Principles of bioactive lipid signalling: lessons from sphingolipids

Key Points

  • The sphingolipids constitute an important class of bioactive lipids, including ceramide and sphingosine-1-phosphate (S1P). Ceramide can be considered to function as a hub in sphingolipid metabolism, and it mediates or regulates antiproliferative responses such as growth inhibition, apoptosis, differentiation and senescence, whereas S1P is a key regulator of cell motility and proliferation.

  • The study of bioactive lipids in general and sphingolipids in particular presents several hurdles to molecular cell biologists. These include the hydrophobicity and biophysical properties of these molecules, the metabolic interconnections of the active metabolites, and the predominantly hydrophobic nature of the enzymes that regulate their metabolism.

  • Enzymes of sphingolipid metabolism function as an interconnected network that regulates the levels and interconversions of the bioactive sphingolipids. Many of these enzymes, such as sphingomyelinases, sphingosine kinases and ceramide synthases, serve to couple the action of extra- and intracellular agonists to downstream effectors.

  • Ceramide can be formed from the de novo pathway or following activation of the sphingomyelinase pathway, in which it functions in metabolic regulation and stress responses. Ceramide action is governed by the specific pathways that regulate its formation, their subcellular localization and their specific mechanisms of regulation.

  • S1P is a product of sphingosine kinases, and acts predominantly on a family of G protein-coupled receptors that, in turn, mediate its action on cell growth, migration, transcription and signal transduction.

  • The cellular actions of ceramide, S1P and other bioactive sphingolipids are increasingly thought to be crucial for the study of angiogenesis, inflammation, immune responses, diabetes, ageing, cancer biology and degenerative diseases.

Abstract

It has become increasingly difficult to find an area of cell biology in which lipids do not have important, if not key, roles as signalling and regulatory molecules. The rapidly expanding field of bioactive lipids is exemplified by many sphingolipids, such as ceramide, sphingosine, sphingosine-1-phosphate (S1P), ceramide-1-phosphate and lyso-sphingomyelin, which have roles in the regulation of cell growth, death, senescence, adhesion, migration, inflammation, angiogenesis and intracellular trafficking. Deciphering the mechanisms of these varied cell functions necessitates an understanding of the complex pathways of sphingolipid metabolism and the mechanisms that regulate lipid generation and lipid action.

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Figure 1: An overview of the roles of sphingolipids in biology.
Figure 2: Sphingolipid metabolism and interconnection of bioactive sphingolipids.
Figure 3: Parallel networks of sphingolipid signalling.
Figure 4: Transport and transbilayer movement of bioactive sphingolipids.
Figure 5: Examples of ceramide signalling pathways and their role in stress responses.
Figure 6: SK–S1P receptors and signalling.

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Acknowledgements

We would like to thank all past and present members of our laboratories. This work was supported by a Veterans Affairs Merit Award (L.M.O.) and the National Institutes of Health (Y.A.H.).

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Glossary

DAG

sn-1,2-diacylglycerol is a key metabolic intermediate in glycerolipid synthesis that also serves as a second messenger in regulating classical and novel protein kinase C enzymes.

Protein kinase C

(PKC). A family of closely related protein kinases that are highly conserved in their catalytic domains. Classical PKCs are regulated by diacylglycerol (DAG) and calcium; novel PKCs are regulated by DAG only; and atypical PKCs are not regulated by either DAG or calcium.

Ceramide synthase

(CerS, Lass). An enzyme that introduces the acyl chain to sphingoid bases, thereby forming dihydroceramides and ceramides with specific N-linked fatty acids.

Acid SMase

A sphingomyelinase enzyme with an acid pH optimum that removes the phosphorylcholine head group from sphingomyelin, generating ceramide (or dihydroceramides). Activity is defective in patients with type A or B Niemann–Pick disease.

Neutral SMase

(nSMases). An emerging family of sphingomyelinase enzymes with a neutral pH optimum that removes the phosphorylcholine head group from sphingomyelin, generating ceramide (or dihydroceramides).

Ceramidase

A hydrolase that removes the fatty acyl groups from ceramides and dihydroceramides. Three distinct enzyme families are recognized on the basis of their pH optima (acid, neutral and alkaline).

Glycosphingolipid

A complex sphingolipid with a carbohydrate head group that is attached to the 1-hydroxy group of ceramide. The simplest glycosphingolipids are glucosylceramide and galactosylceramide with a glucose or galactose group, respectively, from which more complex glycosphingolipids can be synthesized by the incorporation of additional glycose subunits.

Salvage pathway

In addition to de novo synthesis, sphingolipids can be resynthesized following the breakdown of complex sphingolipids (mostly in the lysosome) through the re-incorporation of the liberated sphingosine into ceramide.

ABC transporter superfamily

A family of membrane proteins that regulate the transport of small molecules in an ATP-dependent process.

Ceramide transfer protein

(CERT). Belongs to a family of lipid transporters, and selectively transports ceramide from its site of synthesis in the ER to the site of sphingomyelin biosynthesis in the Golgi.

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Hannun, Y., Obeid, L. Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol 9, 139–150 (2008) doi:10.1038/nrm2329

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