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Journal of Lipid Research, Vol. 48, 288-298, February 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Lipoprotein lipase-facilitated uptake of LDL is mediated by the LDL receptor

Britta Loeffler^*, Joerg Heeren, Mareike Blaeser^*, Herbert Radner, Daniel Kayser^*, Birol Aydin^* and Martin Merkel^1,*

^* Third Department of Internal Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany
Department of Biochemistry and Molecular Cell Biology II, University Hospital Hamburg-Eppendorf, Hamburg, Germany
Institute of Pathology, Johannes-Gutenberg-University, Mainz, Germany

Published, JLR Papers in Press, November 7, 2006.

¹ To whom correspondence should be addressed. e-mail: merkel{at}uke.uni-hamburg.de

LPL mediates the uptake of lipoproteins into different cell types independent of its catalytic activity. The mechanism of this process and its physiological relevance are not clear. Taking into account the importance of the endothelial barrier for lipoprotein uptake, in vitro studies with primary aortic endothelial cells from wild-type and low density lipoprotein receptor (LDLR)-deficient (LDLR^–/–) mice were performed. Addition of LPL almost doubled the uptake of LDL into wild-type cells. However, there was virtually no LPL-mediated change of LDL uptake into LDLR^–/– cells. Upregulation of LDLR by lipoprotein-deficient serum/lovastatin in wild-type cells resulted in a 7-fold increase of LPL-mediated LDL uptake. Uptake of chylomicron remnants was not affected by LDLR expression. In proteoglycan-deficient cells, LPL did not increase the uptake of lipoproteins. The physiological relevance of this pathway was studied in mice that were both LDLR^–/– and transgenic for catalytically inactive LPL in muscle. In the presence of LDLR, inactive LPL reduced LDL cholesterol significantly (13–24%). In the absence of LDLR, LDL cholesterol was not affected by transgenic LPL. Metabolic studies showed that in the presence of LDLR, LPL increased the muscular uptake of LDL by 77%. In the absence of LDLR, transgenic LPL did not augment LDL uptake. Chylomicron uptake was not affected by the LDLR genotype. We conclude that LPL-mediated cellular uptake of LDL, but not of chylomicrons, is dependent on the presence of both LDLR and proteoglycans.

Supplementary key words lipids • cholesterol • atherosclerosis • endothelium • transport • low density lipoprotein

Abbreviations: ATCC, American Type Culture Collection; FCS, fetal calf serum; HSPG, heparan sulfate proteoglycan; LDLR, low density lipoprotein receptor; LPDS, lipoprotein-deficient serum; LRP1, LDLR-related protein 1; Mck-N-LPL, transgenic expression of inactive lipoprotein lipase in muscle; TG, triglyceride; THL, tetrahydrolipostatin; VLDLR, very low density lipoprotein receptor

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