly regulated through the action of mechanisms that modulate their activity in response to environment, substrate availability and the presence of cofactors [1], connecting SLs to other metabolites such as lipids, amino acids or sugars. Indeed, in response to environmental changes, such as oxygen or nitrogen deprivation, stress, cancer or even developmental changes, eucaryotic cells are able to shift their whole metabolism [6,7]. In this section, we review the interconnection between SL biosynthesis and other metabolic pathways and how metabolic shifts under specific environmental conditions affect SL homeostasis. 3.1. Role of lipids in sphingolipid homeostasis 3.1.1. Glycerophospholipids as connectors and regulators of nutrient supply SLs are closely related to GPLs, because they share some parts of their metabolic pathways, such as the synthesis of polar head groups or fatty acyl-CoAs (Fig. 1). Numerous connections exist between SL and GPL metabolism, depending on the organism and its developmental stage. Both lipid classes can feed each other and impact their concentration. Ceramides require GPLs as substrates to synthesize complex SLs. In turn, since complex SL biosynthesis steps are reversible reactions, they might also regulate the amounts of certain GPLs. SL turnover is essential in order to preserve organelle integrity, in particular in the endosome/ lysosomal system [65]. SLs are linked in two ways to GPL classes since SL metabolism either consumes or furnishes head group components: phosphatidylethanolamine (PE), through the irreversible degradation of sphingoid base into EtnP via S1P lyase [25,66], and phosphatidylcholine (PC), phosphatidylinositol (PI), and/or PE as donor of polar head groups in the synthesis of sphingomyelin (SM), inositolphosphorylceramides (IPC and M(IP)2C) and/or ceramidephosphoethanolamine (CPE), respectively. Most organisms produce a mix of complex SLs with different head groups in different quantities. One of these SLs is usually predominant while the others are present in lower amounts and their functions are rarely addressed. As a consequence, the impact of each GPL class on SL homeostasis differs with its contribution (Table 1). For instance, mammals make SM, as their major SL, and CPE, in trace amounts. While CPE concentration doesn't seem to determine the overall amount of SLs in mammals the enzyme that makes it is thought to act as a sensor that modulates SL synthesis. The bulk of SM is produced by sphingomyelin synthases SMS1 in the Golgi and SMS2 at the plasma membrane. CPE can be produced either by the dual specificity SMS2 or by the monospecific SMSr, in the ER lumen. Blocking SMSr activity results in a collapse in SL homeostasis due to ceramide accumulation in the ER and organelle dysfunction [67–69]. In insects, the major phosphosphingolipid is not SM but CPE. CPE can be produced in small amounts by a homolog of the mammalian SMSr (dSMSr) but the bulk production is made by an unrelated CPE synthase. This enzyme, located in the Golgi compartment, is similar to the ethanolamine phosphotransferase of the Kennedy pathway, using EtnP instead of PE as polar headgroup donor [8,70]. In other classes of organisms, such as kinetoplastids, the headgroup donor in SL synthesis depends on the developmental stage of the animal [71,72]. Indeed, parasitic protozoa have a complex life cycle comprising insect and mammalian hosts. They acquire their SLs either from de novo synthesis, through SPT, or salvage pathways, i.e. production of ceramides through the degradation of their host SLs. Leishmania major is able to grow without de novo SL synthesis, thanks to ISCL (inositol phosphosphingolipid phospholipase C-like), an enzyme, which converts IPC or SM from the host into ceramide. Furthermore, while in other organisms GPLs tend to feed the SL metabolic pathway, in Leishmania GPL synthesis depends on the presence of LCBs. Indeed, sphingosine-1-phosphate degradation via S1P lyase (SPL) is the major route to produce their ethanolamine (EtN), precursor for both PE and PC biosynthesis, the major GPLs. This direct connection between GPL and SL biosynthetic pathways allows the parasite to modulate its membrane biophysical properties during different phases of infection. It is also a good example of metabolic adaptation to nutrient sources that change with development [10,24,73,74]. In yeast, this connection is also important to maintain GPL homeostasis. S. cerevisiae produces only inositol-derived phosphoceramides (IPC, MIPC and M(IP)2C) through the transfer of phosphoinositol from PI onto a phytoceramide backbone (PHC) [9]. Evidence that supports a link between SLs and GPLs in yeast has been found recently. It was demonstrated that orm null mutants, which show a clear imbalance in SLs, induce defects in GPL homeostasis by affecting the functional inactivation of Opi1p, a transcriptional repressor of GPL biosynthetic enzymes [32]. 3.1.2. Glycerophospholipids in the control of fatty acid flux Neutral lipid TGs and DGs provide essential substrates in phospholipid synthesis (Fig. 1) and the former represents a major class of storage lipids in all eucaryotes where they are stored in lipid droplets (LDs). TGs consist of a glycerol backbone esterified with three long-chain fatty acids. Their biogenesis takes place in the ER with the esterification of their precursor DGs by acyl-CoA: diacylglycerol acyltransferases. Both DG and TG occupy a central position in the coordination of lipid metabolism, and especially in the regulation of fatty acid (FA) fluxes between membrane and storage lipids through the action of lipases and acyltransferases [75,76]. Indeed, TG synthesis and breakdown directly impacts the acyl composition of both SL and GPLs. As has been recently demonstrated, mutants in the synthesis and mobilization of TG have lower levels of PIs in growing yeast. This defect consequently decreases the pool of SLs, in an inositol-dependent manner [77]. In contrast, induction of TG synthesis in plants (Arabidopsis thaliana) through the expression of an ectopic diacylglycerol acyltransferase from algae led to a specific redirection of fatty acids from SLs to TG, illustrating the interconnection between these two metabolic pathways [78]. Diacylglycerol acyltransferases that ensure TG synthesis are present in the ER and their action could be closely related to the regulation of ceramide synthesis since, in yeast, Lro1p and Dga1p were found to acylate ceramides on the hydroxyl group of the first carbon atom of the long-chain base and can be mobilized when FA biosynthesis is inhibited [79]. Finally, it was shown that TG lipolysis mutants present a defect in FA channeling but also elongation resulting in the decrease of both SLs and GPLs [80]. These observations demonstrate the importance of FA fluxes in the maintenance of membrane lipid homeostasis. With respect to DGs, these molecules also play a pivotal role in the convergence of SL, PL and neutral lipid metabolic pathways, as revealed by a number of metabolic diseases linked to insulin resistance, including type II diabetes or hepatic steatosis [81]. DGs are important metabolic intermediates and bioactive molecules, as essential effectors of the IP3/DG transduction pathway. Their concentration is controlled through different cellular mechanisms that link them to other metabolites. They can result from TG lipolysis in LDs, phospholipase C activity on phosphoinositides, phosphatase action on phosphatidic acid (PA), or be generated during SL synthesis. Indeed, one molecule of DG is produced each time a phospholipid head group is transferred onto a ceramide backbone by SL synthases [75,76] (Table 1). In mammals, it was demonstrated that