Poster only 3rd Metabolic Diseases; Breakthrough Discoveries in Diabetes & Obesity 2022

Ether lipid metabolism in obesity: insights from plasma lipidomics of large population cohort studies (#75)

Yvette Schooneveldt 1 2 , Sudip Paul 1 3 , Kevin Huynh 1 3 , Habtamu B Beyene 1 3 , Eric K Moses 4 , Jonathan S Shaw 1 , Dianna J Magliana 1 5 , Anna C Calkin 1 2 3 , Peter J Meikle 1 2 3
  1. Baker Heart and Diabetes Institute , Melbourne, Victoria, Australia
  2. Central Clinical School, Faculty of Medicine, Nursing & Health Sciences, Monash University, Melbourne, Victoria, Australia
  3. Baker Department of Cardiovascular Research Translation and Implementation, La Trobe University, Bundoora, Victoria, Australia
  4. Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia
  5. School of Public Health and Preventative Medicine , Monash University, Melbourne, Victoria, Australia

Lipidomic profiling of population cohorts has revealed that decreased plasma ether lipids, a unique class of glycero- and glycerophospho-lipids with reported health benefits, are implicated in numerous cardiometabolic diseases. Here, we utilised lipid ratios to define pathways of ether lipid metabolism in obesity.

To achieve this, we analysed plasma lipidomic data (706 individual lipid species across 36 classes) from The Australian Diabetes, Obesity and Lifestyle Study (n= 10,339). We generated 58 ratios of specific lipid species reflective of ether lipid composition, enzymatic activity and key pathways involved in ether lipid and fatty acid synthesis. We performed linear regression analysis to assess the association between each lipid ratio and various markers of obesity including body-mass-index (BMI), waist circumference and waist-to-hip ratio.

BMI was inversely associated with total plasmalogen levels relative to total phospholipids (-0.02 SD-change per unit BMI, p‑value 1.47E-24). Ratios that capture key steps in plasmalogen synthesis (phosphatidylethanolamine-N-methyltransferase) and catabolism (calcium-independent phospholipase A2) showed positive and negative associations with increasing BMI (0.029 and -0.043 SD-change per unit BMI, p-value 2.44E-49 and 9.06E-114, respectively). Changes in omega-3 and omega-6 fatty acid acyl-chains showed a clear divergence of enzymatic activity throughout different regions of these pathways. Specifically, we observed a flux through the earlier stages of the pathways and a subsequent decrease through the later stages, suggesting peroxisomal dysfunction. Additionally, we evaluated sex interactions between these associations and BMI. Of note, ratios reflecting changes in the omega-3 pathway demonstrated opposing associations based on gender (positive association in women and negative association in men). Finally, the lipid ratios were independently validated using lipidomics data from the Busselton Health Study (n=4,793).

Our analyses illustrate the effects of elevated BMI and obesity on ether lipid metabolism, and demonstrate the potential of population lipidomics to define sex-dependent relationships between obesity and lipid metabolism.