Michael Wakelam

Michael Wakelam 1955 - 2020: read the Institute's announcement on hearing about the death of Michael on 31st March.

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

THP-1 macrophage cholesterol efflux is impaired by palmitoleate through Akt activation.
Marshall JD, Courage ER, Elliott RF, Fitzpatrick MN, Kim AD, Lopez-Clavijo AF, Woolfrey BA, Ouimet M, Wakelam MJO, Brown RJ

Lipoprotein lipase (LPL) is upregulated in atherosclerotic lesions and it may promote the progression of atherosclerosis, but the mechanisms behind this process are not completely understood. We previously showed that the phosphorylation of Akt within THP-1 macrophages is increased in response to the lipid hydrolysis products generated by LPL from total lipoproteins. Notably, the free fatty acid (FFA) component was responsible for this effect. In the present study, we aimed to reveal more detail as to how the FFA component may affect Akt signalling. We show that the phosphorylation of Akt within THP-1 macrophages increases with total FFA concentration and that phosphorylation is elevated up to 18 hours. We further show that specifically the palmitoleate component of the total FFA affects Akt phosphorylation. This is tied with changes to the levels of select molecular species of phosphoinositides. We further show that the total FFA component, and specifically palmitoleate, reduces apolipoprotein A-I-mediated cholesterol efflux, and that the reduction can be reversed in the presence of the Akt inhibitor MK-2206. Overall, our data support a negative role for the FFA component of lipoprotein hydrolysis products generated by LPL, by impairing macrophage cholesterol efflux via Akt activation.

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PloS one, 15, 5, 2020

DOI: 10.1371/journal.pone.0233180

PMID: 32437392

MYC regulates fatty acid metabolism through a multigenic program in claudin-low triple negative breast cancer.
Casciano JC, Perry C, Cohen-Nowak AJ, Miller KD, Vande Voorde J, Zhang Q, Chalmers S, Sandison ME, Liu Q, Hedley A, McBryan T, Tang HY, Gorman N, Beer T, Speicher DW, Adams PD, Liu X, Schlegel R, McCarron JG, Wakelam MJO, Gottlieb E, Kossenkov AV, Schug ZT

Recent studies have suggested that fatty acid oxidation (FAO) is a key metabolic pathway for the growth of triple negative breast cancers (TNBCs), particularly those that have high expression of MYC. However, the underlying mechanism by which MYC promotes FAO remains poorly understood.

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British journal of cancer, 1, 1, 16 Jan 2020

DOI: 10.1038/s41416-019-0711-3

PMID: 31942031

Mammalian phospholipase D: Function, and therapeutics.
McDermott MI, Wang Y, Wakelam MJO, Bankaitis VA

Despite being discovered over 60 years ago, the precise role of Phospholipase D (PLD) is still being elucidated. PLD enzymes catalyze the hydrolysis of the phosphodiester bond of glycerophospholipids producing phosphatidic acid and the free headgroup. PLD family members are found in organisms ranging from viruses, and bacteria to plants, and mammals, and they display a range of substrate specificities, are regulated by a diverse range of molecules, and have been implicated in a broad range of cellular processes including receptor signaling, cytoskeletal regulation and membrane trafficking. Recent technological advances including: the development of PLD knockout mice, isoform-specific antibodies, and specific inhibitors are finally permitting a thorough analysis of the in vivo role of mammalian PLDs. These studies are facilitating increased recognition of PLD's role in disease states including cancers and Alzheimer's disease, offering potential as a target for therapeutic intervention.

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Progress in lipid research, 0, 0, 09 Dec 2019

DOI: 10.1016/j.plipres.2019.101018

PMID: 31830503