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 of EL in mice results in a dose-dependent increase in postheparin plasma phospholipase activity, catabolic rate of HDL-apolipoprotein, and uptake of apoA-I in both kidney and liver.