Available online 12 August 2022
HIGHLIGHTS•Phenotypic description of family members with primary hyperalphalipoproteinemia
•Identification of a novel likely pathogenic variant of LIPG in three subjects
•Large HDL particles and reduced preβ-HDL content found in variant carriers
•Decreased ABCA1- and ABCG1-mediated cholesterol efflux capacity of carriers’ sera Increased cholesterol loading capacity of carriers’ sera in human macrophages
ABSTRACTBackgroundLoss of function variants of LIPG gene encoding endothelial lipase (EL) are associated with primary hyperalphalipoproteinemia (HALP), a lipid disorder characterized by elevated plasma levels of high density lipoprotein cholesterol (HDL-C).
ObjectiveAim of the study was the phenotypic and genotypic characterization of a family with primary HALP.
MethodsHDL subclasses distribution was determined by polyacrylamide gradient gel electrophoresis. Serum content of preβ-HDL was assessed by (2D)-electrophoresis. Cholesterol efflux capacity (CEC) of serum mediated by ABCA1, ABCG1 or SR-BI was assessed using cells expressing these proteins. Cholesterol loading capacity (CLC) of serum was assayed using cultured human macrophages. Next generation sequencing was used for DNA analysis. Plasma EL mass was determined by ELISA.
ResultsThree family members had elevated plasma HDL-C, apoA-I and total phospholipids, as well as a reduced content of preβ-HDL. These subjects were heterozygous carriers of a novel variant of LIPG gene [c.526 G>T, p.(Gly176Trp)] found to be deleterious in silico. Plasma EL mass in carriers was lower than in controls. CEC of sera mediated by ABCA1 and ABCG1 transporters was substantially reduced in the carriers. This effect was maintained after correction for serum HDL concentration. The sera of carriers were found to have a higher CLC in cultured human macrophages than control sera.
ConclusionThe novel p.(Gly176Trp) variant of endothelial lipase is associated with changes in HDL composition and subclass distribution as well as with functional changes affecting cholesterol efflux capacity of serum which suggest a defect in the early steps of revere cholesterol transport.
KEY WORDSPrimary hyperalphalipoproteinemia
endothelial Lipase
missense variant
high density lipoprotein composition
high density lipoprotein subclasses
cholesterol efflux capacity
cholesterol loading capacity
View full text© 2022 Published by Elsevier Inc. on behalf of National Lipid Association.
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