Abstract 3729: Scavenger Receptor Bi (sr-bi)-mediated Selective Uptake Is Required For The Remodelling Of Hdl By Endothelial Lipase
Objectives Endothelial lipase (EL) is a negative regulator of HDL cholesterol plasma levels, and scavenger receptor BI (SR-BI) is involved in remodelling of HDL. The present study investigates the requirement of SR-BI for the effects of EL-mediated phospholipid hydrolysis on HDL metabolism in vivo.
Methods and Results 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). FPLC analysis and non-denaturing gel electrophoresis revealed that EL expression resulted in the generation of small HDL particles in wild-type mice, while in SR-BI−/− mice small HDL were preferentially removed. In kinetic experiments the fractional catabolic rate (FCR) of HDL cholesteryl ester (CE) increased by 110% (p<0.001) and the FCR of HDL apolipoproteins 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, no further increase in HDL CE catabolism. The apparent whole body selective uptake was increased 3-fold by EL in wild-type mice (p<0.001), while there was no selective uptake in SR-BI ko mice. EL overexpression increased hepatic selective uptake as well as holoparticle uptake (each p<0.01) in wild-type mice, while in SR-BI ko mice only holoparticle uptake increased (p<0.01).
Conclusions Our results indicate that SR-BI-mediated selective uptake of HDL cholesteryl ester is essential for the remodelling of large alpha-migrating HDL particles by EL.