Endothelial Lipase Concentrations Are Increased in Metabolic Syndrome and Associated with Coronary Atherosclerosis

Endothelial Lipase Concentrations Are Increased in Metabolic Syndrome and Associated with Coronary Atherosclerosis

Badellino Karen O., Rader Daniel J., Reilly Muredach P., Wolfe Megan L.
December 2005
Published: December 2005
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Two members of the lipase family, lipoprotein lipase (LPL) and hepatic lipase (HL) are known to influence plasma lipoprotein metabolism and risk of atherosclerosis in humans.1-5 Endothelial lipase (EL) is a more recently discovered member of this family of lipases.1 In contrast to LPL and HL, it is expressed in endothelial cells and, in the majority of reports, has relatively more phospholipase activity than the other two enzymes. Similar to HL and LPL, it is secreted and binds to the endothelial surface. In vitro, EL effectively hydrolyzes high-density lipoprotein (HDL) phospholipids. In mice, EL has a major influence on HDL metabolism. Adenovirally mediated overexpression of human EL in mice dramatically reduced HDL cholesterol (HDL-C) concentrations,6 shown to be due to rapid catabolism of HDL.8 Transgenic overexpression of human EL was shown to reduce HDL-C concentrations as well.9 Conversely, antibody inhibition of EL in mice significantly increased HDL-C concentrations,10 and EL knockout mice have a significant increase in HDL-C concentrations.9,11 Furthermore, EL knockout mice crossed onto the apolipoprotein E knockout background have decreased atherosclerosis.12 Based on these studies in mice, it has been suggested that EL may be an important risk factor and may affect the development of atherosclerosis in humans.

The relationship of EL to variation in lipoprotein concentrations and atherosclerosis in humans has not been reported. Several genetic association studies have suggested that rare variants and common polymorphisms in the human EL gene might be associated with variation in HDL-C concentrations,11,13,14 but they have not been conclusive and were not accompanied by direct measurement of EL concentrations. We hypothesized that concentrations of EL are inversely associated with HDL-C concentrations and directly associated with the metabolic syndrome and atherosclerosis in humans. To test this, we developed an immunoassay for human EL and used it to measure EL mass concentrations in both pre-heparin and post-heparin plasma samples in individuals enrolled in the Study of the Inherited Risk of Atherosclerosis (SIRCA). We determined the association of EL concentrations with lipoprotein concentrations, other cardiovascular risk factors and coronary artery calcification (CAC), a noninvasive measure of coronary atherosclerosis.15-17

Methods Study Protocol
SIRCA is a cross-sectional study of asymptomatic individuals and their families designed to investigate novel biomarkers and genetic factors associated with coronary atherosclerosis. The study design and initial findings have previously been published.18-19 Briefly, persons were eligible for SIRCA if they had a family history of premature coronary artery disease (CAD), were free of clinical CAD, and were men, 20–75 years of age or women, 30–75 years. Exclusion criteria included other major CAD risk factors: known diabetes, total cholesterol higher than 300 mg/dl, cigarette smoking of one pack or more per day, or blood pressure higher than 160/100 mm Hg. The University of Pennsylvania Institutional Review Board approved the study protocol. Informed consent was obtained from each participant. This report focuses on 858 random unrelated individuals from the SIRCA in whom plasma EL concentrations were measured.

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