SMS1 and SMS2 activities influenced the intracellular localization of DGs [82] with consequences on signaling. Silencing of SMS1 or 2, for instance, leads to a decrease of DG in the Golgi and the delocalization of the DG binding protein kinase D (PKD) resulting in the destabilization of trafficking proteins from Golgi to the plasma membrane [83]. In addition, an increase of DG has an effect on metabolism. An excess of palmitic acid intake from a high-fat diet, for instance, stimulates de novo SL synthesis through SPT upregulation. This increased activity, coupled to a consequent increase of GSLs and DG Please cite this article as: A. Aguilera-Romero, et al., Sphingolipid homeostasis in the web of metabolic routes, Biochim. Biophys. Acta (2013), http://dx.doi.org/10.1016/j.bbalip.2013.10.014 A. Aguilera-Romero et al. / Biochimica et Biophysica Acta xxx (2013) xxx–xxx 5 Table 1 Crosstalk between phosphosphingolipid and glycerophospholipid metabolic pathways. ORGANISM REACTIONS ENZYMES DLP1 (S1pl) S1P –> EtnP + hexadecanal AUR1, KEI1 (IPC synthase) PI + PHC <–> IPC + DG Fungi [9] IPT1, SKN1 (Inositolphosphotransferase) PI + MIPC <–> MIP2C + DG IPC/MIPC/MIP2C <–> Ceramide + Phosphoinositol [20] AtDLP1 (S1pl) S1P –> EtnP + hexadecanal [17] Plants (A.thaliana) [17] AtERH1 (IPC synthase) PI + PHC <–> GIPC + DG [17, 50] T. brucei [71, 72] L. major ISC1 (IPS phospholipase C) S1P –> EtnP + hexadecanal SPL (S1pl) PI + Ceramide <–> IPC + DG TbSLS1 (IPC synthase) PC/PE + Ceramide <–> SM/CPE + DG TbSLS2–4 (CPE/SM synthase) SM/CPE <–> Ceramide + Phosphocholine SMase (sphingomyelinase) S1P –> EtnP + aldehyde, major route of PE synthesis SPL (S1pl) PI + Ceramide <–> IPC + DG IPCS SM/IPC –> Ceramide + Phosphocholine/Inositol ISCL S1P –> EtnP + hexadecanal SPL PI/PC/PE + Ceramide <–> IPC/SM/PE + DG TcIPC1 and TcIPC2 SM/IPC + DG <–> Ceramide + Phosphocholine/inositol [146] (Sphingolipid synthase) S1P –> EtnP + hexadecanal Sply (S1pl) CDP – Eth + Ceramides <–> CPE + CMP CPES (CPE synthase) S1P –> EtnP + hexadecanal [147] SPL(S1pl) PC + Ceramide <–> SM + DG [67] SMS (SM synthase) SM + DG <–> Ceramide + Phosphocholine sphingomyelinase homologs S1P –> EtnP + hexadecanal [66] SPL (S1pl) PC/PE + Ceramide <–> SM/CPE + DG SMS1, 2, SMSr (sphingolipid synthase) SM/CPE + DG [67–69] SMase (sphingomyelinase) Protozoa [10, 24, 73] L. dosomanii [74] T. cruzii [71, 145] D. melanogaster Auxotrophic Invertebrates [8, 62, 70] C. elegans Mammals Vertebrates Sphingolipid (black) substrates (red) and products (blue) connected with another pathway; (↔) reversible and (→) irreversible reactions. CDP-PE, CDP-ethanolamine; CMP, cytosine monophosphate; CPE, ceramide phosphoethanolamine; DG, diacylglycerol; EtnP, phosphoethanolamine; GIPC, glycosyl inositolphosphoceramide; GPI, glycosylphosphoinositol; IPC, inositol phosphoceramide; IPS, inositol phosphosphingolipid; MIPC, mannose-(inositol phosphate)-ceramide; MIP2C, mannose-(inositol phosphate)2ceramide; PHC, phytoceramide; PI, phosphatidylinositol; PC, phosphatidylcholine; PE, phosphatidylethanolamine; S1P, sphingosine-1-phosphate; SM, sphingomyeline; S1pl/SPL, sphingosine-1-phosphate lyase. Further information about the table can be found in references [9,10,17,50,66,67,69,71–74,145–147]. synthesis in the Golgi, is proposed to lead to insulin resistance [81]. This last example shows that the action of the neutral lipids DG and TG on SL homeostasis is closely related to the control of fatty acid concentration and fluxes. 3.1.3. Fatty acids FAs are either produced in cells by FA synthases or can be provided by the environment. Mammals, for instance, cannot synthesize the “essential” polyunsaturated linoleic and α-linolenic acids themselves and need to find them in their food (vegetal or fish) to ensure fluidity of their cell membranes [84]. Both essential and non-essential FAs can be ingested but excesses of certain FAs relative to others are thought to favor metabolic syndromes, often directly linked to the regulation of SL synthesis, as described above with palmitic acid. The crosstalk between SL and FA metabolism starts with the enzyme SPT, serine and fatty acyl-CoA (Table 2). The chain length of sphingoid bases ranges from 12 to 22 carbons with the most common being C18 in fungi and mammals. Palmitoyl-CoA, a long chain fatty acid (LCFA), is the major substrate of SPT in most eucaryotes, with some exceptions, such as Drosophila and Caenorhabditis elegans which produce C14 and branched-chain C17 sphingoid bases, respectively. Mammalian cells can also produce different amounts of C16 and C20 LCBs, depending on the organs [85,86]. For instance, the pool of C16 sphingoid base is more important in plasma SLs or in bovine milk [85,87]. This diversity, based on acyl-CoA chain length, is ensured by the combination of subunits that form SPT. In mammals, the SPT complex comprises a catalytic core SPTLC1–SPTLC2 heterodimer and the small ssSPTs. SPTLC2 carries pyridoxal 5′-phosphate. An isoform of SPTLC2, called SPTLC3 can be expressed in some tissues [88]. While SPTLC2 shows specificity Please cite this article as: A. Aguilera-Romero, et al., Sphingolipid homeostasis in the web of metabolic routes, Biochim. Biophys. Acta (2013), http://dx.doi.org/10.1016/j.bbalip.2013.10.014 6 A. Aguilera-Romero et al. / Biochimica et Biophysica Acta xxx (2013) xxx–xxx Table 2 Ceramide synthases activity in eucaryotes. Organism Fungi Enzyme CerS S. cerevisiae 100] P. pastoris [98] C. albicans [99] Protozoa Trypanosoma cruzi [148] Plants (A. thaliana) [101] Auxotrophic invertebrates Mammals [97] Drosophila melanogaster [102] C. elegans [104] CerS substrates Downstream products Fatty acyl-CoAa Sphingoid baseb Lag1p Lac1p Bar1p Lag1p CaLag1p CaLac1p TcCerS1 26:0 DHCer → IPC PHCer → IPC DHCer → GlcCer PHCer → IPC PHCer → IPC DHCer → GlcCer DHCer → Phosphoceramide LOH1 LOH2 20:0–28:0 16:0 LOH3 Schlank Hyl-1 Hyl-2 Lagr1 CerS1 CerS2 CerS3 CerS4 CerS5 CerS6 20:0–28:0 – 24:0–26:0 20:0–22:0 – 18:0/1 22:0/1–26:0/1 18:0–24:0 18:0–20:0 16:0–18:0 14:0–16:0 d18:0 (DHS) t18:0 (PHS) d18:0 (DHS) t18:0 (PHS) t18:0 (PHS) d18:0 (DHS) d18:0 (DHS) d18:1 (Sph) t18:0 (PHS) d18:0 (DHS) t18:0 (PHS) t18:0 (PHS) – Isosphingoid base d18:0 (DHS) d18:1 (Sph) DHCer → SM/GlcCer Cer → SM/GlcCer 18:0 24:0 24:0–26:0 18:0 16:0 PHCer → IPC/GIPC/GlcCer DH/PHCer → GlcCer PHCer → IPC/GIPC/GlcCer Broad panel of ceramides → CPE Ceramide → SM/GlcCer a Preferred fatty acyl-CoA (x:y); x: number of carbons; y: unsaturation degree. Preferred sphingoid bases: d/t for dihydro- or trihydro-CerS: ceramide synthase; DHS: dihydrosphingosine/sphinganine; DHCer: dihydroceramide; Sph: sphingosine/sphing-4-enine; PHCer: phytoceramide/4-hydroxyceramide; PHS: phytosphingosine/4-hydroxysphinganine; IPC: inositol-phosphorylceramide; GlcCer: glucosylceramide; – : unknown. b for the canonical palmitoyl-CoA, SPTLC3 prefers myristoyl-CoA [89]. Chemical diversity of sphingoid bases also depends on enzymes able to modify fatty acids upstream of SPT. In C. elegans, for instance, LCBs are iso-branched C17 sphingoid bases [90]. Nematodes get branched acyl-CoA precursor from diet (bacteria) or through de novo synthesis. Branched acyl-CoA precursors are made from metabolites of amino acid breakdown such as isovaleric acid instead of acetyl-CoA for straight FAs. Then, the iso-branched C13 fatty acid precursor is modified by elongases ELO5/6 and reductase LET-767 to give iso-branched C15 acyl-CoA. Defects in these enzymes block SL biosynthesis and subsequently cause an accumulation of branched-chain FA in TG and GPLs [91]. After synthesis, 3-ketodihydrosphinganine is reduced and becomes the backbone of all SLs. This backbone undergoes several chemical modifications along the SL biosynthesis