The hepatic uptake of VLDL in lrp-ldlr-/-vldlr-/- mice is regulated by LPL activity and involves proteoglycans and SR-BI
article
LPL activity plays an important role in preceding the VLDL remnant clearance via the three major apolipoprotein E (apoE)-recognizing receptors: the LDL receptor (LDLr), LDL receptor-related protein (LRP), and VLDL receptor (VLDLr). The aim of this study was to determine whether LPL activity is also important for VLDL remnant clearance irrespective of these receptors and to determine the mechanisms involved in the hepatic remnant uptake. Administration of an adenovirus expressing LPL (AdLPL) into lrp-ldlr-/-vldlr-/- mice reduced both VLDL-triglyceride (TG) and VLDL-total cholesterol (TC) levels. Conversely, inhibition of LPL by AdAPOC1 increased plasma VLDL-TG and VLDL-TC levels. Metabolic studies with radiolabeled VLDL-like emulsion particles showed that the clearance and hepatic association of their remnants positively correlated with LPL activity. This hepatic association was independent of the bridging function of LPL and HL, since heparin did not reduce the liver association. In vitro studies demonstrated that VLDL-like emulsion particles avidly bound to the cell surface of primary hepatocytes from lrp-ldlr-/-vldlr-/- mice, followed by slow internalization, and involved heparin-releaseable cell surface proteins as well as scavenger receptor class B type I (SR-BI). Collectively, we conclude that hepatic VLDL remnant uptake in the absence of the three classical apoE-recognizing receptors is regulated by LPL activity and involves heparan sulfate proteoglycans and SR-BI. Copyright © 2008 by the American Society for Biochemistry and Molecular Biology, Inc.
Topics
ApolipoproteinDenovirus-mediated gene transferLipoprotein lipaseLow density lipoprotein receptorLow density lipoprotein receptor-related proteinTransgenic miceTriglyceride-rich emulsion particlesVery low density lipoprotein receptorapolipoprotein Ecell surface proteincholesterollow density lipoprotein receptorlow density lipoprotein receptor related proteinproteoglycanproteoheparan sulfatescavenger receptor BItriacylglycerolvery low density lipoproteinvery low density lipoprotein receptorCD36 antigenligandvery low density lipoprotein cholesterolAdenovirusanimal cellanimal experimentanimal tissuecell isolationcell surfacecontrolled studyenzyme activityin vitro studyin vivo studyinternalizationlipid analysisliver cellmousenonhumanprotein expressionregulatory mechanismanimalbloodemulsiongeneticsmetabolismmouse mutantAnimalsAntigens, CD36Cholesterol, VLDLEmulsionsLDL-Receptor Related ProteinsLigandsLipoprotein LipaseLiverMaleMiceMice, KnockoutProteoglycansReceptors, LDL
TNO Identifier
241187
ISSN
00222275
Source
Journal of Lipid Research, 49(7), pp. 1553-1561.
Pages
1553-1561