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Biochimica et Biophysica Acta xxx (2013) xxx–xxx
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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
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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
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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
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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),
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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
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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),
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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
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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
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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.
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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