pathways, including N-acylation of LCFAs or VLCFAs by ceramide synthase (Table 2). VLCFAs result from successive elongations of C16:0/1–C18:0/1 fatty acyl substrates by a range of chain-length specific elongases from the elovl (elongation-ofvery-long-chain-fatty-acids) gene family in the ER. They can be incorporated into TGs, GPLs, SLs and plant waxes [92]. The VLCFA content of SL is of great importance for cell growth and development. For example, in yeast the major acyl chain in ceramides is C26 and accumulation of C26ceramides is toxic, while C16 or C18 ceramide is not toxic when accumulated, but will sustain growth and many cellular functions [93]. sur4 (elo3) mutants also produce shorter acyl chained ceramides and also show reduced toxicity due to ceramide accumulation [94]. In other organisms, such as A. thaliana, elongases directly impact on organ development through the regulation of VLCFA SLs [95]. Finally, recent studies suggest a coordinated regulation between elongases and ceramide synthases. For instance in mammals, ELOVL1, which controls VLCFA synthesis up to 26:0 is produced depending on the need of ceramide synthases 2 and 3, which use C24:0-CoA and larger substrates for ceramide synthesis [96]. The acyl chain length found in ceramides is dictated by the enzymatic properties of the ceramide synthases (Table 2). In mammals, the six ceramide synthases (CerS1–6) present different affinities for substrate acyl-CoAs dependent upon their chain-length [97]. As mentioned above, ceramide synthase activity can be regulated by dimerization. This dimerization is not only important for the activity of the enzyme but will also impact its selectivity for acyl-CoA chain length [58]. Ceramide synthase selectivity is also present in plants and some fungi. Interestingly, in some fungal species, such as Pichia pastoris and Candida albicans, ceramide synthases show affinities for specific sphingoid bases and/or acyl-CoA substrates (Table 2) [98,99]. Contrary to their S. cerevisiae homologs, Lag1p and Lac1p, which are functionally redundant [100], their specificity allows them to catalyze two classes of ceramide precursors that will be specifically destined to the production of either IPCs or glucosylceramides. This coordinated specificity between CerS and subsequent enzymatic steps is also found in plants where the three different enzymes LOH1–3 combine different fatty acyl-CoA and sphingoid bases to form the specific ceramide precursors of phosphosphingolipids and glycosphingolipids [101]. Some organisms have only one CerS with broader specificity, able to synthesize a panel range of ceramides, such as Schlank in Drosophila, whose role is essential in the development through coordination of GPL, FA and SL homeostasis [102,103]. In C. elegans, the two CerS Hyl-1 and Hyl-2 that catalyze attachment of different fatty-acyl chains confer to worms different abilities to survive environmental changes [104]. In some cases defects in ceramide synthases cause a disruption of SL homeostasis leading to cell growth arrest or differentiation but not necessarily death. Organisms can compensate these defects through different mechanisms, such as the functional redundancy of CerS in some eucaryotes, the use of SL in the recycling pathways or sequestering of host SLs in the case of parasites. In mammals, mutations in ceramide synthases lead to a large range of diseases, affecting specifically SL acyl chain length composition of the membrane that loses its tissue-specific biophysical properties [97]. For example in humans, mutations of CerS3, a CerS prevalent in skin and testis, impairs very long acyl chain ceramide synthesis, which in turn prevents keratinocyte differentiation and development of the skin barrier. It leads to autosomal recessive congenital ichthyosis [105]. The additional role of ceramides in the proliferation of different cancers makes CerS potential drug targets [106]. In S. cerevisiae, the first gene coding for ceramide synthase was called LAG1 for longevity assurance gene 1, in order to underline its role in the life span of yeast. Deleting one of the two CerS genes, LAG1 or LAC1, is viable while the double knockout is lethal, except in some strain backgrounds [100]. In these strains, even mutants lacking both ceramide synthases and the two ceramidases Please cite this article as: A. Aguilera-Romero, et al., Sphingolipid homeostasis in the web of metabolic routes, Biochim. Biophys. Acta (2013), http://dx.doi.org/10.1016/j.bbalip.2013.10.014 A. Aguilera-Romero et al. / Biochimica et Biophysica Acta xxx (2013) xxx–xxx continue to make ceramides through a still unknown pathway, to make abnormal SLs, very long chain lyso-PI and incorporate the ceramides into GPI-anchors [107]. In yeast, GPI-anchored proteins contain either diacylglycerol or ceramide moieties [108]. The GPI remodeling pathway with ceramides is a mechanism that links glycolipid metabolic routes to SLs. Finally, another link between SLs and FAs has been reinforced recently by the discovery of the pathway that generates acyl-CoA from the degradation product of sphingosine-1P, hexadecenal, and its essential role in health [109]. 3.1.4. Sterols Contrary to GPLs and FAs, there is no interconversion possible between sterols and SL biosynthesis in eucaryotes. However, they do share the same precursor acetyl-CoA, which is required for both the synthesis of HMG-CoA and FAs. Several examples in literature reveal strong connections between these lipid classes. First, SLs and cholesterol are transported in the same lipoprotein particles in mammals [110]. Second, yeast cells adjust their SL profile in response to changes in sterol structures, and genetic experiments show that sterols and SLs functionally interact in biological membranes [111]. Another example of tight coordination of the regulation of both metabolic routes has been provided in mammals where changes in SL levels at the plasma membrane promote changes in cholesterol distribution from the plasma membrane to the ER [112]. The increase or decrease in ER cholesterol is sensed by the SREBP2, major transcription regulator of cholesterol uptake and biosynthesis, which modulates cholesterol synthesis to compensate imbalances in cholesterol levels. A detailed description of the mechanism of action of SREBP can be found in a recent review [113]. In mammals, a family of 12 proteins, called ORPs (OSBP-related proteins), have been proposed to coordinate sterol and SL metabolism between ER and the Golgi apparatus. Even though they are not certain to regulate sterol homeostasis, it was found that their association with 25-hydroxycholesterol, upon cholesterol depletion triggers their binding to CERT increasing subsequently the non-vesicular transfer of ceramides from ER to Golgi to enhance the production of SM and DGs [114]. Moreover, a yeast member of the family, Osh4p is required to maintain the levels of LCBs, ceramides and complex SLs [115]. Furthermore, Osh family proteins bind to PI4P and have been implicated in the regulation of Sac1p, which complexes with SPT in S. cerevisiae [116] establishing a new link between phosphoinositides, SLs and sterols. Nevertheless, the specific function and influence of this connection in metabolism is still to be understood. 