Comparative lipidomic profiling of plasma and aorta from ldlr-KO, pcsk9-KO and C57bl/6 mice

Background. Lipidomics is a powerful tool to highlight the involvement of lipid species in pathological conditions, including atherosclerosis. Aim. Lipidomic changes induced by genotype and/or diet were evaluated in plasma and aorta of hyperlipidemic/athero-prone Ldlr-KO, hypolipidemic/athero-resistant Pcsk9-KO and C57Bl/6 (WT) mice. Methods. Plasma and aorta from mice fed chow or Western diet (WD) for 16 weeks were extracted for lipids and analyzed by mass spectrometry: 200 lipid species belonging to 21 lipid classes were quantified. Results. On chow diet, plasma lipidome was lower in Pcsk9-KO (2039 μM) vs WT mice (3770 μM) and was much higher in Ldlr-KO (9392 μM) vs WT and Pcsk9-KO mice. WD increased with different degree all lipid classes in each group and the lipidome increased by 2-3 fold in Pcsk9-KO and WT mice and by 5 fold in Ldlr-KO mice. The lipids quantitatively more relevant in each group and dietary condition were cholesteryl esters (CE), phosphatidylcholines, free cholesterol and triglycerides. Among minor lipid species, interestingly, Ceramides(d18:0) levels on chow diet were comparable in Pcsk9-KO and WT mice and were moderately increased by WD, whereas they were 10 fold higher in Ldlr-KO mice on chow diet vs the other groups and increased by another 10 fold on WD. Aorta lipidome of Pcsk9-KO mice was unaffected by diet (chow: 20.7 pmol/μg; WD: 20.2 pmol/μg) whereas it was increased by WD in WT (chow: 18.2 pmol/μg; WD: 38.7 pmol/μg) and Ldlr-KO mice (chow: 19.7 pmol/μg; WD: 49.9 pmol/μg). Among major lipids, WD drastically affected CE concentration in Ldlr-KO mice (chow: 0.1 pmol/μg, WD: 5.3 pmol/μg), whereas it only doubled CE levels in Pcsk9-KO and WT mice. Triglycerides were unaffected by diet in Pcsk9-KO mice, but increased by 2.5 fold with WD in both WT and Ldlr-KO mice. WD did not substantially modify minor lipids in Pcsk9-KO and WT mice, whereas it drastically changed phosphatidylglycerol, glucosyl/galactosylceramides and Lactosylceramides levels in Ldlr-KO aorta. Conclusions. This lipidomic profiling indicates that diet and/or a genetic background can drastically affect not only major lipid classes, but also minor lipid species, suggesting a possible implication of these molecules in hyperlipidemia and atherosclerosis development.