TY - JOUR
T1 - Differential additive effects of endothelial lipase and scavenger receptor-class B type I on high-density lipoprotein metabolism in knockout mouse models
AU - Ma, Ke
AU - Forte, Trudy
AU - Otvos, James D.
AU - Chan, Lawrence
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2005/1
Y1 - 2005/1
N2 - 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.
AB - 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.
KW - Endothelial lipase
KW - High-density lipoprotein
KW - Scavenger receptor-class B type I
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U2 - 10.1161/01.ATV.0000150414.89591.6a
DO - 10.1161/01.ATV.0000150414.89591.6a
M3 - Article
C2 - 15539616
AN - SCOPUS:11144240602
VL - 25
SP - 149
EP - 154
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
SN - 1079-5642
IS - 1
ER -