3.2. Amino acid determination in de novo sphingolipid synthesis LCB synthesis by SPT, the rate-limiting step in de novo sphinganine synthesis, is also strongly influenced by the availability of SPT substrates L-serine and fatty acyl-CoA [117]. The need for L-serine links amino acid and SL metabolism. In yeast, a clear connection has been recently demonstrated. During heat stress response, an increase in the uptake of extracellular serine is enough to raise the production of LCBs, suggesting that the rise in serine is sufficient to induce de novo SL synthesis [118]. Hannun and co-workers explain this behavior as a consequence of the high Km of SPT for serine, which is near the usual intracellular serine concentration and makes the enzyme sensitive to normal oscillations in the amino acid concentration [118]. Conversely, in yeast, SLs have also been involved in the negative feedback regulation of serine metabolism. LCBs serve as sensors of serine availability and mediate upregulation of the serine deaminase CHA1. This enzyme decreases serine accumulation and consequently, de novo SL synthesis [119]. These two feed forward/feedback mechanisms contribute to maintain both serine and SL homeostasis. The importance of serine regulation in the de novo pathway has been also demonstrated in mammals where the SPT activity is limited by intracellular serine which, in this instance, is controlled by extracellular serine concentration [117,120]. The relation between amino acids and SLs is not only restricted to serine, SPT has also a 7 significant but lower affinity for other amino acids [121]. In mammals when ceramide synthases are inhibited by Fumonisin-B1, SPT continues to make new sphingoid bases and can also accept alanine or glycine, as substrate, to form 1-deoxysphinganines and 1-(deoxymethyl)sphinganines, respectively [122]. Deoxysphingoid bases can neither be converted into complex SLs, nor degraded by the S1P/lyase pathway and are cytotoxic. Normally, these products are present in very small quantities in cells [1]. In humans, mutations in the SPTLC1 or SPTLC2 subunit cause a shift in the substrate specificity of SPT to prefer alanine instead of serine and therefore to produce more deoxysphinganine. The accumulation of these neurotoxic compounds is responsible for a rare disease, the Hereditary Sensory Neuropathy Type 1 (HSAN1) [123,124]. In other situations, these bioactive molecules show anticancer properties. Thus, as other sphingoid bases, their concentration has to be tightly regulated. As reviewed by Merrill, many factors can influence deoxyceramide concentration since serine, alanine and glycine are connected to major metabolic pathways such as glycolysis and the TCA cycle [1,125]. 3.3. Sugars Sugars are components of several complex SLs. They enter in the composition of glycosphingolipids that represents a highly diverse class of molecules in eucaryotes [1,126]. Ceramides can be converted to galactosylceramides in the ER or to glucosylceramides in the Golgi compartment by the addition of a sugar from UDP-glucose or UDPgalactose onto the ceramide [127]. Glucosylceramide is the unique glycosphingolipid common to plants, fungi and animals [128] and the precursor of most of GSLs. It ensures several functions [126] indispensable to cell survival [129] and development [130]. Moreover, several diseases are associated with its misregulation [131]. Control of GSL homeostasis is not clearly understood yet. Other cross talks between SL synthesis and carbohydrate metabolism exists. Glucose enters glycolysis and forms 3-phosphoglycerate a precursor of serine, the first substrate in de novo SL synthesis [125,132]. Acetyl-CoA and glycerol-3-P, derived from glycolysis are precursors of FA and PL, respectively. Thus, changes in glucose and more generally in carbon metabolism can impact SL homeostasis, as seen when cells shift from a respiratory to a fermentative metabolism [6]. In addition, SLs and glucose metabolism are regulated by similar signaling pathways, such as insulin [81] or the AMP kinase pathways. In yeast, inhibition of de novo SL synthesis by myriocin is sufficient to induce several changes in energy metabolism through the activation of the Snf1/AMPK pathway and down-regulation of the protein kinase A (PKA) and TORC1 pathways [133]. In Drosophila, overexpression of glucosylceramide synthase directly increased levels of fat and carbohydrates while its knockdown reversely decreased them, by activating an intracellular signaling pathway [134]. 3.4. Cofactors The SL biosynthesis pathway is greatly influenced by the presence of small metabolites acting as signaling factors or enzyme cofactors, whose concentration directly influences SL concentration. For instance, the initial and the final step of the SL pathway, SPT and sphingosine-1phosphate lyase, belong to the superfamily of the pyridoxal 5′-phosphate dependent enzymes [135]. Magnesium (Mg2+) is a cofactor of neutral SMSases in mammals [136]. Decrease in magnesium uptake is associated with upregulation of de novo ceramide and SM synthesis [137,138]. Conversely, the concentration of SL species influences the intracellular content of Mg2+ in a calcium-dependent manner [139]. Manganese ions are required for the optimal activity of glucosylceramide synthase [140]. Other metal ions, such as iron (Fe), function as cofactors of several enzymes required for lipid metabolism, for instance, the enzymes involved in SL hydroxylation in yeast [141]. Iron deprivation or increase leads to strong SL changes but mechanisms involved in this Please cite this article as: A. Aguilera-Romero, et al., Sphingolipid homeostasis in the web of metabolic routes, Biochim. Biophys. Acta (2013), http://dx.doi.org/10.1016/j.bbalip.2013.10.014 8 A. Aguilera-Romero et al. / Biochimica et Biophysica Acta xxx (2013) xxx–xxx phenomenon still remain to be elucidated [5,40,142]. Other metabolites play a role more related to signaling but their concentration still directly influence SL synthesis. For instance, calcium and nitric oxide have been shown to greatly influence SL levels in several studies [143]. 4. Conclusion A snapshot of SL homeostasis reveals a complex network comprising several levels of regulation. The activity of enzymes of the pathway can be controlled by posttranslational modifications, changes in enzyme levels and in their subcellular distribution. In addition, their activity is also regulated by the availability of their substrates. As mentioned throughout this review, the de novo SL pathway shares common substrates with other metabolic routes. Therefore, the control of this network should be highly sensitive to environmental changes. The response to the environment through signaling pathways usually involves the coordination of several metabolic routes. This fact highlights the importance of having an integrated view of SLs that fits into the whole metabolic net. This will clearly be an important step in the future. Recent advances in the various -omics techniques and development of systems biology approaches will provide a more complete picture of what happens in cells under controlled conditions and will help to model precisely how metabolic networks work together to maintain homeostasis. Such techniques are already used in the field of parasitology where the complex host–pathogen interactions are now better understood and provide a strong tool to adapt drug treatment [144] and systemic studies have also been started in yeast. In the same manner, knowing how the SL levels are controlled in different diseases where they are involved would help to better identify precise drug targets. Acknowledgements The authors acknowledge support from SystemsX.ch, evaluated by the Swiss National Science Foundation, The Swiss National Science Foundation (HR), the NCCR Chemical Biology and the EU ITN, Sphingonet. The authors are grateful to Dr. J. Thomas Hannich and Aline Xavier da Silveira dos Santos for fruitful discussions. References [1] A.H. Merrill Jr., Sphingolipid and glycosphingolipid metabolic pathways in the era of sphingolipidomics, Chem. Rev. 111 (2011) 