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, Rader Daniel, Reilly Muredach, Wolfe Megan
PLoS Med 3(2): e22, December 20, 2005
Published: February 2006
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Background
Endothelial lipase (EL), a new member of the lipase family, has been shown to modulate high-density lipoprotein (HDL-C) metabolism and atherosclerosis in mouse models. We hypothesized that EL concentrations would be associated with decreased HDL-C and increased atherosclerosis in humans.


Methods and Findings
Healthy individuals with a family history of premature coronary heart disease (n ¼858) were recruited as part of the Study of the Inherited Risk of Atherosclerosis. Blood was drawn in the fasting state before and, in a subgroup (n ¼ 510), after administration of a single dose of intravenous heparin. Plasma lipids were measured enzymatically, lipoprotein subclasses were assessed by nuclear magnetic resonance, and coronary artery calcification (CAC) was quantified by electron beam computed tomography. Plasma EL mass was measured using a newly developed enzyme-linked immunosorbent assay. Median EL mass in pre-heparin plasma was 442 (interquartile range¼324–617) ng/ml. Median post-heparin mass was approximately 3-fold higher, 1,313 (888–1,927) ng/ml. The correlation between pre-heparin EL mass and postheparin EL mass was 0.46 (p , 0.001). EL mass concentrations in both pre- and post-heparin plasma significantly correlated with all NCEP ATPIII-defined metabolic syndrome factors: waist circumference (r¼0.28 and 0.22, respectively, p , 0.001 for each), blood pressure (r¼0.18 and 0.24, p , 0.001 for each), triglycerides (r¼0.22, p , 0.001; and 0.13, p¼0.004), HDL cholesterol (r¼0.11, p¼0.002; and0.18, p , 0.001), and fasting glucose (r¼0.11 and 0.16, p¼0.001 for both). EL mass in both routine (odds ratio [OR]¼1.67, p¼0.01) and post-heparin (OR¼2.42, p¼ 0.003) plasma was associated with CAC as determined by ordinal regression after adjustment for age, gender, waist circumference, vasoactive medications, hormone replacement therapy (women), and established cardiovascular risk factors.

Conclusions
We report, to our knowledge for the first time, that human plasma EL concentrations, in both post-heparin and routine pre-heparin plasma, are significantly associated with metabolic syndrome features and with subclinical atherosclerosis. EL may be a pro-atherogenic factor in humans, especially in overweight individuals and those with metabolic syndrome.

Introduction
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 humans1–5. Endothelial lipase (EL) is a more recently discovered member of this family of lipases 6,7. 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. Adeno virally mediated over expression of human EL in mice dramatically reduced HDL cholesterol (HDL-C) concentrations 6, shown to be due to rapid catabolism of HDL 8. Transgenic over expression of human EL was shown to reduce HDL-C concentrations as well 9.

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