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

The circadian clock components BMAL1 and REV-ERBα regulate flavivirus replication.
Zhuang X, Magri A, Hill M, Lai AG, Kumar A, Rambhatla SB, Donald CL, Lopez-Clavijo AF, Rudge S, Pinnick K, Chang WH, Wing PAC, Brown R, Qin X, Simmonds P, Baumert TF, Ray D, Loudon A, Balfe P, Wakelam M, Butterworth S, Kohl A, Jopling CL, Zitzmann N, McKeating JA

The circadian clock regulates immune responses to microbes and affects pathogen replication, but the underlying molecular mechanisms are not well understood. Here we demonstrate that the circadian components BMAL1 and REV-ERBα influence several steps in the hepatitis C virus (HCV) life cycle, including particle entry into hepatocytes and RNA genome replication. Genetic knock out of Bmal1 and over-expression or activation of REV-ERB with synthetic agonists inhibits the replication of HCV and the related flaviruses dengue and Zika via perturbation of lipid signaling pathways. This study highlights a role for the circadian clock component REV-ERBα in regulating flavivirus replication.

+ View Abstract

Nature communications, 10, 2041-1723, 377, 2019

PMID: 30670689

LIPID MAPS: Serving the next generation of lipid researchers with tools, resources, data, and training.
O'Donnell VB, Dennis EA, Wakelam MJO, Subramaniam S

Lipids are increasingly recognized as dynamic, critical metabolites affecting human physiology and pathophysiology. LIPID MAPS is a free resource dedicated to serving the lipid research community.

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Science signaling, 12, 1937-9145, , 2019

PMID: 30622195

Modeling Meets Metabolomics-The WormJam Consensus Model as Basis for Metabolic Studies in the Model Organism .
Witting M, Hastings J, Rodriguez N, Joshi CJ, Hattwell JPN, Ebert PR, van Weeghel M, Gao AW, Wakelam MJO, Houtkooper RH, Mains A, Le Novère N, Sadykoff S, Schroeder F, Lewis NE, Schirra HJ, Kaleta C, Casanueva O

Metabolism is one of the attributes of life and supplies energy and building blocks to organisms. Therefore, understanding metabolism is crucial for the understanding of complex biological phenomena. Despite having been in the focus of research for centuries, our picture of metabolism is still incomplete. Metabolomics, the systematic analysis of all small molecules in a biological system, aims to close this gap. In order to facilitate such investigations a blueprint of the metabolic network is required. Recently, several metabolic network reconstructions for the model organism have been published, each having unique features. We have established the WormJam Community to merge and reconcile these (and other unpublished models) into a single consensus metabolic reconstruction. In a series of workshops and annotation seminars this model was refined with manual correction of incorrect assignments, metabolite structure and identifier curation as well as addition of new pathways. The WormJam consensus metabolic reconstruction represents a rich data source not only for network-based approaches like flux balance analysis, but also for metabolomics, as it includes a database of metabolites present in , which can be used for annotation. Here we present the process of model merging, correction and curation and give a detailed overview of the model. In the future it is intended to expand the model toward different tissues and put special emphasizes on lipid metabolism and secondary metabolism including ascaroside metabolism in accordance to their central role in physiology.

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Frontiers in molecular biosciences, 5, 2296-889X, 96, 2018

PMID: 30488036

Group Members

Latest Publications

The circadian clock components BMAL1 and REV-ERBα regulate flavivirus replication.

Zhuang X, Magri A, Hill M

Nature communications
10 2041-1723:377 (2019)

PMID: 30670689

LIPID MAPS: Serving the next generation of lipid researchers with tools, resources, data, and training.

O'Donnell VB, Dennis EA, Wakelam MJO

Science signaling
12 1937-9145: (2019)

PMID: 30622195

Modeling Meets Metabolomics-The WormJam Consensus Model as Basis for Metabolic Studies in the Model Organism .

Witting M, Hastings J, Rodriguez N

Frontiers in molecular biosciences
5 2296-889X:96 (2018)

PMID: 30488036

3D growth of cancer cells elicits sensitivity to kinase inhibitors but not lipid metabolism modifiers.

Jones DT, Valli A, Haider S

Molecular cancer therapeutics
1538-8514: (2018)

PMID: 30478149

CD151 regulates expression of FGFR2 in breast cancer cells via PKC-dependent pathways.

Sadej R, Lu X, Turczyk L

Journal of cell science
1477-9137: (2018)

PMID: 30257985

C. elegans Eats Its Own Intestine to Make Yolk Leading to Multiple Senescent Pathologies.

Ezcurra M, Benedetto A, Sornda T

Current biology : CB
1879-0445: (2018)

PMID: 30100339

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