6387–6422. [2] A.M. Alayoubi, J.C. Wang, B.C. Au, S. Carpentier, V. Garcia, S. Dworski, S. El-Ghamrasni, K.N. Kirouac, M.J. Exertier, Z.J. Xiong, G.G. Prive, C.M. Simonaro, J. Casas, G. Fabrias, E.H. Schuchman, P.V. Turner, R. Hakem, T. Levade, J.A. Medin, Systemic ceramide accumulation leads to severe and varied pathological consequences, EMBO Mol. Med. 5 (2013) 827–842. [3] T. Kolter, A view on sphingolipids and disease, Chem. Phys. Lipids 164 (2011) 590–606. [4] D.K. Breslow, Sphingolipid homeostasis in the endoplasmic reticulum and beyond, Cold Spring Harb. Perspect. Biol. 5 (2013) a013326. [5] R.L. Lester, B.R. Withers, M.A. Schultz, R.C. Dickson, Iron, glucose and intrinsic factors alter sphingolipid composition as yeast cells enter stationary phase, Biochim. Biophys. Acta 1831 (2013) 726–736. [6] K. Natter, S.D. Kohlwein, Yeast and cancer cells—common principles in lipid metabolism, Biochim. Biophys. Acta 1831 (2013) 314–326. [7] P.W. Chen, L.L. Fonseca, Y.A. Hannun, E.O. Voit, Coordination of rapid sphingolipid responses to heat stress in yeast, PLoS Comput. Biol. 9 (2013) e1003078. [8] U. Acharya, J.K. Acharya, Enzymes of sphingolipid metabolism in Drosophila melanogaster, Cell Mol. Life Sci. 62 (2005) 128–142. [9] R.C. Dickson, Thematic review series: sphingolipids. New insights into sphingolipid metabolism and function in budding yeast, J. Lipid Res. 49 (2008) 909–921. [10] K. Zhang, S.M. Beverley, Phospholipid and sphingolipid metabolism in Leishmania, Mol. Biochem. Parasitol. 170 (2010) 55–64. [11] C.R. Gault, L.M. Obeid, Y.A. Hannun, An overview of sphingolipid metabolism: from synthesis to breakdown, Adv. Exp. Med. Biol. 688 (2010) 1–23. [12] J.T. Hannich, K. Umebayashi, H. Riezman, Distribution and functions of sterols and sphingolipids, Cold Spring Harb. Perspect. Biol. 3 (2011). [13] K. Hanada, K. Kumagai, N. Tomishige, T. Yamaji, CERT-mediated trafficking of ceramide, Biochim. Biophys. Acta 1791 (2009) 684–691. [14] M. Bektas, M.L. Allende, B.G. Lee, W. Chen, M.J. Amar, A.T. Remaley, J.D. Saba, R.L. Proia, Sphingosine 1-phosphate lyase deficiency disrupts lipid homeostasis in liver, J. Biol. Chem. 285 (2010) 10880–10889. [15] C. Mao, R. Xu, A. Bielawska, L.M. Obeid, Cloning of an alkaline ceramidase from Saccharomyces cerevisiae. An enzyme with reverse (CoA-independent) ceramide synthase activity, J. Biol. Chem. 275 (2000) 6876–6884. [16] N. Okino, X. He, S. Gatt, K. Sandhoff, M. Ito, E.H. Schuchman, The reverse activity of human acid ceramidase, J. Biol. Chem. 278 (2003) 29948–29953. [17] M.O. Pata, Y.A. Hannun, C.K. Ng, Plant sphingolipids: decoding the enigma of the Sphinx, New Phytol. 185 (2010) 611–630. [18] Y.A. Hannun, L.M. Obeid, Principles of bioactive lipid signalling: lessons from sphingolipids, Nat. Rev. Mol. Cell Biol. 9 (2008) 139–150. [19] D. Canals, D.M. Perry, R.W. Jenkins, Y.A. Hannun, Drug targeting of sphingolipid metabolism: sphingomyelinases and ceramidases, Br. J. Pharmacol. 163 (2011) 694–712. [20] N. Matmati, Y.A. Hannun, Thematic review series: sphingolipids. ISC1 (inositol phosphosphingolipid-phospholipase C), the yeast homologue of neutral sphingomyelinases, J. Lipid Res. 49 (2008) 922–928. [21] K. Kitatani, J. Idkowiak-Baldys, Y.A. Hannun, The sphingolipid salvage pathway in ceramide metabolism and signaling, Cell. Signal. 20 (2008) 1010–1018. [22] G. Tettamanti, R. Bassi, P. Viani, L. Riboni, Salvage pathways in glycosphingolipid metabolism, Biochimie 85 (2003) 423–437. [23] K. Zhang, F.F. Hsu, D.A. Scott, R. Docampo, J. Turk, S.M. Beverley, Leishmania salvage and remodelling of host sphingolipids in amastigote survival and acidocalcisome biogenesis, Mol. Microbiol. 55 (2005) 1566–1578. [24] O. Zhang, W. Xu, A. Balakrishna Pillai, K. Zhang, Developmentally regulated sphingolipid degradation in Leishmania major, PloS one 7 (2012) e31059. [25] N. Hagen-Euteneuer, D. Lutjohann, H. Park, A.H. Merrill Jr., G. van Echten-Deckert, Sphingosine 1-phosphate (S1P) lyase deficiency increases sphingolipid formation via recycling at the expense of de novo biosynthesis in neurons, J. Biol. Chem. 287 (2012) 9128–9136. [26] N. Matmati, A. Metelli, K. Tripathi, S. Yan, B.K. Mohanty, Y.A. Hannun, Identification of c18:1-phytoceramide as the candidate lipid mediator for hydroxyurea resistance in yeast, J. Biol. Chem. 288 (2013) 17272–17284. [27] R.T. Dobrowsky, C. Kamibayashi, M.C. Mumby, Y.A. Hannun, Ceramide activates heterotrimeric protein phosphatase 2A, J. Biol. Chem. 268 (1993) 15523–15530. [28] K. Liu, X. Zhang, C. Sumanasekera, R.L. Lester, R.C. Dickson, Signalling functions for sphingolipid long-chain bases in Saccharomyces cerevisiae, Biochem. Soc. Trans. 33 (2005) 1170–1173. [29] D.K. Breslow, J.S. Weissman, Membranes in balance: mechanisms of sphingolipid homeostasis, Mol. Cell 40 (2010) 267–279. [30] Rotem Tidhar, H. Anthony, Futerman, The complexity of sphingolipid biosynthesis in the endoplasmic reticulum, Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1833 (11) (2013) 2511–2518. [31] D.K. Breslow, S.R. Collins, B. Bodenmiller, R. Aebersold, K. Simons, A. Shevchenko, C.S. Ejsing, J.S. Weissman, Orm family proteins mediate sphingolipid homeostasis, Nature 463 (2010) 1048–1053. [32] S. Han, M.A. Lone, R. Schneiter, A. Chang, Orm1 and Orm2 are conserved endoplasmic reticulum membrane proteins regulating lipid homeostasis and protein quality control, Proc. Natl. Acad. Sci. U. S. A. 107 (2010) 5851–5856. [33] F.M. Roelants, D.K. Breslow, A. Muir, J.S. Weissman, J. Thorner, Protein kinase Ypk1 phosphorylates regulatory proteins Orm1 and Orm2 to control sphingolipid homeostasis in Saccharomyces cerevisiae, Proc. Natl. Acad. Sci. U. S. A. 108 (2011) 19222–19227. [34] D. Berchtold, M. Piccolis, N. Chiaruttini, I. Riezman, H. Riezman, A. Roux, T.C. Walther, R. Loewith, Plasma membrane stress induces relocalization of Slm proteins and activation of TORC2 to promote sphingolipid synthesis, Nat. Cell Biol. 14 (2012) 542–547. [35] Y. Sun, Y. Miao, Y. Yamane, C. Zhang, K.M. Shokat, H. Takematsu, Y. Kozutsumi, D.G. Drubin, Orm protein phosphoregulation mediates transient sphingolipid biosynthesis response to heat stress via the Pkh–Ypk and Cdc55–PP2A pathways, Mol. Biol. Cell 23 (2012) 2388–2398. [36] M. Liu, C. Huang, S.R. Polu, R. Schneiter, A. Chang, Regulation of sphingolipid synthesis through Orm1 and Orm2 in yeast, J. Cell Sci. 125 (2012) 2428–2435. [37] M. Shimobayashi, W. Oppliger, S. Moes, P. Jeno, M.N. Hall, TORC1-regulated protein kinase Npr1 phosphorylates Orm to stimulate complex sphingolipid synthesis, Mol. Biol. Cell 24 (2013) 870–881. [38] S. Aronova, K. Wedaman, P.A. Aronov, K. Fontes, K. Ramos, B.D. Hammock, T. Powers, Regulation of ceramide biosynthesis by TOR complex 2, Cell Metab. 7 (2008) 148–158. [39] K.J. Hsu, S.E. Turvey, Functional analysis of the impact of ORMDL3 expression on inflammation and activation of the unfolded protein response in human airway epithelial cells, Allergy Asthma Clin. Immunol. 9 (2013) 4. [40] Y.J. Lee, X. Huang, J. Kropat, A. Henras, S.S. Merchant, R.C. Dickson, G.F. Chanfreau, Sphingolipid signaling mediates iron toxicity, Cell Metab. 