Lipidome of high-density lipoprotein is strongly perturbed in hyperalphalipoproteinemia resulting from a rare mutation in endothelial lipase

TL;DR

A rare mutation in the LIPG gene causes high HDL cholesterol and changes the HDL lipid composition, which may affect its heart-protective functions.

Contribution

The study reveals novel lipidomic changes in HDL caused by a rare LIPG mutation linked to hyperalphalipoproteinemia.

Findings

HDL from HALP patients shows increased levels of phosphatidylcholine, phosphatidylserine, and other phospholipids.

Some lipid changes are also observed in whole plasma, suggesting broader metabolic effects.

Altered lipid profiles may impair the atheroprotective functions of HDL particles.

Abstract

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.

•A rare heterozygous variant in the LIPG gene causes hyperalphalipoproteinemia.•The lipidome of HDL is significantly altered in this condition.•These lipidomic changes involve an enrichment of various phospholipids.•Such alterations may impact biological activities of HDL particles.

A rare heterozygous variant in the LIPG gene causes hyperalphalipoproteinemia.

The lipidome of HDL is significantly altered in this condition.

These lipidomic changes involve an enrichment of various phospholipids.

Such alterations may impact biological activities of HDL particles.

Figures