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Lipid signalling in disease

Key Points

  • Lipids act as extracellular and intracellular messengers to control cell fate in normal physiology and disease. When deregulated, lipid signalling contributes to inflammation and cancer, metabolic, cardiovascular and degenerative disease.

  • Signals such as growth factors, cytokines and chemokines, but also constituents of nutrients, modulate the activity of lipid-modifying enzymes: phosphoinositide 3-kinase (PI3K), sphingosine kinase (SphK), phospholipase C (PLC) and PLD function upstream of the activation of phospholipase A2 (PLA2), prostaglandin H2 synthase (PGH2S) and 5-lipoxygenase (5-LO), which are required for eicosanoid release.

  • Eicosanoids such as prostaglandins and leukotrienes have been known to have a role in inflammation. Recently, their extracellular action on G protein-coupled receptors (GPCRs) has been deciphered, and intracellular binding partners of eicosanoids have also been identified, which opens new possibilities for more selective drug-targeting strategies in inflammation and cancer.

  • Inflammation and cancer are both characterized by excess activation of PI3K and SphK pathways, which enforces growth-factor-receptor signalling, cell growth and survival, cell motility and degranulation. This overrides the pro-apoptotic actions of ceramide and sphingosine.

  • Although the nutritional energy supply normally increases insulin and lipid signalling through PI3K, excess circulating fatty acids induce long-term insulin resistance and function as pro-inflammatory agents. This occurs through signalling via the Toll-like receptor TLR4 and through endoplasmic reticulum stress promoted by intracellular lipid accumulation. It results in the production of reactive oxygen species and the activation of inflammatory kinase pathways (PKC, IKKβ), terminating the relay of signals through insulin receptor substrate (IRS).

  • Lipid-modifying enzymes, pathways and their downstream targets, including nuclear receptors and lipid-binding proteins, form a complex signalling network. Although many of these lipid mediators emerge from the same membranes, they are usually studied in isolation. Here, we present an integrated overview of lipid signalling in disease and highlight nodes of lipid signalling pathway interaction, and discuss emerging strategies for therapeutic interventions.

Abstract

Signalling lipids such as eicosanoids, phosphoinositides, sphingolipids and fatty acids control important cellular processes, including cell proliferation, apoptosis, metabolism and migration. Extracellular signals from cytokines, growth factors and nutrients control the activity of a key set of lipid-modifying enzymes: phospholipases, prostaglandin synthase, 5-lipoxygenase, phosphoinositide 3-kinase, sphingosine kinase and sphingomyelinase. These enzymes and their downstream targets constitute a complex lipid signalling network with multiple nodes of interaction and cross-regulation. Imbalances in this network contribute to the pathogenesis of human disease. Although the function of a particular signalling lipid is traditionally studied in isolation, this review attempts a more integrated overview of the key role of these signalling lipids in inflammation, cancer and metabolic disease, and discusses emerging strategies for therapeutic intervention.

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Figure 1: Mounting walls.
Figure 2: Lipid signalling in inflammation and allergy.
Figure 3: Pro- and anti-tumorigenic signals originate from membranes.
Figure 4: Excess fatty acids induce insulin resistance and metabolic syndrome.

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Acknowledgements

We apologize for not citing many original publications due to space restrictions. We thank P. Fotiadou and R. Marone for corrections and discussions. M.P.W. is supported by grants from Oncosuisse, the Krebsliga beider Basel, the Swiss National Science Foundation and the EU FP6 programme. R.S. is supported by grants from the Swiss National Science Foundation and Novartis Stiftung.

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Correspondence to Matthias P. Wymann.

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DATABASES

UniProtKB

PLC

COX2

PLD

SphK

CerK

cPLA2

5-LO

PGH2S

PKB

nSMase

aSMase

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Targeting lipid signalling in disease

Glossary

G protein-coupled receptor

(GPCR). A seven-transmembrane helix cell-surface receptor that signals through heterotrimeric GTP-binding proteins. GPCRs trigger the dissociation of trimeric G proteins into Gα and Gβγ subunits by facilitating loading of GTP onto Gα. Both Gα and Gβγ subunits interact with downstream effector proteins. Relay of GPCR signals terminates when GTP is hydrolysed by the intrinsic GTPase activity of Gα.