16 (2012) 90–96. [41] Z. Szentpetery, P. Varnai, T. Balla, Acute manipulation of Golgi phosphoinositides to assess their importance in cellular trafficking and signaling, Proc. Natl. Acad. Sci. U. S. A. 107 (2010) 8225–8230. [42] L. Hjelmqvist, M. Tuson, G. Marfany, E. Herrero, S. Balcells, R. Gonzalez-Duarte, ORMDL proteins are a conserved new family of endoplasmic reticulum membrane proteins, Genome Biol. 3 (2002)RESEARCH0027. [43] D.L. Siow, B.W. Wattenberg, Mammalian ORMDL proteins mediate the feedback response in ceramide biosynthesis, J. Biol. Chem. 287 (2012) 40198–40204. [44] C. Gururaj, R. Federman, A. Chang, Orm proteins integrate multiple signals to maintain sphingolipid homeostasis, J. Biol. Chem. 288 (2013) 20453–20463. [45] R. Jin, H.G. Xu, W.X. Yuan, L.L. Zhuang, L.F. Liu, L. Jiang, L.H. Zhu, J.Y. Liu, G.P. Zhou, Mechanisms elevating ORMDL3 expression in recurrent wheeze patients: role of Ets-1, p300 and CREB, Int. J. Biochem. Cell Biol. 44 (2012) 1174–1183. [46] M. Miller, A.B. Tam, J.Y. Cho, T.A. Doherty, A. Pham, N. Khorram, P. Rosenthal, J.L. Mueller, H.M. Hoffman, M. Suzukawa, M. Niwa, D.H. Broide, ORMDL3 is an Please cite this article as: A. Aguilera-Romero, et al., Sphingolipid homeostasis in the web of metabolic routes, Biochim. Biophys. Acta (2013), http://dx.doi.org/10.1016/j.bbalip.2013.10.014 A. Aguilera-Romero et al. / Biochimica et Biophysica Acta xxx (2013) xxx–xxx [47] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] [68] [69] [70] [71] [72] inducible lung epithelial gene regulating metalloproteases, chemokines, OAS, and ATF6, Proc. Natl. Acad. Sci. U. S. A. 109 (2012) 16648–16653. R. Qiu, Y. Yang, H. Zhao, J. Li, Q. Xin, S. Shan, Y. Liu, J. Dang, X. Yu, Y. Gong, Q. Liu, Signal transducer and activator of transcription 6 directly regulates human ORMDL3 expression, FEBS J. 280 (2013) 2014–2026. L.L. Zhuang, R. Jin, L.H. Zhu, H.G. Xu, Y. Li, S. Gao, J.Y. Liu, G.P. Zhou, Promoter characterization and role of cAMP/PKA/CREB in the basal transcription of the mouse ORMDL3 gene, PloS one 8 (2013) e60630. A. Nohturfft, S.C. Zhang, Coordination of lipid metabolism in membrane biogenesis, Annu. Rev. Cell Dev. Biol. 25 (2009) 539–566. J.G. Mina, Y. Okada, N.K. Wansadhipathi-Kannangara, S. Pratt, H. Shams-Eldin, R.T. Schwarz, P.G. Steel, T. Fawcett, P.W. Denny, Functional analyses of differentially expressed isoforms of the Arabidopsis inositol phosphorylceramide synthase, Plant Mol. Biol. 73 (2010) 399–407. H. Yoshimoto, K. Saltsman, A.P. Gasch, H.X. Li, N. Ogawa, D. Botstein, P.O. Brown, M.S. Cyert, Genome-wide analysis of gene expression regulated by the calcineurin/Crz1p signaling pathway in Saccharomyces cerevisiae, J. Biol. Chem. 277 (2002) 31079–31088. S. Kabani, K. Fenn, A. Ross, A. Ivens, T.K. Smith, P. Ghazal, K. Matthews, Genomewide expression profiling of in vivo-derived bloodstream parasite stages and dynamic analysis of mRNA alterations during synchronous differentiation in Trypanosoma brucei, BMC Genomics 10 (2009) 427. S. Iwaki, A. Kihara, T. Sano, Y. Igarashi, Phosphorylation by Pho85 cyclindependent kinase acts as a signal for the down-regulation of the yeast sphingoid long-chain base kinase Lcb4 during the stationary phase, J. Biol. Chem. 280 (2005) 6520–6527. B. Bodenmiller, S. Wanka, C. Kraft, J. Urban, D. Campbell, P.G. Pedrioli, B. Gerrits, P. Picotti, H. Lam, O. Vitek, M.Y. Brusniak, B. Roschitzki, C. Zhang, K.M. Shokat, R. Schlapbach, A. Colman-Lerner, G.P. Nolan, A.I. Nesvizhskii, M. Peter, R. Loewith, C. von Mering, R. Aebersold, Phosphoproteomic analysis reveals interconnected system-wide responses to perturbations of kinases and phosphatases in yeast, Sci. Signal. 3 (2010) rs4. T. Fugmann, A. Hausser, P. Schoffler, S. Schmid, K. Pfizenmaier, M.A. Olayioye, Regulation of secretory transport by protein kinase D-mediated phosphorylation of the ceramide transfer protein, J. Cell Biol. 178 (2007) 15–22. N. Tomishige, K. Kumagai, J. Kusuda, M. Nishijima, K. Hanada, Casein kinase I {gamma}2 down-regulates trafficking of ceramide in the synthesis of sphingomyelin, Mol. Biol. Cell 20 (2009) 348–357. S.D. Kobayashi, M.M. Nagiec, Ceramide/long-chain base phosphate rheostat in Saccharomyces cerevisiae: regulation of ceramide synthesis by Elo3p and Cka2p, Eukaryot. Cell 2 (2003) 284–294. E.L. Laviad, S. Kelly, A.H. Merrill Jr., A.H. Futerman, Modulation of ceramide synthase activity via dimerization, J. Biol. Chem. 287 (2012) 21025–21033. B. Vallee, H. Riezman, Lip1p: a novel subunit of acyl-CoA ceramide synthase, EMBO J. 24 (2005) 730–741. K. Gable, H. Slife, D. Bacikova, E. Monaghan, T.M. Dunn, Tsc3p is an 80-amino acid protein associated with serine palmitoyltransferase and required for optimal enzyme activity, J. Biol. Chem. 275 (2000) 7597–7603. G. Han, S.D. Gupta, K. Gable, S. Niranjanakumari, P. Moitra, F. Eichler, R.H. Brown Jr., J.M. Harmon, T.M. Dunn, Identification of small subunits of mammalian serine palmitoyltransferase that confer distinct acyl-CoA substrate specificities, Proc. Natl. Acad. Sci. U. S. A. 106 (2009) 8186–8191. X.L. Guan, G. Cestra, G. Shui, A. Kuhrs, R.B. Schittenhelm, E. Hafen, F.G. van der Goot, C.C. Robinett, M. Gatti, M. Gonzalez-Gaitan, M.R. Wenk, Biochemical membrane lipidomics during Drosophila development, Dev. Cell 24 (2013) 98–111. G. D'Angelo, L.R. Rega, M.A. De Matteis, Connecting vesicular transport with lipid synthesis: FAPP2, Biochim. Biophys. Acta 1821 (2012) 1089–1095. G. D'Angelo, T. Uemura, C.C. Chuang, E. Polishchuk, M. Santoro, H. Ohvo-Rekila, T. Sato, G. Di Tullio, A. Varriale, S. D'Auria, T. Daniele, F. Capuani, L. Johannes, P. Mattjus, M. Monti, P. Pucci, R.L. Williams, J.E. Burke, F.M. Platt, A. Harada, M.A. De Matteis, Vesicular and non-vesicular transport feed distinct glycosylation pathways in the Golgi, Nature 501 (2013) 116–120. F.M. Platt, B. Boland, A.C. van der Spoel, The cell biology of disease: lysosomal storage disorders: the cellular impact of lysosomal dysfunction, J. Cell Biol. 199 (2012) 723–734. F. Bourquin, H. Riezman, G. Capitani, M.G. Grutter, Structure and function of sphingosine-1-phosphate lyase, a key enzyme of sphingolipid metabolism, Structure 18 (2010) 1054–1065. K. Huitema, J. van den Dikkenberg, J.F. Brouwers, J.C. Holthuis, Identification of a family of animal sphingomyelin synthases, EMBO J. 23 (2004) 33–44. A.M. Vacaru, F.G. Tafesse, P. Ternes, V. Kondylis, M. Hermansson, J.F. Brouwers, P. Somerharju, C. Rabouille, J.C. Holthuis, Sphingomyelin synthase-related protein SMSr controls ceramide homeostasis in the ER, J. Cell Biol. 185 (2009) 1013–1027. P. Ternes, J.F. Brouwers, J. van den Dikkenberg, J.C. Holthuis, Sphingomyelin synthase SMS2 displays dual activity as ceramide phosphoethanolamine synthase, J. Lipid Res. 50 (2009) 2270–2277. A.M. Vacaru, J. van den Dikkenberg, P. Ternes, J.C. Holthuis, Ceramide phosphoethanolamine biosynthesis in Drosophila is mediated by a unique ethanolamine phosphotransferase in the Golgi lumen, J. Biol. Chem. 288 (2013) 11520–11530. S.S. Sutterwala, F.F. Hsu, E.S. Sevova, K.J. Schwartz, K. Zhang, P. Key, J. Turk, S.M. Beverley, J.D. Bangs, Developmentally regulated sphingolipid synthesis in African trypanosomes, Mol. Microbiol. 70 (2008) 281–296. T.K. Smith, P. Butikofer, Lipid metabolism in Trypanosoma brucei, Mol. Biochem. Parasitol. 172 (2010) 66–79. 