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

Abstract

BackgroundEndothelial 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 FindingsHealthy individuals with a family history of premature coronary heart disease (n = 858) 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 = 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 range = 324–617) 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 post-heparin 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 (r = 0.28 and 0.22, respectively, p < 0.001 for each), blood pressure (r = 0.18 and 0.24, p < 0.001 for each), triglycerides (r = 0.22, p < 0.001; and 0.13, p = 0.004), HDL cholesterol (r = –0.11, p = 0.002; and –0.18, p < 0.001), and fasting glucose (r = 0.11 and 0.16, p = 0.001 for both). EL mass in both routine (odds ratio [OR] = 1.67, p = 0.01) and post-heparin (OR = 2.42, p = 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.ConclusionsWe 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.

Lack of association between a common polymorphism of the endothelial lipase gene and early-onset coronary artery disease in a Chinese Han population

“…The EL concentration is negatively correlated with the level of HDL-C, and some studies have determined that EL may influence the regression of AS directly (Ishida et al, 2004;Yasuda et al, 2007;Shiu et al, 2008). Ishida et al (2004) revealed that EL may have direct pro-atherosclerotic functions by recruiting monocytes and facilitating the uptake of cholesterol, while other studies showed that EL may play an important role in the progress of CVD (Badellino et al, 2006;Fang et al, 2007). The hypothesis, therefore, exists that reduced EL levels delay the progression of AS.…”

“…Evidence suggests, however, that EL may influence the regression of atherosclerosis (AS) directly (Ishida et al, 2004;Yasuda et al, 2007;Shiu et al, 2008). Ishida et al (2004) identified potential direct pro-atherosclerotic actions of EL, namely monocyte recruitment and cholesterol uptake, while Yasuda et al (2007) found that EL was upgraded by inflammation and induced macrophages to take up native LDL-C. Additional studies also revealed that EL may play an important role in the pathogenesis of cardiovascular disease (CVD) (Badellino et al, 2006;Fang et al, 2007).…”

Recent advances in physiological lipoprotein metabolism

“…Endothelial lipase is synthesized primarily by the vascular endothelial cells and to a lesser extent by macrophages and smooth muscle cells. In humans' plasma endothelial cell mass was inversely correlated with HDL-cholesterol levels [305]. HL can hydrolyze triglycerides in all lipoproteins but is predominant in the conversion IDL to LDL, and can also convert postprandial triglyceride rich HDL into post-absorptive triglyceride poor HDL [306].…”

ELISA System for Human Endothelial Lipase

“…Experiments in engineered mice with a disrupted native EL locus, as well as in mice overexpressing human EL (hEL), have revealed an inverse relationship between plasma HDL-C concentration and EL expression (11,14 ). Previous studies have shown that plasma EL mass measured by ELISA is inversely correlated with HDL-C concentrations in humans (15,16 ). Association-based human genetic studies have provided evidence that variations in the EL genomic LIPG locus such as T111I, G26S, and N396S are linked to differences in circulating HDL-C concentrations or CVD (17)(18)(19)(20)(21), although recent studies with a large number of subjects have established associations between LIPG single-nucleotide polymorphism and HDL-C concentrations, but none with CVD (21)(22)(23).…”