Differential Additive Effects of Endothelial Lipase and Scavenger Receptor-Class B Type I on High-Density Lipoprotein Metabolism in Knockout Mouse Models

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Abstract
Objective— Endothelial lipase (EL) is a vascular phospholipase that hydrolyzes high-density lipoprotein (HDL) as its preferred substrate. Scavenger receptor-class B type I (SR-BI) is an HDL receptor that mediates the selective uptake of cholesteryl ester. This study investigates the role of EL and SR-BI in the regulation of HDL metabolism in gene knockout mouse models. Methods and Results— We cross-bred EL −/− and SR-BI −/− mice and generated single- and double-null mice. We used biochemical, molecular biology, and nuclear magnetic resonance methods to analyze HDL concentration, composition, and structure. We found that EL and SR-BI display additive effects on HDL with evident gene dosage effects, but their mechanisms to regulate HDL concentration and composition are different. Whereas the elevated HDL cholesterol level in EL −/− mice is associated with increased phospholipid content in HDL particles, SR-BI −/− mice display markedly enlarged HDL particles shifted to larger subclasses with a phospholipid content similar to that of wild-type mice. Furthermore, absence of EL is associated with a 40% to 50% inhibition and absence of SR-BI, a ≈90% inhibition of endogenous lecithin cholesterol:acyltransferase rate. Conclusions— EL and SR-BI are major genetic determinants of HDL metabolism in vivo, each exercising independent and additive effects on HDL structure and function.