9 [73] K. Zhang, J.M. Pompey, F.F. Hsu, P. Key, P. Bandhuvula, J.D. Saba, J. Turk, S.M. Beverley, Redirection of sphingolipid metabolism toward de novo synthesis of ethanolamine in Leishmania, EMBO J. 26 (2007) 1094–1104. [74] S. Majumder, R. Dey, S. Bhattacharjee, A. Rub, G. Gupta, S. Bhattacharyya Majumdar, B. Saha, S. Majumdar, Leishmania-induced biphasic ceramide generation in macrophages is crucial for uptake and survival of the parasite, J. Infect. Dis. 205 (2012) 1607–1616. [75] S.A. Henry, S.D. Kohlwein, G.M. Carman, Metabolism and regulation of glycerolipids in the yeast Saccharomyces cerevisiae, Genetics 190 (2012) 317–349. [76] S.D. Kohlwein, M. Veenhuis, I.J. van der Klei, Lipid droplets and peroxisomes: key players in cellular lipid homeostasis or a matter of fat—store ‘em up or burn’em down, Genetics 193 (2013) 1–50. [77] M.L. Gaspar, H.F. Hofbauer, S.D. Kohlwein, S.A. Henry, Coordination of storage lipid synthesis and membrane biogenesis: evidence for cross-talk between triacylglycerol metabolism and phosphatidylinositol synthesis, J. Biol. Chem. 286 (2011) 1696–1708. [78] Sanjaya, R. Miller, T.P. Durrett, D.K. Kosma, T.A. Lydic, B. Muthan, A.J. Koo, Y.V. Bukhman, G.E. Reid, G.A. Howe, J. Ohlrogge, C. Benning, Altered lipid composition and enhanced nutritional value of Arabidopsis leaves following introduction of an algal diacylglycerol acyltransferase 2, Plant Cell 25 (2013) 677–693. [79] N.S. Voynova, C. Vionnet, C.S. Ejsing, A. Conzelmann, A novel pathway of ceramide metabolism in Saccharomyces cerevisiae, Biochem. J. 447 (2012) 103–114. [80] S. Rajakumari, R. Rajasekharan, G. Daum, Triacylglycerol lipolysis is linked to sphingolipid and phospholipid metabolism of the yeast Saccharomyces cerevisiae, Biochim. Biophys. Acta 1801 (2010) 1314–1322. [81] G.M. Deevska, M.N. Nikolova-Karakashian, The twists and turns of sphingolipid pathway in glucose regulation, Biochimie 93 (2011) 32–38. [82] M. Villani, M. Subathra, Y.B. Im, Y. Choi, P. Signorelli, M. Del Poeta, C. Luberto, Sphingomyelin synthases regulate production of diacylglycerol at the Golgi, Biochem. J. 414 (2008) 31–41. [83] M. Subathra, A. Qureshi, C. Luberto, Sphingomyelin synthases regulate protein trafficking and secretion, PloS one 6 (2011) e23644. [84] A.P. Simopoulos, Essential fatty acids in health and chronic disease, Am. J. Clin. Nutr. 70 (1999) 560S–569S. [85] S.T. Pruett, A. Bushnev, K. Hagedorn, M. Adiga, C.A. Haynes, M.C. Sullards, D.C. Liotta, A.H. Merrill Jr., Biodiversity of sphingoid bases (“sphingosines”) and related amino alcohols, J. Lipid Res. 49 (2008) 1621–1639. [86] A.H. Merrill Jr., De novo sphingolipid biosynthesis: a necessary, but dangerous, pathway, J. Biol. Chem. 277 (2002) 25843–25846. [87] S.B. Russo, R. Tidhar, A.H. Futerman, L.A. Cowart, Myristate-derived d16:0 sphingolipids constitute a cardiac sphingolipid pool with distinct synthetic routes and functional properties, J. Biol. Chem. 288 (2013) 13397–13409. [88] K. Hanada, Serine palmitoyltransferase, a key enzyme of sphingolipid metabolism, Biochim. Biophys. Acta 1632 (2003) 16–30. [89] T. Hornemann, A. Penno, M.F. Rutti, D. Ernst, F. Kivrak-Pfiffner, L. Rohrer, A. von Eckardstein, The SPTLC3 subunit of serine palmitoyltransferase generates short chain sphingoid bases, J. Biol. Chem. 284 (2009) 26322–26330. [90] M. Kniazeva, Q.T. Crawford, M. Seiber, C.Y. Wang, M. Han, Monomethyl branched-chain fatty acids play an essential role in Caenorhabditis elegans development, PLoS Biol. 2 (2004) E257. [91] E.V. Entchev, D. Schwudke, V. Zagoriy, V. Matyash, A. Bogdanova, B. Habermann, L. Zhu, A. Shevchenko, T.V. Kurzchalia, LET-767 is required for the production of branched chain and long chain fatty acids in Caenorhabditis elegans, J. Biol. Chem. 283 (2008) 17550–17560. [92] A. Kihara, Very long-chain fatty acids: elongation, physiology and related disorders, J. Biochem. 152 (2012) 387–395. [93] S. Epstein, G.A. Castillon, Y. Qin, H. Riezman, An essential function of sphingolipids in yeast cell division, Mol. Microbiol. 84 (2012) 1018–1032. [94] M. Tani, O. Kuge, Defect of synthesis of very long-chain fatty acids confers resistance to growth inhibition by inositol phosphorylceramide synthase repression in yeast Saccharomyces cerevisiae, J. Biochem. 148 (2010) 565–571. [95] L. Bach, J.D. Faure, Role of very-long-chain fatty acids in plant development, when chain length does matter, C. R. Biol. 333 (2010) 361–370. [96] Y. Ohno, S. Suto, M. Yamanaka, Y. Mizutani, S. Mitsutake, Y. Igarashi, T. Sassa, A. Kihara, ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis, Proc. Natl. Acad. Sci. U. S. A. 107 (2010) 18439–18444. [97] T.D. Mullen, Y.A. Hannun, L.M. Obeid, Ceramide synthases at the centre of sphingolipid metabolism and biology, Biochem. J. 441 (2012) 789–802. [98] P. Ternes, T. Wobbe, M. Schwarz, S. Albrecht, K. Feussner, I. Riezman, J.M. Cregg, E. Heinz, H. Riezman, I. Feussner, D. Warnecke, Two pathways of sphingolipid biosynthesis are separated in the yeast Pichia pastoris, J. Biol. Chem. 286 (2011) 11401–11414. [99] S.A. Cheon, J. Bal, Y. Song, H.M. Hwang, A.R. Kim, W.K. Kang, H.A. Kang, H.K. Hannibal-Bach, J. Knudsen, C.S. Ejsing, J.Y. Kim, Distinct roles of two ceramide synthases, CaLag1p and CaLac1p, in the morphogenesis of Candida albicans, Mol. Microbiol. 83 (2012) 728–745. [100] A. Teufel, T. Maass, P.R. Galle, N. Malik, The longevity assurance homologue of yeast lag1 (Lass) gene family (review), Int. J. Mol. Med. 23 (2009) 135–140. [101] P. Ternes, K. Feussner, S. Werner, J. Lerche, T. Iven, I. Heilmann, H. Riezman, I. Feussner, Disruption of the ceramide synthase LOH1 causes spontaneous cell death in Arabidopsis thaliana, New Phytol. 192 (2011) 841–854. [102] R. Bauer, A. Voelzmann, B. Breiden, U. Schepers, H. Farwanah, I. Hahn, F. Eckardt, K. Sandhoff, M. Hoch, Schlank, a member of the ceramide synthase family controls growth and body fat in Drosophila, EMBO J. 28 (2009) 3706–3716. Please cite this article as: A. Aguilera-Romero, et al., Sphingolipid homeostasis in the web of metabolic routes, Biochim. Biophys. Acta (2013), http://dx.doi.org/10.1016/j.bbalip.2013.10.014 10 A. Aguilera-Romero et al. / Biochimica et Biophysica Acta xxx (2013) xxx–xxx [103] J. Pepperl, G. Reim, U. Luthi, A. Kaech, G. Hausmann, K. Basler, Sphingolipid depletion impairs endocytic traffic and inhibits Wingless signaling, Mech. Dev. 130 (9– 10) (2013) 493–505. [104] V. Menuz, K.S. Howell, S. Gentina, S. Epstein, I. Riezman, M. Fornallaz-Mulhauser, M.O. Hengartner, M. Gomez, H. Riezman, J.C. Martinou, Protection of C. elegans from anoxia by HYL-2 ceramide synthase, Science 324 (2009) 381–384. [105] F.P. Radner, S. Marrakchi, P. Kirchmeier, G.J. Kim, F. Ribierre, B. Kamoun, L. Abid, M. Leipoldt, H. Turki, W. Schempp, R. Heilig, M. Lathrop, J. Fischer, Mutations in CERS3 cause autosomal recessive congenital ichthyosis in humans, PLoS Genet. 9 (2013) e1003536. [106] S.A. Saddoughi, B. Ogretmen, Diverse functions of ceramide in cancer cell death and proliferation, Adv. Cancer Res. 117 (2013) 37–58. [107] C. Vionnet, C. Roubaty, C.S. Ejsing, J. Knudsen, A. Conzelmann, Yeast cells lacking all known ceramide synthases continue to make complex sphingolipids and to incorporate ceramides into glycosylphosphatidylinositol (GPI) anchors, J. Biol. Chem. 286 (2011) 6769–6779. [108] O.T. Yoko, D. Ichikawa, Y. Miyagishi, A. Kato, M. Umemura, K. Takase, M. Ra, K. Ikeda, R. Taguchi, Y. Jigami, Determination and physiological roles of the glycosylphosphatidylinositol lipid remodelling pathway in yeast, Mol. Microbiol. 88 (2013) 140–155. [109] K. Nakahara, A. Ohkuni, T. Kitamura, K. Abe, T. Naganuma, Y. Ohno, R.A. Zoeller, A. Kihara, The Sjogren–Larsson syndrome gene encodes a hexadecenal dehydrogenase of the sphingosine 1-phosphate degradation pathway, Mol. Cell 46 (2012) 461–471. [110] A. Nilsson, R.D. Duan, Absorption and lipoprotein transport of sphingomyelin, J. Lipid Res. 47 (2006) 154–171. [111] X.L. Guan, C.M. Souza, H. Pichler, G. Dewhurst, O. Schaad, K. Kajiwara, H. Wakabayashi, T. Ivanova, G.A. Castillon, M. Piccolis, F. Abe, R. Loewith, K. Funato, M.R. Wenk, H. Riezman, Functional interactions between sphingolipids and sterols in biological membranes regulating cell physiology, Mol. Biol. Cell 20 (2009) 2083–2095. [112] J.P. Slotte, E.L. Bierman, Depletion of plasma-membrane sphingomyelin rapidly alters the distribution of cholesterol between plasma membranes and intracellular cholesterol pools in cultured fibroblasts, Biochem. J. 250 (1988) 653–658. [113] R. Sato, Sterol metabolism and SREBP activation, Arch. Biochem. Biophys. 