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.

Objectives Inflammation may directly impair HDL functions, in particular reverse cholesterol transport (RCT), but limited data support this concept in humans. Methods and Results We employed low-dose human endotoxemia to assess the effects of inflammation on HDL and RCT-related parameters in vivo. Endotoxemia induced remodelling of HDL with depletion of pre-β1a HDL particles determined by 2-D gel electrophoresis (-32.2 ± 9.3% at 24h, p<0.05) as well as small (-23.0 ± 5.1%, p<0.01, at 24h) and medium (-57.6 ± 8.0% at 16h, p<0.001) HDL estimated by nuclear magnetic resonance (NMR). This was associated with induction of class II secretory phospholipase A2 (~36 fold increase) and suppression of lecithin:cholesterol acyltransferase activity (-20.8 ± 3.4% at 24h, p<0.01) and cholesterol ester transfer protein mass (-22.2 ± 6.8% at 24h, p<0.001). The HDL fraction, isolated following endotoxemia, had reduced capacity to efflux cholesterol in vitro from SR-BI and ABCA1, but not ABCG1 transporter cell models. Conclusions These data support the concept that “atherogenic-HDL dysfunction” and impaired RCT occur in human inflammatory syndromes, largely independent of changes in plasma HDL-C and ApoA-I levels.

Background-Endothelial lipase (EL) is a plasma lipase that we previously reported to be significantly correlated with all features of the metabolic syndrome in humans, including directly with measures of adiposity and inversely with high-density lipoprotein cholesterol levels. We hypothesized that inflammation associated with obesity results in upregulation of EL. We determined the relationship between inflammatory markers and EL levels in a cohort of healthy persons recruited on the basis of family history of coronary disease. Furthermore, we directly tested the hypothesis that plasma EL concentrations would increase with induction of an inflammatory state by low-dose endotoxin in humans. Methods and Results-High-sensitivity C-reactive protein, interleukin 6, soluble tumor necrosis factor receptor II, soluble intercellular adhesion molecule 1, leptin, and adiponectin were measured in plasma of 858 subjects. Significant direct correlations (PϽ0.001 for all) were found between EL concentrations and high-sensitivity C-reactive protein (rϭ0.28), interleukin-6 (rϭ0.22), soluble tumor necrosis factor receptor II (rϭ0.22), soluble intercellular adhesion molecule 1 (rϭ0.24), and leptin (rϭ0.20). An inverse correlation was present with adiponectin (rϭϪ0.15, PϽ0.001). Adiponectin inhibited the tumor necrosis factor-␣-stimulated EL secretion from cultured human coronary endothelial cells in a dose-dependent manner. Experimental low-dose endotoxemia in 20 subjects resulted in a 2.5-fold increase in EL concentrations 12 to 16 hours after injection, which correlated temporally with decreases in both total and high-density lipoprotein phospholipid. Conclusions-In humans, plasma inflammatory markers are directly correlated with plasma EL concentrations, and experimental endotoxemia significantly increases plasma EL concentrations, proving that EL is upregulated by inflammation in humans. This mechanism may partially explain the low high-density lipoprotein cholesterol levels seen in obesity and metabolic syndrome. (Circulation. 2008;117:678-685.)