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Papers In Press, published online ahead of print September 1, 2009
J. Lipid Res., doi:10.1194/jlr.P900020-JLR200

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Journal of Lipid Research, Vol. 50, 1910-1916, September 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Patient-Oriented and Epidemiological Research

A naturally occurring variant of endothelial lipase associated with elevated HDL exhibits impaired synthesis^[S]

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 and Daniel J. Rader¹

Department of Medicine and Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104

¹ To whom correspondence should be addressed. e-mail: rader{at}mail.med.upenn.edu

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.

Supplementary key words high density lipoprotein • human subjects • single nucleotide polymorphism • protein translation • lysosomal degradation • proteosomal degradation

Abbreviations: ALLN, N-acetyl-leucinyl-leucinyl-norleucinal; DPPC, dipalmitoylphosphatidyl choline; EL, endothelial lipase; ER, endoplasmic reticulum; HDL-C, HDL cholesterol; HHDL, University of Pennsylvania High HDL Cholesterol Study; HL, hepatic lipase; PennCAC, University of Pennsylvania Coronary Artery Calcification Study; PBS, phosphate-buffered saline; SIRCA, Study of Inherited Risk of Coronary Atherosclerosis; WT, wild-type

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