501 (2010) 177–181. [114] V.M. Olkkonen, S. Li, Oxysterol-binding proteins: sterol and phosphoinositide sensors coordinating transport, signaling and metabolism, Prog. Lipid Res. 52 (4) (2013) 529–538. [115] M.A. LeBlanc, G.D. Fairn, S.B. Russo, O. Czyz, V. Zaremberg, L.A. Cowart, C.R. McMaster, The yeast oxysterol binding protein Kes1 maintains sphingolipid levels, PloS one 8 (2013) e60485. [116] C.J. Stefan, A.G. Manford, D. Baird, J. Yamada-Hanff, Y. Mao, S.D. Emr, Osh proteins regulate phosphoinositide metabolism at ER-plasma membrane contact sites, Cell 144 (2011) 389–401. [117] A.H. Merrill Jr., E. Wang, R.E. Mullins, Kinetics of long-chain (sphingoid) base biosynthesis in intact LM cells: effects of varying the extracellular concentrations of serine and fatty acid precursors of this pathway, Biochemistry 27 (1988) 340–345. [118] L.A. Cowart, Y.A. Hannun, Selective substrate supply in the regulation of yeast de novo sphingolipid synthesis, J. Biol. Chem. 282 (2007) 12330–12340. [119] D.J. Montefusco, B. Newcomb, J.L. Gandy, S.E. Brice, N. Matmati, L.A. Cowart, Y.A. Hannun, Sphingoid bases and the serine catabolic enzyme CHA1 define a novel feedforward/feedback mechanism in the response to serine availability, J. Biol. Chem. 287 (2012) 9280–9289. [120] E.R. Smith, A.H. Merrill Jr., Differential roles of de novo sphingolipid biosynthesis and turnover in the “burst” of free sphingosine and sphinganine, and their 1-phosphates and N-acyl-derivatives, that occurs upon changing the medium of cells in culture, J. Biol. Chem. 270 (1995) 18749–18758. [121] J. Lowther, J.H. Naismith, T.M. Dunn, D.J. Campopiano, Structural, mechanistic and regulatory studies of serine palmitoyltransferase, Biochem. Soc. Trans. 40 (2012) 547–554. [122] N.C. Zitomer, T. Mitchell, K.A. Voss, G.S. Bondy, S.T. Pruett, E.C. Garnier-Amblard, L.S. Liebeskind, H. Park, E. Wang, M.C. Sullards, A.H. Merrill Jr., R.T. Riley, Ceramide synthase inhibition by fumonisin B1 causes accumulation of 1-deoxysphinganine: a novel category of bioactive 1-deoxysphingoid bases and 1-deoxydihydroceramides biosynthesized by mammalian cell lines and animals, J. Biol. Chem. 284 (2009) 4786–4795. [123] A. Penno, M.M. Reilly, H. Houlden, M. Laura, K. Rentsch, V. Niederkofler, E.T. Stoeckli, G. Nicholson, F. Eichler, R.H. Brown Jr., A. von Eckardstein, T. Hornemann, Hereditary sensory neuropathy type 1 is caused by the accumulation of two neurotoxic sphingolipids, J. Biol. Chem. 285 (2010) 11178–11187. [124] S.M. Murphy, D. Ernst, Y. Wei, M. Laura, Y.T. Liu, J. Polke, J. Blake, J. Winer, H. Houlden, T. Hornemann, M.M. Reilly, Hereditary sensory and autonomic [125] [126] [127] [128] [129] [130] [131] [132] [133] [134] [135] [136] [137] [138] [139] [140] [141] [142] [143] [144] [145] [146] [147] [148] neuropathy type 1 (HSANI) caused by a novel mutation in SPTLC2, Neurology 80 (2013) 2106–2111. M. Kanehisa, The KEGG database, Novartis Found. Symp. 247 (2002) 91–101(discussion 101–103, 119–128, 244–152). S. Degroote, J. Wolthoorn, G. van Meer, The cell biology of glycosphingolipids, Semin. Cell Dev. Biol. 15 (2004) 375–387. M. Leipelt, D. Warnecke, U. Zahringer, C. Ott, F. Muller, B. Hube, E. Heinz, Glucosylceramide synthases, a gene family responsible for the biosynthesis of glucosphingolipids in animals, plants, and fungi, J. Biol. Chem. 276 (2001) 33621–33629. D. Warnecke, E. Heinz, Recently discovered functions of glucosylceramides in plants and fungi, Cell Mol. Life Sci. 60 (2003) 919–941. R. Jennemann, H.J. Grone, Cell-specific in vivo functions of glycosphingolipids: lessons from genetic deletions of enzymes involved in glycosphingolipid synthesis, Prog. Lipid Res. 52 (2013) 231–248. K.H. Nomura, D. Murata, Y. Hayashi, K. Dejima, S. Mizuguchi, E. Kage-Nakadai, K. Gengyo-Ando, S. Mitani, Y. Hirabayashi, M. Ito, K. Nomura, Ceramide glucosyltransferase of the nematode Caenorhabditis elegans is involved in oocyte formation and in early embryonic cell division, Glycobiology 21 (2011) 834–848. D.J. Sillence, F.M. Platt, Introduction: glycosphingolipids in cell biology and disease, Semin. Cell Dev. Biol. 15 (2004) 371–373. J.W. Locasale, Serine, glycine and one-carbon units: cancer metabolism in full circle, Nat. Rev. Cancer 13 (2013) 572–583. J. Liu, X. Huang, B.R. Withers, E. Blalock, K. Liu, R.C. Dickson, Reducing sphingolipid synthesis orchestrates global changes to extend yeast lifespan, Aging Cell 12 (2013) 833–841. A. Kohyama-Koganeya, T. Nabetani, M. Miura, Y. Hirabayashi, Glucosylceramide synthase in the fat body controls energy metabolism in Drosophila, J. Lipid Res. 52 (2011) 1392–1399. F. Bourquin, G. Capitani, M.G. Grutter, PLP-dependent enzymes as entry and exit gates of sphingolipid metabolism, Protein Sci. 20 (2011) 1492–1508. N. Marchesini, Y.A. Hannun, Acid and neutral sphingomyelinases: roles and mechanisms of regulation, Biochem. Cell Biol. 82 (2004) 27–44. B.M. Altura, N.C. Shah, Z. Li, X.C. Jiang, J.L. Perez-Albela, B.T. Altura, Magnesium deficiency upregulates serine palmitoyl transferase (SPT 1 and SPT 2) in cardiovascular tissues: relationship to serum ionized Mg and cytochrome c, Am. J. Physiol. Heart Circ. Physiol. 299 (2010) H932–H938. B.M. Altura, N.C. Shah, G. Shah, A. Zhang, W. Li, T. Zheng, J.L. Perez-Albela, B.T. Altura, Short-term magnesium deficiency upregulates ceramide synthase in cardiovascular tissues and cells: cross-talk among cytokines, Mg2+, NF-kappaB, and de novo ceramide, Am. J. Physiol. Heart Circ. Physiol. 302 (2012) H319–H332. T. Zheng, W. Li, B.T. Altura, N.C. Shah, B.M. Altura, Sphingolipids regulate [Mg2+]o uptake and [Mg2+]i content in vascular smooth muscle cells: potential mechanisms and importance to membrane transport of Mg2+, Am. J. Physiol. Heart Circ. Physiol. 300 (2011) H486–H492. H.J. Senn, M. Wagner, K. Decker, Ganglioside biosynthesis in rat liver. Characterization of UDPgalactose–glucosylceramide galactosyltransferase and UDPgalactose– GM2 galactosyltransferase, Eur. J. Biochem. 135 (1983) 231–236. T.M. Dunn, D. Haak, E. Monaghan, T.J. Beeler, Synthesis of monohydroxylated inositolphosphorylceramide (IPC-C) in Saccharomyces cerevisiae requires Scs7p, a protein with both a cytochrome b5-like domain and a hydroxylase/desaturase domain, Yeast (Chichester Engl.) 14 (1998) 311–321. M. Shakoury-Elizeh, O. Protchenko, A. Berger, J. Cox, K. Gable, T.M. Dunn, W.A. Prinz, M. Bard, C.C. Philpott, Metabolic response to iron deficiency in Saccharomyces cerevisiae, J. Biol. Chem. 285 (2010) 14823–14833. I. Guillas, A. Zachowski, E. Baudouin, A matter of fat: interaction between nitric oxide and sphingolipid signaling in plant cold response, Plant Signal. Behav. 6 (2011) 140–142. D.J. Creek, J. Anderson, M.J. McConville, M.P. Barrett, Metabolomic analysis of trypanosomatid protozoa, Mol. Biochem. Parasitol. 181 (2012) 73–84. C.M. Koeller, N. Heise, The sphingolipid biosynthetic pathway is a potential target for chemotherapy against Chagas disease, Enzyme Res. 2011 (2011) 648159. M.C. Fernandes, M. Cortez, A.R. Flannery, C. Tam, R.A. Mortara, N.W. Andrews, Trypanosoma cruzi subverts the sphingomyelinase-mediated plasma membrane repair pathway for cell invasion, J. Exp. Med. 208 (2011) 909–921. J. Mendel, K. Heinecke, H. Fyrst, J.D. Saba, Sphingosine phosphate lyase expression is essential for normal development in Caenorhabditis elegans, J. Biol. Chem. 278 (2003) 22341–22349. J.M. Figueiredo, D.C. Rodrigues, R.C. Silva, C.M. Koeller, J.C. Jiang, S.M. Jazwinski, J.O. Previato, L. Mendonca-Previato, T.P. Urmenyi, N. Heise, Molecular and functional characterization of the ceramide synthase from Trypanosoma cruzi, Mol. Biochem. Parasitol. 182 (2012) 62–74. Please cite this article as: A. Aguilera-Romero, et al., Sphingolipid homeostasis in the web of metabolic routes, Biochim. Biophys. Acta (2013), http://dx.doi.org/10.1016/j.bbalip.2013.10.014