Dose-Dependent Acceleration of High-Density Lipoprotein Catabolism by Endothelial Lipase

Abstract

Background-Factors that regulate the metabolism of HDL and apolipoprotein A-I (apoA-I) are incompletely understood.Overexpression of endothelial lipase (EL) markedly reduces plasma levels of HDL cholesterol and apoA-I in mice, but the mechanisms of this effect remain unknown. Methods and Results-We used different doses of a recombinant adenoviral vector to overexpress human EL in mice and studied the effects on plasma phospholipase activity, plasma lipids, HDL particle size, HDL turnover, and tissue sites of HDL degradation in mice. Overexpression of EL was associated with a significant dose-dependent increase in postheparin plasma phospholipase activity. Plasma phospholipid, HDL cholesterol, and apoA-I levels were markedly decreased, even at the lowest dose of vector. Kinetic studies demonstrated a significant dose-dependent increase in the fractional catabolic rate of HDL-apolipoprotein in EL-overexpressing mice. The postheparin plasma phospholipase activity was significantly positively correlated with HDL-apolipoprotein fractional catabolic rate. The uptake of apoA-I by the kidney and the liver was significantly increased by 2.5-fold and 3-fold, respectively, in mice overexpressing EL. Conclusions-Expression

Glomerular structural and functional changes in a high-fat diet mouse model of early-stage Type 2 diabetes

“…We are unaware of another study that has measured HDL cholesterol and LDL cholesterol after administering a high-fat diet to C57BL/6 mice. However, our baseline values (13-week-old mice fed a normal diet) of 1.91 mmol/l for HDL cholesterol and 0.35 mmol/l for LDL cholesterol were similar to the values of 1.74 mmol/l and 0.51 mmol/l found by Maugeais et al in C57BL/6 mice [19].…”

Angiopoietin‐Like Protein 4 Is a High‐Density Lipoprotein (HDL) Component for HDL Metabolism and Function in Nondiabetic Participants and Type‐2 Diabetic Patients

“…Plasma levels of ANGPTL4 were quantified by enzyme‐linked immunosorbent assay to further confirm the phenotype (Figure 3C). EL is a member of the LPL family and mediates cholesterol hydrolysis in HDLs 29. To further determine whether ANGPTL4 in HDLs acted on EL and thus led to the reduced HDL‐c in T2DM, HEK 293 cells were transfected with the plasmid encoding human EL cDNA and then purified by fluorescence‐activated cell sorting.…”

Scavenger Receptor BI-mediated Selective Uptake Is Required for the Remodeling of High Density Lipoprotein by Endothelial Lipase

“…EL has merely phospholipase and very little apparent triglyceridase activity (6), and HDL phospholipids represent a preferred substrate for the enzyme in in vitro assays (6,7). The physiological relevance of EL-mediated hydrolysis of HDL particles for determining the plasma levels of HDL cholesterol has been established in experimental animals using both overexpression (5,8) as well as loss-of-function models (9 -11). Overexpression of EL resulted in significantly decreased HDL cholesterol plasma levels by increasing the catabolic rate of HDL apolipoproteins (8), whereas inhibition (10) or genetic ablation (9,11) of EL raised plasma HDL cholesterol.…”

“…Post-heparin plasma was generated as described (8). Western blots for EL were carried out using a commercially available polyclonal rabbit antihuman EL antibody (Novus Biologicals, Littleton, CO) to visualize EL followed by the appropriate secondary antibody.…”