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Review
, 19 (3), 175-191

Sphingolipids and Their Metabolism in Physiology and Disease

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Review

Sphingolipids and Their Metabolism in Physiology and Disease

Yusuf A Hannun et al. Nat Rev Mol Cell Biol.

Erratum in

Abstract

Studies of bioactive lipids in general and sphingolipids in particular have intensified over the past several years, revealing an unprecedented and unanticipated complexity of the lipidome and its many functions, which rivals, if not exceeds, that of the genome or proteome. These results highlight critical roles for bioactive sphingolipids in most, if not all, major cell biological responses, including all major cell signalling pathways, and they link sphingolipid metabolism to key human diseases. Nevertheless, the fairly nascent field of bioactive sphingolipids still faces challenges in its biochemical and molecular underpinnings, including defining the molecular mechanisms of pathway and enzyme regulation, the study of lipid-protein interactions and the development of cellular probes, suitable biomarkers and therapeutic approaches.

Conflict of interest statement

Competing interests statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1. Overview of sphingolipid metabolism
It is convenient to envision sphingolipid metabolism as organized into blocks. Aa | The de novo biosynthetic pathway is initiated in the endoplasmic reticulum by the action of serine palmitoyltransferase (SPT). Sequential reactions lead to the generation of ceramides. Preferential substrates include serine and palmitoyl-CoA, but alanine or glycine and stearate or myristate can also be used. Ab–Ad | Ceramides are then incorporated into various complex sphingolipids (predominantly in the Golgi) through modifications at the 1-hydroxyl position to generate ceramide-1-phosphate (C1P), sphingomyelin or glycoceramides, which in turn serve as the precursors for the various glycosphingolipids. Ae | Ceramides can be acylated to form 1-O-acyl-ceramides. Af | In sphingolipid catabolic pathways, sphingomyelin, C1P and glycosphingolipids are hydrolysed, resulting in the formation of ceramide (see parts b, c and d). Constitutive catabolism occurs in the lysosome. Ceramide can then be deacylated to generate sphingosine, which in turn is phosphorylated to sphingosine-1-phosphate (S1P). Ag | Exit from sphingolipids is initiated by the action of S1P lyase, which cleaves S1P (or dihydroS1P) to a fatty aldehyde and ethanolamine phosphate. The fatty aldehyde undergoes further metabolism, resulting in the formation of palmitoyl-CoA. Ah | The fatty acid (FA) elongation module is an important adjunct component of the sphingolipid pathway, as sphingolipids are the primary lipids with very-long (C22–26) and ultra-long (longer than C26) fatty acyl chains. B | As the precursor of all complex sphingolipids, ceramides constitute a family of closely related molecules that contain a sphingoid base and an amino-linked FA. Different enzymes introduce variations to the basic structure. Fatty acid 2-hydroxylase introduces an OH on the fatty acyl group (variation 1). Sphingolipidδ (4)-desaturase DES1 (DEGS1) introduces a double bond in the 4–5 position of the sphingoid base (variation 2), whereas DEGS2 can introduce an OH on position 4 (not shown). Ceramide synthases introduce fatty acyl groups of distinct chain length (variation 3). SPT can utilize myristate or stearate instead of palmitate, thus introducing variations in the length of the sphingoid backbone (variation 4). SPT can also utilize alanine or glycine, thus introducing variation 5. For easy nomenclature of ceramides, the chain length of the fatty acyl group is indicated (for example, C18 Cer for the N-stearoyl ceramide). More complete nomenclature indicates the sphingoid base length and degree of FA chain desaturation, for example, 18:1C18 ceramide refers to ceramide with canonical sphingosine and stearate in amide linkage. Non-chemical terminology can also be used, for example, dihydroCer refers to ceramides lacking the 4–5 double bond. ELOVLs, elongation of very-long-chain fatty acids proteins.
Figure 2
Figure 2. Intracellular compartmentalization and transport of sphingolipids
