Differential additive effects of endothelial lipase and scavenger receptor-class B type I on high-density lipoprotein metabolism in knockout mouse models.
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.


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 approximately 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.
Ma
Ke
K
Section of Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, and St. Luke's Episcopal Hospital, Houston, Tex 77030, USA.
Forte
Trudy
T
Otvos
James D
JD
Chan
Lawrence
L
D000818:Animals; D016632:Apolipoprotein A-I / Q000097:blood; D001057:Apolipoproteins E / Q000097:blood; D001947:Breeding; D018955:CD36 Antigens; D004727:Endothelium / Q000201:enzymology*; D008049:Lipase / Q000096:biosynthesis / Q000172:deficiency* / Q000378:metabolism*; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000737:chemistry; D008075:Lipoproteins, HDL / Q000737:chemistry / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000378:metabolism; D049294:Phospholipid Transfer Proteins / Q000378:metabolism; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000172:deficiency* / Q000378:metabolism*; D051116:Receptors, Scavenger
D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; D018955:CD36 Antigens; D008055:Lipids; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D008565:Membrane Proteins; D049294:Phospholipid Transfer Proteins; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; C025121:apolipoprotein E-rich HDL; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; D008049:Lipase; C495700:Lipc protein, mouse