PLASMA HDL PATTERN, CHOLESTEROL EFFLUX AND CHOLESTEROL LOADING CAPACITY OF SERUM IN CARRIERS OF A NOVEL MISSENSE VARIANT (Gly176Trp) OF ENDOTHELIAL LIPASE

Elsevier

Available online 12 August 2022

Journal of Clinical LipidologyHIGHLIGHTS•

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

ABSTRACTBackground

Loss 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).

Objective

Aim of the study was the phenotypic and genotypic characterization of a family with primary HALP.

Methods

HDL 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.

Results

Three 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.

Conclusion

The 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 WORDS

Primary 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.

留言 (0)

沒有登入
gif