J. Lipid Res.
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A more recent version of this article appeared on May 1, 2007

Papers In Press, published online ahead of print February 24, 2007
J. Lipid Res., doi:10.1194/jlr.M600535-JLR200
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Submitted on December 18, 2006
Revised on February 9, 2007
Accepted on February 23, 2007

Glycosylation of endothelial lipase at asparagine-116 reduces activity and hydrolysis of native lipoproteins in vitro and in vivo

Robert J. Brown, Gwen C. Miller, Nathalie Griffon, Christopher J. Long, and Daniel J. Rader

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

Corresponding Author: robbrown{at}mail.med.upenn.edu

We previously identified that four of five putative N-linked glycosylation sites of human endothelial lipase (EL) are utilized, and suggested that the substitution of Asn-116 with Ala (N116A) increased the hydrolytic activity of EL. The current study demonstrates that mutagenesis of either Asn-116 to Thr or Thr-118 to Ala also disrupted glycosylation of EL and enhanced catalytic activity toward synthetic substrates by 3-fold versus wild-type EL. Furthermore, we assessed the hydrolysis of native lipoprotein lipids by EL-N116A. EL-N116A exhibited a 5-fold increase in low density lipoprotein (LDL) hydrolysis and a 1.8-fold increase in high density lipoprotein (HDL) 2 hydrolysis. Consistent with these observations, adenoviral-mediated expression of EL-N116A in mice significantly reduced levels of both LDL and HDL cholesterol beyond the reductions observed by the expression of wild-type EL alone. Finally, we introduced Asn-116 of EL into the analogous positions within lipoprotein lipase (LPL) and hepatic lipase (HL), resulting in N-linked glycosylation at this site. Glycosylation at this site suppressed LPL hydrolysis of synthetic substrates, LDL, HDL2, and HDL3, but had little effect on HL activity. These data suggest that N-linked glycosylation at Asn-116 reduces the ability of EL to hydrolyse lipids in LDL and HDL2.


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