Scavenger receptor BI-mediated selective uptake is required for the remodeling of high density lipoprotein by endothelial lipase.
Endothelial lipase (EL) is a negative regulator of high density lipoprotein (HDL) cholesterol plasma levels, and scavenger receptor BI (SR-BI) is involved in remodeling of HDL. The present study investigates the requirement of SR-BI for the effects of EL-mediated phospholipid hydrolysis on HDL metabolism in vivo. In vitro, selective uptake from EL-modified HDL was 129% higher than selective uptake from control HDL in SR-BI-overexpressing cells (p=0.01). In vivo overexpression of human EL by means of recombinant adenovirus decreased HDL plasma levels significantly (p<0.01). Fast protein liquid chromatography analysis and agarose gel electrophoresis revealed that EL expression resulted in the generation of small pre-beta HDL particles in wild-type mice, whereas in SR-BI-/- mice small HDL were preferentially removed. In kinetic experiments the fractional catabolic rate (FCR) of HDL cholesteryl ester increased by 110% (p<0.001), and the FCR of HDL apolipoproteins increased by 64% (p<0.001) in response to EL overexpression in wild-type mice. In SR-BI-/- mice a similar increase in the HDL apolipoprotein FCR occurred (p<0.001); however, there was no further increase in HDL cholesteryl ester catabolism. The apparent whole body selective uptake was increased 3-fold by EL in wild-type mice (p<0.001), whereas there was no selective uptake in SR-BI knock-out mice. EL overexpression increased hepatic selective uptake as well as holoparticle uptake (each p<0.01) in wild-type mice, whereas in SR-BI knock-out mice only holoparticle uptake increased (p<0.01). Our results indicate that SR-BI-mediated selective uptake of HDL cholesteryl ester is essential for the remodeling of large alpha-migrating HDL particles by EL.
Nijstad
Niels
N
Center for Liver, Digestive and Metabolic Diseases, Laboratory of Pediatrics, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands.
Wiersma
Harmen
H
Gautier
Thomas
T
van der Giet
Markus
M
Maugeais
Cyrille
C
Tietge
Uwe J F
UJ
D000818:Animals; D045744:Cell Line, Tumor; D002788:Cholesterol Esters / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008049:Lipase / Q000235:genetics / Q000378:metabolism*; D008075:Lipoproteins, HDL / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D051122:Scavenger Receptors, Class B / Q000235:genetics / Q000378:metabolism*
D002788:Cholesterol Esters; C059714:HDL cholesteryl ester; D008075:Lipoproteins, HDL; C495124:SCARB1 protein, human; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; C410382:LIPG protein, human; D008049:Lipase; C498741:Lipg protein, mouse