on November 11, 2004
Published online before print November 11, 2004, doi: 10.1161/01.ATV.0000150414.89591.6a
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Submitted on May 22, 2004
Accepted on November 1, 2004
Differential Additive Effects of Endothelial Lipase and Scavenger Receptor-Class B Type I on High-Density Lipoprotein Metabolism in Knockout Mouse Models
Ke Ma ;
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.
* To whom correspondence should be addressed. 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.
Key words: endothelial lipase • scavenger receptor-class B type I • high-density lipoprotein
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