A naturally occurring variant of endothelial lipase associated with elevated HDL exhibits impaired synthesis.
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.
Department of Medicine and Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104.
Robert J
RJ
Brown
Andrew C
AC
Edmondson
Nathalie
N
Griffon
Theophelus B
TB
Hill
Ilia V
IV
Fuki
Karen O
KO
Badellino
Mingyao
M
Li
Megan L
ML
Wolfe
Muredach P
MP
Reilly
Daniel J
DJ
Rader
D001741:Black or African American / Q000235:genetics; D000818:Animals; D055162:Biocatalysis; D002460:Cell Line; D008076:Cholesterol, HDL / Q000096:biosynthesis* / Q000097:blood / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008049:Lipase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation
D008076:Cholesterol, HDL; D050505:Mutant Proteins; C410382:LIPG protein, human; D008049:Lipase