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A neuroscientist's guide to lipidomics

Key Points

  • Lipids are amphipathic or lipophilic biomolecules that influence the elastic properties and supramolecular organization of cell membranes, and regulate the activity of proteins involved in intracellular and transcellular signalling. The goal of neural lipidomics is to understand how large-scale changes in lipid profiles affect neuronal and glial cell function.

  • Membrane lipids adopt characteristic molecular shapes — conical, inverse conical and cylindrical — that influence the curvature and supramolecular organization of neural cell membranes. Important biological events regulated by lipid shape include ion-channel activity and membrane nanodomain formation.

  • Cone-shaped lipids (for example, arachidonic acid) affect the activity of mechanosensitive ion pores such as Twik 1-related arachidonic acid-stimulated K+ (TRAAK) channels and glutamate N-methyl-D-aspartate (NMDA) channels.

  • Cylindrical lipids (for example, sphingomyelin) are important in the assembly of lateral membrane domains, such as lipid rafts, which are used to stabilize the clustering of neurotransmitter receptors with proteins involved in intracellular signalling, promote endocytosis and control the activity of neurotransmitter transporters.

  • Lipids also regulate ion channels, receptors and other proteins that are involved in signal transduction by directly binding to them. Hundreds of lipid-derived molecules use this signalling mechanism. Three kinds of membrane compartmentalization may help to regulate these functions: lateral heterogeneity, bilayer asymmetry and anatomical specialization.

  • Lateral membrane heterogeneity promoted by the temporary segregation of lipid molecules in nanodomains (for example, lipid rafts) may help recruit effector proteins to specific membrane sites during cellular events that require a high degree of membrane localization (for example, synaptic vesicle exocytosis). Bilayer asymmetry generated by membrane lipid transporters (for example, flippases) may be used to produce signals during neural cell apoptosis and injury. Specialized junctions containing lipid-metabolizing enzymes and receptors may provide an anatomical framework for short-range forms of lipid signalling, such as endocannabinoid-mediated retrograde signalling.

Abstract

Nerve cells mould the lipid fabric of their membranes to ease vesicle fusion, regulate ion fluxes and create specialized microenvironments that contribute to cellular communication. The chemical diversity of membrane lipids controls protein traffic, facilitates recognition between cells and leads to the production of hundreds of molecules that carry information both within and across cells. With so many roles, it is no wonder that lipids make up half of the human brain in dry weight. The objective of neural lipidomics is to understand how these molecules work together; this difficult task will greatly benefit from technical advances that might enable the testing of emerging hypotheses.

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Figure 1: Strategies to identify, measure and image lipids in membranes.
Figure 2: Brain lipids.
Figure 3: Lipid geometry.
Figure 4: Key features of lipid signalling: the example of the phosphatidylinositol (4,5) bisphosphate cascade.
Figure 5: Representative bioactive neural lipids and their cellular receptors.
Figure 6: Specialized lipid signalling junctions in the brain.

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Acknowledgements

Supporting grants were made to D.P. from the Agilent Technologies Foundation and the National Institutes of Health.

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Correspondence to Daniele Piomelli.

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Supplementary information

Supplementary information S1 (table)

Representative enzymes involved in neural lipid metabolism. (PDF 268 kb)

Supplementary information S2 (box)

Lipid receptors (PDF 153 kb)

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FURTHER INFORMATION

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Lipid MAPS

Cyberlipids

Lipid Library

Glossary

Hydrophobic effect

The tendency of hydrophobic molecules to associate in order to diminish contact with water.

Lipidomics

The large-scale analysis of lipid profiles in cells and tissues.

Lysophospholipid

A phospholipid containing a single fatty-acid chain; examples include signalling lipids, such as 1-oleoyl-sn-glycero-3-phosphate (lysophosphatidic acid).

Phosphoinositide

Phosphatidylinositol derivative in which the inositol head-group is in ester form with one or more phosphates; examples include signalling lipids, such as PI(4,5)P2.

Phospholipase A2

An enzyme that hydrolyses the sn-2 position of phospholipids, producing fatty acids and lysophospholipids.

Liposome

An artificial membrane-bound vesicle generally composed of phospholipids and cholesterol.

Endocannabinoid

An endogenous lipid that acts as a ligand for G-protein-coupled cannabinoid receptors; examples include 2-arachidonoyl-sn-glycerol and anandamide.

Eicosanoid

A signalling lipid that is involved in pain and neuroinflammation. It is derived from the enzymatic oxygenation of arachidonic acid and other polyunsaturated fatty acids. Examples include prostaglandins, prostacyclin, thromboxane, leukotrienes and lipoxins.

Phospholipase D

An enzyme that hydrolyses the distal phosphodiester bond of phospholipids, such as phosphatidylcholine, producing choline and phosphatidic acid.

Kv channel

Voltage-gated K+ channel that controls action-potential repolarization, action-potential frequency and interspike interval in excitable cells.

Annulus

A thin ring-shaped sheet of lipids that separates transmembrane proteins from bulk membrane phospholipids.

Phospholipid remodelling

Hydrolytic removal of fatty acids from the sn-1 or sn-2 positions of phospholipids (catalysed by phospholipases A1 and A2, respectively) followed by their replacement with new fatty acids (catalysed by lysophospholipid acyltransferases).

Flippase

The enzyme responsible for the energy-dependent transfer of phospholipids across the membrane bilayer ('flip-flop' process).

Anandamide

Endogenous amide of arachidonic acid and ethanolamine produced by the cleavage of N-arachidonoyl-phosphatidylethanolamine. It activates CB1 cannabinoid receptors with nanomolar potency.

Neurosteroid

Steroid paracrine messenger synthesized de novo in the brain, which acts by binding neurotransmitter-gated ion channels; examples include the progesterone metabolite 5α-pregnan-3α-ol-20-one.

Oleoylethanolamide

Endogenous amide of oleic acid and ethanolamine produced by cleavage of N-oleoyl-phosphatidyleth-anolamine. It is a nanomolar agonist of peroxisome proliferator-activated receptor-α.

Resolvin

A signalling lipid implicated in the termination of acute inflammation. It is derived from the enzymatic oxygenation of eicosapentenoic and docosahexaenoic acid.

Neuroprotectin

A signalling lipid implicated in neuronal survival. It is derived from the enzymatic oxygenation of docosahexaenoic acid.

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Piomelli, D., Astarita, G. & Rapaka, R. A neuroscientist's guide to lipidomics. Nat Rev Neurosci 8, 743–754 (2007). https://doi.org/10.1038/nrn2233

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