Pisciotta_2025_Atheroscler.Plus_61_35

Both low and extremely high concentrations of high-density lipoprotein (HDL)-cholesterol are associated with elevated cardiovascular risk. As extremely high HDL-cholesterol states of hyperalphalipoproteinemia (HALP) are rare, HDL particles in this condition remain poorly characterised. HALP may result from mutations in endothelial lipase (EL), a hydrolytic enzyme present in the circulation. Using targeted LC/MS-MS, we quantified the lipidome of HDL isolated from three female subjects with HALP caused by a heterozygous [c.526 G > T, p.(Gly176Trp)] variant of the LIPG gene and compared them with two healthy female controls. Our findings revealed a strongly perturbed HDL lipidome primarily involving enrichment in several phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine plasmalogen, and lysophosphatidylethanolamine species. Some of these differences were equally observed in whole plasma. These alterations may reflect perturbations of lipoprotein metabolism secondary to defective lipid hydrolysis by EL and may have consequences for atheroprotective HDL functions.