It is now becoming clear that the cellular actions of bioactive sphingolipids are ‘local’. Therefore, the site of production of these lipids is critical, and it is determined by the location of the specific enzymes involved in the regulatory pathways. For details of the compartmentalization of these processes, please refer to box 1 in REF. . Moreover, the metabolic and cellular functions of bioactive lipids are further controlled by specific translocases and lipid transport proteins. A strong case can now be made that ceramides (Cers) generated in the endoplasmic reticulum (ER) can reach the Golgi either by a vesicular route, where they are coupled to the synthesis of glucosylceramide, or by specific translocation via the action of ceramide transfer protein (CERT), which couples ceramides to the synthesis of sphingomyelin (SM). Likewise, the transfer protein phosphatidylinositol-four-phosphate adaptor protein 2 (FAPP2) can transfer glucosylceramide (GlcCer) between Golgi networks and couple it specifically to the synthesis of globosides (globo series of neutral glycosphingolipids) as opposed to the anionic ganglio series. Ceramide-1-phosphate (C1P) is the target of the non-vesicular translocation activity of C1P transfer protein (CPTP), which is involved in transferring it from the Golgi to other compartments such as the plasma membrane. Protein spinster homologue 2 (SPNS2) flips sphingosine-1-phosphate (S1P) across the plasma membrane to deliver it to exocytoplasmic leaflets, where it can access its receptors (a subfamily of G protein-coupled receptors (GPCRs)). VAP, vesicle-associated membrane protein-associated protein.
Figure 3
Figure 3. Examples of cellular functions and downstream targets of bioactive sphingolipids
a | Several factors, including insulin and growth factors, have been shown to activate sphingosine kinases (SKs) in a mechanism involving their phosphorylation in a phospholipase D (PLD)-dependent, protein kinase C (PKC)-dependent and ERK-dependent manner, resulting in the formation of sphingosine-1-phosphate (S1P) from sphingosine (Sph) intracellularly. S1P has to flip extra-cytosolically (with the involvement of protein spinster homologue 2 (SPNS2)) in order to interact with one (or more) of its five receptors (S1P receptor 1–5 (S1PR1–5)). S1P can also be released from the plasma membrane into the blood, and it is present in relatively high levels in the circulation. S1PRs transmit signals to key downstream targets such as serine/threonine protein kinase AKT, RHO and the Ras–ERK and tyrosine protein kinase JAK–signal transducer and activator of transcription (STAT) pathways. Signalling through S1PRs also has other cellular targets. For example, S1PR actions result in robust phosphorylation of ezrin, which affects actin dynamics, promoting filopodia formation and cell migration (including cancer cell invasion). S1P also has nuclear actions — it binds and inhibits histone deacetylases (HDACs), leading to alterations in protein (histone) acetylation. Ceramides (Cers) can be formed in several compartments. At the plasma membrane, ceramide generation from the action of sphingomyelinases (SMases) results in activation of protein phosphatase PP1Cα, which induces dephosphorylation of its substrates, including ezrin. Ceramide formed metabolically from the supply of palmitate can activate PP2A phosphatases to result in dephosphorylation and inactivation of AKT. Activation of PP2A by ceramide also occurs in the context of apoptosis. In this case, the pro-apoptotic protein Bcl-2 homologous antagonist/killer (BAK) promotes ceramide synthesis (through activation of ceramide synthase (CerS)), followed by PP2A activation and dephosphorylation and inactivation of anti-apoptotic BCL-2 proteins. In addition, mitochondrial ceramide was shown to promote the activity of the apoptosis regulator BAX, a pro-apoptotic protein. b | Bioactive lipids are increasingly appreciated to regulate membrane dynamics. Formation of ceramide at the plasma membrane by acid SMase (aSMase) has been shown to induce formation of distinct membrane domains that affect endocytosis and receptor signalling (for example, tumour necrosis factor receptor superfamily member 6 (FAS)) signalling. Neutral SMase2 (nSMase) and ceramide have been implicated in exocytosis, and SK1 and S1P have been implicated in endocytosis. c | Egress of lymphocytes from lymphoid tissues to the blood is controlled by a gradient of S1P (high in blood and low in lymphoid tissue). The response to this gradient is primarily driven by S1PRs, especially S1PR1. The clinical compound FTY720 is converted to the active FTY720 phosphate through phosphorylation mediated by SK2 to suppress S1PR1 function and therefore lymphoid egress. ApoM, apolipoprotein M; ER, endoplasmic reticulum; HDL, high-density lipoprotein; TRK, tyrosine kinase receptor.

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