Lysolipid

An asymmetrical lipid that contains only one acyl chain.

GTPase-activating protein

(GAP). One of a family of proteins that inactivate small GTP-binding proteins, such as Ras family members, by increasing their rate of GTP hydrolysis.

Neutrophil

The most abundant phagocytic cell of the myeloid lineage, which has an important role in host defence and chronic inflammatory disease. It undergoes chemotaxis towards sites of infection, which involves GPCR signalling.

Mast cell

A tissue-resident cell with large secretory granules that contain histamine and various inflammatory mediators. Mast cells are key in inflammation and IgE-mediated allergy.

Granulocyte

A type of white blood cell (including neutrophils, eosinophils and basophils) that is dedicated to the release of granules.

Lipid raft

A membrane microdomain that is enriched in cholesterol, sphingolipids and lipid-modified proteins such as GPI-linked proteins, as well as palmitoylated proteins. These microdomains often function as platforms for distinct signalling events.

SH2 domain

(Src-homology-2 domain). A protein domain that recognizes and binds specific tyrosine-phosphorylated sequences, and thereby has a key role in the directed delivery of signal transduction effector proteins. The SH2 domains of the p85 regulatory subunit of PI3K, for example, specifically recognize phosphoTyr-X-X-Met motifs.

PH domain

(pleckstrin homology domain). A sequence of 100 amino acids that is present in many signalling molecules and binds to lipid products of phosphoinositide kinases. PH domains can have individual specificities for polyphospho-inositides.

Store-operated calcium channel

A plasma membrane ion channel of uncertain identity that opens in response to depletion of internal Ca2+ stores.

Peroxisome

An organelle that contains the machinery to oxidize fatty acids. A site of H2O2 production and destruction.

Statin

One of a class of cholesterol-lowering drugs that inhibit the key enzyme HMG-CoA reductase in the synthesis of cholesterol.

Triterpenoid

A hydrocarbon that results from the condensation of 5 carbon isoprene units. Triterpenoids contain 6 isoprene units and 30 carbon atoms, as found in the steroid precursor squalene.

Lipodystrophy

A disorder that features the loss of adipocytes.

Acanthosis nigricans

A velvety light-brown to black pigmentation of the skin caused by insulin spill-over from excessive production due to obesity or insulin resistance, which results in abnormal growth.

Basal lamina

A thin sheet of extracellular matrix molecules, which consists mainly of collagens, laminins, nidogen and proteoglycans, and forms a region between cells and adjacent connective tissue. It has an important influence on the organization of tissues.

FOXO transcription factor

One of a family of >40 proteins that belong to the winged-helix class of DNA-binding proteins. They are involved in diverse cellular functions, including glucose metabolism, apoptosis and cell-cycle regulation.

Guanine nucleotide-exchange factor

(GEF). A protein that facilitates the exchange of GDP for GTP in the nucleotide-binding pocket of a GTP-binding protein.

Rho GTPase

A Ras-related small GTPase that functions as a molecular switch to control signal transduction pathways. Traditionally it is known as a regulator of actin polymerization.

14-3-3 protein

An adaptor or scaffold protein that forms homo- and heterodimers. It binds through specialized phosphorylated peptide motifs (mostly containing phosphoserine) to various proteins that are involved in signal transduction and cell-cycle control.

Hepatosteatosis

Fat accumulation in liver cells, which gives rise to fatty liver disease.

Innate immune system

Components of the immune system that constitute the immediate, first line of defence against antigens. Pathogen recognition is mediated by pattern-recognition receptors, such as Toll-like receptors.

Salicylate

A group of compounds with anti-inflammatory properties. A prominent member is acetylsalicylate, also known as aspirin.

Complement

Nine interacting serum proteins (C1–C9), many of them with proteolytic activity, that are activated in a coordinated way and participate in bacterial lysis and, as fragments, in leukocyte chemotaxis.

Anaphylaxis

A severe, potentially fatal, allergic reaction that involves histamine release from mast cells. This triggers dilation of blood vessels, a drop in blood pressure and increased vascular permeability.

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Wymann, M., Schneiter, R. Lipid signalling in disease. Nat Rev Mol Cell Biol 9, 162–176 (2008). https://doi.org/10.1038/nrm2335

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