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The hepatic uptake of VLDL in lrp-ldlr-/-vldlr-/- mice is regulated by LPL activity and involves proteoglycans and SR-BI

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Author: Hu, L. · Hoogt, C.C. van der · Espirito Santo, S.M.S. · Out, R. · Kypreos, K.E. · Vlijmen, B.J.M. van · Berkel, T.J.C. van · Romijn, J.A. · Havekes, L.M. · Dijk, K.W. van · Rensen, P.C.N.
Type:article
Date:2008
Institution: TNO Kwaliteit van Leven
Source:Journal of Lipid Research, 7, 49, 1553-1561
Identifier: 241187
doi: doi:10.1194/jlr.M800130-JLR200
Keywords: Biology · Apolipoprotein · Denovirus-mediated gene transfer · Lipoprotein lipase · Low density lipoprotein receptor · Low density lipoprotein receptor-related protein · Transgenic mice · Triglyceride-rich emulsion particles · Very low density lipoprotein receptor · apolipoprotein E · cell surface protein · cholesterol · lipoprotein lipase · low density lipoprotein receptor · low density lipoprotein receptor related protein · proteoglycan · proteoheparan sulfate · scavenger receptor BI · triacylglycerol · very low density lipoprotein · very low density lipoprotein receptor · CD36 antigen · ligand · very low density lipoprotein cholesterol · Adenovirus · animal cell · animal experiment · animal tissue · article · cell isolation · cell surface · controlled study · enzyme activity · in vitro study · in vivo study · internalization · lipid analysis · liver cell · male · mouse · nonhuman · priority journal · protein expression · regulatory mechanism · animal · blood · emulsion · genetics · liver · metabolism · mouse mutant · Animals · Antigens, CD36 · Cholesterol, VLDL · Emulsions · LDL-Receptor Related Proteins · Ligands · Lipoprotein Lipase · Liver · Male · Mice · Mice, Knockout · Proteoglycans · Receptors, LDL · Healthy for Life · Healthy Living

Abstract

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.