Life Sciences Research for Lifelong Health

Michael Wakelam

Research Summary

We aim to understand the essential physiological functions of lipids. Lipids are highly dynamic structures with structural, metabolic and signalling roles. To fully understand the roles that lipids have in cell function during ageing we need the ability to determine their individual changes.

The cellular lipidome is extremely complex, with distinct classes of lipids each containing many molecular species that can differ both in the length of each acyl chain present and in the number and position of double bonds.

In our lab we have pioneered the use of high-sensitivity liquid chromatography-mass spectrometry (LC-MS) technology to rapidly and comprehensively measure the levels of lipids in a wide range of cell types, tissues and tumours. The lipidome of a cell typically comprises of ~ 1500 distinct lipid species measurable with current LC-MS technology. However, this number is most likely an underestimate since there are theoretically closer to 10 000 distinct lipid species in the lipidome.

The principal aim of our laboratory is to better understand how the distinct lipid species of a cell’s lipidome function during the healthy ageing of the whole animal.

​To achieve this we use a multidisciplinary approach combining LC-MS analysis, protein biochemistry, cell biology and genetic manipulation of model organisms. This allows us to identify the cellular signalling pathways and processes that individual lipid species regulate, and to investigate how the enzymes that determine the composition of the lipidome are regulated in response to changes in the environment.

Latest Publications

Host lipidome analysis during rhinovirus replication in human bronchial epithelial cells identifies potential therapeutic targets.
Nguyen A, Guedan A, Mousnier A, Swieboda D, Zhang Q, Horkai D, Le Novere N, Solari R, Wakelam MJO

In patients with asthma or chronic obstructive pulmonary disease rhinovirus infections can provoke acute worsening of disease and limited treatment options exist. Viral replication in the host cell induces significant remodeling of intracellular membranes, but few studies have explored this mechanistically or as a therapeutic opportunity. We performed unbiased lipidomic analysis on human bronchial epithelial cells infected over a 6 hour period with the RV-A1b strain of rhinovirus to determine changes in 493 distinct lipid species. Through pathway and network analysis we identified temporal changes in the apparent activities of a number of lipid metabolizing and signaling enzymes. In particular, analysis highlighted fatty acid synthesis and ceramide metabolism as potential anti-rhinoviral targets. To validate the importance of these enzymes in viral replication, we explored the effects of commercially-available enzyme inhibitors upon RV-A1b infection and replication. Ceranib-1, D609 and C75 were the most potent inhibitors, which confirmed that fatty acid synthase and ceramidase are potential inhibitory targets in rhinoviral infections. More broadly, this study demonstrates the potential of lipidomics and pathway analysis to identify novel targets to treat human disorders.

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Journal of lipid research, , 1539-7262, , 2018

PMID: 29946055

Flotillin proteins recruit sphingosine to membranes and maintain cellular sphingosine-1-phosphate levels.
Riento K, Zhang Q, Clark J, Begum F, Stephens E, Wakelam MJ, Nichols BJ

Sphingosine-1-phosphate (S1P) is an important lipid signalling molecule. S1P is produced via intracellular phosphorylation of sphingosine (Sph). As a lipid with a single fatty alkyl chain, Sph may diffuse rapidly between cellular membranes and through the aqueous phase. Here, we show that the absence of microdomains generated by multimeric assemblies of flotillin proteins results in reduced S1P levels. Cellular phenotypes of flotillin knockout mice, including changes in histone acetylation and expression of Isg15, are recapitulated when S1P synthesis is perturbed. Flotillins bind to Sph in vitro and increase recruitment of Sph to membranes in cells. Ectopic re-localisation of flotillins within the cell causes concomitant redistribution of Sph. The data suggest that flotillins may directly or indirectly regulate cellular sphingolipid distribution and signalling.

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PloS one, 13, 1932-6203, e0197401, 2018

PMID: 29787576

Extracellular vesicles : lipids as key components of their biogenesis and functions.
Record M, Silvente-Poirot S, Poirot M, Wakelam MJO

Intercellular communication has been known for decades to involve either direct contact between cells or to operate by spreading molecules such as cytokines, growth factors, or lipid mediators. Through the last decade we have begun to appreciate the increasing importance of intercellular communication mediated by extracellular vesicles released by viable cells either from plasma membrane shedding microvesicles, also named microparticles), or from an intracellular compartment (exosomes). Exosomes and microvesicles circulate in all biological fluids and can trigger biological responses at distance. Their effects include a large variety of biological processes such as immune surveillance, modification of tumor microenvironment, or regulation of inflammation. They carry a large set of active molecules, including lipid mediators such as eicosanoids, proteins and nucleic acids, able to modify the phenotype of receiving cells. This review will highlight the role of the various lipidic pathways involved in the biogenesis and functions of microvesicles and exosomes.

+ View Abstract

Journal of lipid research, , 1539-7262, , 2018

PMID: 29764923

Group Members

Latest Publications

Extracellular vesicles : lipids as key components of their biogenesis and functions.

Record M, Silvente-Poirot S, Poirot M

Journal of lipid research
1539-7262: (2018)

PMID: 29764923

Phospholipid signaling in innate immune cells.

O'Donnell VB, Rossjohn J, Wakelam MJ

The Journal of clinical investigation
1558-8238: (2018)

PMID: 29683435

Deciphering lipid structures based on platform-independent decision rules.

Hartler J, Triebl A, Ziegl A

Nature methods
1548-7105: (2017)

PMID: 29058722

Autotaxin-lysophosphatidic acid receptor signalling regulates hepatitis C virus replication.

Farquhar MJ, Humphreys IS, Rudge SA

Journal of hepatology
1600-0641: (2017)

PMID: 28126468

Runx1 Orchestrates Sphingolipid Metabolism and Glucocorticoid Resistance in Lymphomagenesis.

Kilbey A, Terry A, Wotton S

Journal of cellular biochemistry
118 1097-4644:1432-1441 (2017)

PMID: 27869314

Using lipidomics analysis to determine signalling and metabolic changes in cells.

Nguyen A, Rudge SA, Zhang Q

Current opinion in biotechnology
43 1879-0429:96-103 (2017)

PMID: 27816901

Insulin resistance uncoupled from dyslipidemia due to C-terminal PIK3R1 mutations.

Huang-Doran I, Tomlinson P, Payne F

JCI insight
1 :e88766 (2016)

PMID: 27766312

The Phospholipase D2 Knock Out Mouse Has Ectopic Purkinje Cells and Suffers from Early Adult-Onset Anosmia.

Vermeren MM, Zhang Q, Smethurst E

PloS one
11 1932-6203:e0162814 (0)

PMID: 27658289