A naturally occurring variant of endothelial lipase associated with elevated HDL exhibits impaired synthesis

Robert J Brown,Andrew C Edmondson,Nathalie Griffon,Theophelus B Hill,Ilia V Fuki,Karen O Badellino,Mingyao Li,Megan L Wolfe,Muredach P Reilly,Daniel J Rader

doi:10.1194/jlr.p900020-jlr200

Abstract

Human endothelial lipase (EL) is a member of a family of lipases and phospholipases that are involved in the metabolism of plasma lipoproteins. EL displays a preference to hydrolyze lipids in HDL. We report here that a naturally occurring low frequency coding variant in the EL gene (LIPG), glycine-26 to serine (G26S), is significantly more common in African-American individuals with elevated HDL cholesterol (HDL-C) levels. To test the hypothesis that this variant results in reduced EL function, we extensively characterized and compared the catalytic and noncatalytic functions of the G26S variant and wild-type (WT) EL. While the catalytic-specific activity of G26S EL is similar to WT EL, its secretion is markedly reduced. Consistent with this observation, we found that carriers of the G26S variant had significantly reduced plasma levels of EL protein. Thus, this N-terminal variant results in reduced secretion of EL protein, plausibly leading to increased HDL-C levels.

Highlights

Human endothelial lipase (EL) is a member of a family of lipases and phospholipases that are involved in the metabolism of plasma lipoproteins
We failed to identify any carriers for the glycine-26 to serine (G26S) variant in Caucasians (n=851/885) from the Study of Inherited Risk of Coronary Atherosclerosis (SIRCA) cohort, strengthening the likelihood that the G26S variant is specific to African-Americans
This study demonstrates that a G26S substitution in the N-terminal region of the EL protein results in markedly reduced synthesis and secretion of EL, leading to reduced levels of EL in plasma and plausibly explaining the association of this variant with elevated HDL cholesterol (HDL-C) levels

Summary

Introduction

Human endothelial lipase (EL) is a member of a family of lipases and phospholipases that are involved in the metabolism of plasma lipoproteins. We have recently shown that a previously reported nonsynonymous coding variant of EL that exhibits impaired enzymatic functions in vitro and in vivo is directly associated with elevated HDL-C in multiple cohorts [14].

Results

Conclusion