Plasmalogen modulation as a therapeutic approach for fatty liver disease

Student research project

Supervisors: Professor Peter Meikle, Dr Graeme Lancaster, Dr Sudip Paul

Research focus

The Metabolomics Laboratory uses state-of-the-art tandem mass spectrometry to obtain metabolic/lipid profiles from cell and animal models in addition to clinically relevant human samples to develop new approaches to diagnosis, risk assessment and therapy for diabetes and cardiovascular disease.

Project summary

Plasmalogens are glycerophospholipids that are present in numerous mammalian tissues and can act as a natural antioxidant¹. Lipidomic profiling of multiple populations and clinical cohorts has identified decreased levels of plasmalogens to be associated with aging and obesity² as well as prediabetes and type 2 diabetes³. Modulation of plasmalogens can be achieved by oral administration of their metabolic precursors, naturally occurring compounds known as alkylglycerols or by suppressing the activity of plasmalogen catabolising enzyme, TMEM86B. Plasmalogen modulation has reported to suppress diseases related to oxidative stress such as atherosclerosis⁴. However, the capacity of plasmalogen modulation to attenuate different aspects of metabolic disease is not fully defined and our understanding of the mechanisms involved is limited. Fatty liver diseases are closely associated with metabolic diseases and involve dysregulation of lipid metabolism, heightened oxidative stress and chronic inflammation.

We hypothesise that upregulation of plasmalogens will reduce the pathologies association with fatty liver disease by their multifaceted roles in lipid metabolism, oxidative stress, and inflammation.

The specific aims are to:

1. Define the potential of plasmalogen upregulation as a therapeutic approach against fatty liver diseases.
2. Identify the underlying mechanisms for the therapeutic potential of plasmalogen modulation against fatty liver diseases.

This project is suitable for an Honours or PhD student and will ccombine our lipidomics expertise with our unique mouse models of plasmalogen modification as well as established mouse models of fatty liver diseases to define the therapeutic potential of plasmalogen modulation against fatty liver diseases. Identification of the mechanisms operating to attenuate disease pathogenesis will provide a clear rationale for the subsequent translation and commercialisation of this new prophylactic therapy.

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References

1. Plasmalogens: a potential therapeutic target for neurodegenerative and cardiometabolic disease. Progress in lipid research 2019;74(9):186–95.
2. Plasma lipid profiling in a large population-based cohort. Journal of lipid research 2013;54(10):2898–908.
3. Plasma lipid profiling shows similar associations with prediabetes and type 2 diabetes. PloS one 2013;8(9):e74341.
4. Plasmalogen modulation attenuates atherosclerosis in ApoE-and ApoE/GPx1-deficient mice. Atherosclerosis 2015;243(2):598–608.