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Journal of Lipid Research, Vol. 49, 1553-1561, July 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

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

Lihui Hu^1,*,, Caroline C. van der Hoogt^1,*,, Sonia M. S. Espirito Santo^*,, Ruud Out, Kyriakos E. Kypreos^**, Bart J. M. van Vlijmen^*,, Theo J. C. Van Berkel, Johannes A. Romijn, Louis M. Havekes^*,,, Ko Willems van Dijk^, and Patrick C. N. Rensen^2,*,

^* Netherlands Organization for Applied Scientific Research-Quality of Life, Gaubius Laboratory, 2301 CE Leiden, The Netherlands
Department of General Internal Medicine, Endocrinology and Metabolic Diseases, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, 2300 RA Leiden, The Netherlands
^** Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118
Department of Cardiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
Department of Human Genetics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands

This work was performed in the framework of the Leiden Center for Cardiovascular Research LUMC-TNO and was supported by the Leiden University Medical Center (Gisela Thier Fellowship to P.C.N.R.), the Netherlands Organization for Scientific Research (NWO Grant 908-02-097 and NWO VIDI Grant 917.36.351 to P.C.N.R.), and the Netherlands Heart Foundation (NHS Grant 2003B136 to P.C.N.R.).

Published, JLR Papers in Press, March 26, 2008.

¹ These authors contributed equally to this study.

² To whom correspondence should be addressed: e-mail: p.c.n.rensen{at}lumc.nl

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.

Supplementary key words lipoprotein lipase • low density lipoprotein receptor • very low density lipoprotein receptor • low density lipoprotein receptor-related protein • triglyceride-rich emulsion particles • transgenic mice • adenovirus-mediated gene transfer • apolipoprotein E

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