Effect of diet and genotype on the lipidome of mice with altered lipoprotein metabolism.

The present study describes and compares the impact of PCSK9 and LDLR, two pivotal players in cholesterol metabolism, on the whole lipidome of plasma, liver and aorta in different dietary conditions. This issue is relevant, since several lipid species, circulating at very low concentrations, have the ability to impair lipid metabolism and promote atherosclerosis development. To this aim, wild-type, hypercholesterolemic Ldlr-KO, and hypocholesterolemic Pcsk9-KO mice were fed a standard chow or a Western-type diet up to 30 and 16 weeks of age, respectively. 42 lipids including cholesterol, cholesteryl esters, several sphingolipids, phospholipids, and lysophospholipids, accumulated uniquely in the atherosclerotic aorta of Western-type diet-fed Ldlr-KO mice. In addition, multiple organ/tissue comparisons allowed us to identify 16 lipids whose plasma and hepatic patterns mirrored the lipidome of the atherosclerotic aorta. These lipid species, belonging to cholesteryl esters, glucosyl/galactosylceramide, lactosylceramide, globotriaosylceramide, sphingomyelin, and phosphatidylcholine could be further investigated as circulating biomarkers or therapeutic targets.