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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:149.)
© 2005 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

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

Ke Ma; Trudy Forte; James D. Otvos; Lawrence Chan

From the Section of Endocrinology and Metabolism (K.M., L.C.), Departments of Medicine and Molecular & Cellular Biology, Baylor College of Medicine, and St. Luke’s Episcopal Hospital, Houston, Tex; Lawrence Berkeley National Laboratory (T.F.), Berkeley, Calif; and LipoScience (J.D.O.), Raleigh, NC.

Correspondence to Lawrence Chan, Division of Endocrinology & Metabolism, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. E-mail lchan{at}bcm.tmc.edu

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.

We created EL and SR-BI single- and double-null mice and compared their effects on HDL concentration, composition, and structure. We demonstrated that EL and SR-BI display additive effects on plasma HDL in vivo with evident gene dosage effects. The 2 genes use different mechanisms to regulate HDL concentration and composition.

Key Words: endothelial lipase • scavenger receptor-class B type I • high-density lipoprotein

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