Scavenger Receptor BI-mediated Selective Uptake Is Required for the Remodeling of High Density Lipoprotein by Endothelial Lipase

Cyrille Maugeais,Harmen Wiersma,Thomas Gautier,Niels Nijstad,Uwe J.F. Tietge,Markus van der Giet

doi:10.1074/jbc.m807683200

Abstract

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.

Highlights

Plasma levels of high density lipoprotein (HDL)3 cholesterol and its major apolipoprotein apoA-I are inversely correlated with the risk of atherosclerotic cardiovascular disease, a major
endothelial lipase (EL) Modification Increases scavenger receptor BI (SR-BI)-mediated Selective Uptake of HDL Cholesteryl Ester in Vitro—To test the hypothesis that cholesteryl ester within EL-modified HDL are more susceptible toward SR-BI-mediated selective uptake, HDL was isolated from AdNull as well as AdhEL injected wild-type mice, radiolabeled with 125I-tyramine cellobiose and 3H-cholesteryl ether, and incubated in vitro with LdlA cells stably transfected with a murine SR-BI cDNA
AdhEL injection resulted in a 55% decrease in plasma cholesterol levels in SR-BI knock-out mice compared with SR-BI knock-out mice receiving the control virus AdNull (229 Ϯ 12 versus 104 Ϯ 18 mg/dl, p Ͻ 0.001; Fig. 2A)

Summary

Introduction

Plasma levels of high density lipoprotein (HDL) cholesterol and its major apolipoprotein apoA-I are inversely correlated with the risk of atherosclerotic cardiovascular disease, a major. Overexpression of EL resulted in significantly decreased HDL cholesterol plasma levels by increasing the catabolic rate of HDL apolipoproteins [8], whereas inhibition [10] or genetic ablation [9, 11] of EL raised plasma HDL cholesterol. Another key determinant of HDL remodeling and catabolism is the scavenger receptor BI (SR-BI) [12, 13].

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