Plasmalogens are glycerophospholipids that are present in numerous mammalian tissues and can act as a natural antioxidant (1). Lipidomic profiling of multiple populations and clinical cohorts has identified decreased levels of plasmalogens to be associated with aging and obesity (2) as well as prediabetes and type 2 diabetes (3). 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 atherosclerosis (4). 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. In this project we will combine 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. References: 1. Paul S, Lancaster GI, Meikle PJ. Plasmalogens: A potential therapeutic target for neurodegenerative and cardiometabolic disease. Progress in lipid research. 2019;74(9):186-95. 2. Weir JM, Wong G, Barlow CK, Greeve MA, Kowalczyk A, Almasy L, et al. Plasma lipid profiling in a large population-based cohort. Journal of lipid research. 2013;54(10):2898-908. 3. Meikle PJ, Wong G, Barlow CK, Weir JM, Greeve MA, MacIntosh GL, et al. Plasma lipid profiling shows similar associations with prediabetes and type 2 diabetes. PloS one. 2013;8(9):e74341. 4. Rasmiena AA, Barlow CK, Stefanovic N, Huynh K, Tan R, Sharma A, et al. Plasmalogen modulation attenuates atherosclerosis in ApoE-and ApoE/GPx1-deficient mice. Atherosclerosis. 2015;243(2):598-608.
therapy, lipid metabolism, lipidomics, mass spectrometry
Top-up scholarship funding available
Baker Heart & Diabetes Instititute, Prahran (Next to Alfred Hospital)