Inhibition of endothelial lipase causes increased HDL cholesterol levels in vivo
Weijun Jin, … , Jane M. Glick, Daniel J. Rader
Weijun Jin, … , Jane M. Glick, Daniel J. Rader
Published February 1, 2003
Citation Information: J Clin Invest. 2003;111(3):357-362. https://doi.org/10.1172/JCI16146.
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Article Metabolism

Inhibition of endothelial lipase causes increased HDL cholesterol levels in vivo

Abstract

Endothelial lipase (EL) is a recently discovered member of the lipoprotein lipase gene family that hydrolyzes HDL phospholipids ex vivo and reduces HDL cholesterol (HDL-C) levels when overexpressed in vivo in mice. To gain further insight into the physiological role of EL in the metabolism of HDL in vivo, studies were performed in which EL was inhibited in wild-type, hepatic lipase knockout (HL–/–), and human apoA-I transgenic mice by intravenous infusion of a polyclonal antibody inhibitory to murine EL. As compared with infusion of a control antibody, infusion of the inhibitory antibody resulted in a 25–60% increase in HDL-C levels in the three mouse models, with the peak HDL-C levels occurring at 48 hours after injection. Inhibition of EL also generated larger HDL particles in the HL–/– mice. The clearance of HDL phospholipid was significantly slower in human apoA-I transgenic mice injected with an antibody against murine EL (mEL) than in mice injected with a control antibody. We conclude that inhibition of EL results in increased HDL-C levels and that EL is an important enzyme in the physiological regulation of HDL metabolism.

Authors

Weijun Jin, John S. Millar, Uli Broedl, Jane M. Glick, Daniel J. Rader

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Figure 1

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Characterization of the inhibitory effects of the anti-mEL antibody and ...
Characterization of the inhibitory effects of the anti-mEL antibody and its specificity. (a) Conditioned media from HEK293 cells transfected with the mEL cDNA were preincubated with increasing amounts of control IgG or anti-mEL IgG, and effects on triglyceride lipase and phospholipase activity were determined and compared with effects in untreated (PBS) media. The results are presented as the percentage of activity in medium preincubated with PBS alone and are the means ± SD of triplicate determinations. (b) Conditioned media from HEK293 cells transfected with mEL, mHL, and mLPL cDNAs were preincubated with PBS, control IgG, or anti-mEL IgG, and the effects on triglyceride lipase activity were determined. The results are presented as the percentage of activity in medium preincubated with PBS alone and are the means ± SD of triplicate determinations. (c) Homogenized liver lysates (15 μg protein) from wild-type, human apoA-I transgenic, and HL–/– mice and conditioned media from mEL-, mHL-, and mLPL-transfected cells were separated by SDS-PAGE and immunoblotted with an anti-mEL antibody. Both forms of mEL were detected in the liver lysates of all three mouse models and were of slightly smaller size than mELs in conditioned media. The additional band detected in the human apoA-I transgenic and HL–/– mouse liver lysates was also seen on immunoblotting of these same liver lysates using a control antibody (data not shown). No bands were seen in the mHL or mLPL conditioned media.