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Journal of Lipid Research, Vol. 46, 1097-1102, June 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Rapid Communication

Triglyceride-rich lipoprotein metabolism in unique VLDL receptor, LDL receptor, and LRP triple-deficient mice

Sonia M. S. Espirito Santo^*,, Patrick C. N. Rensen^1,*,, Jeltje R. Goudriaan^*, André Bensadoun, Niels Bovenschen^*,**, Peter J. Voshol^*,, Louis M. Havekes^*,, and Bart J. M. van Vlijmen^2,*

^* Netherlands Organization for Applied Scientific Research-Quality of Life, Gaubius Laboratory, Leiden, The Netherlands
Departments of General Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands
Endocrinology and Metabolism, Leiden University Medical Center, Leiden, The Netherlands
Division of Nutritional Sciences, Cornell University, Ithaca, NY
^** Department of Plasma Proteins, Sanquin Research at Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, Amsterdam, The Netherlands
Departments of Cardiology, Leiden University Medical Center, Leiden, The Netherlands

Published, JLR Papers in Press, March 16, 2005. DOI 10.1194/jlr.C500007-JLR200

² Present address of B. J. M. van Vlijmen: Department of Hematology, C2-R, Hemostasis and Thrombosis Research Center, Leiden University Medical Center, Leiden, The Netherlands.

¹ To whom correspondence should be addressed. e-mail: p.c.n.rensen{at}lumc.nl

ABSTRACT

The very low density lipoprotein receptor (VLDLR), low density lipoprotein receptor (LDLR), and low density lipoprotein receptor-related protein (LRP) are the three main apolipoprotein E-recognizing endocytic receptors involved in the clearance of triglyceride (TG)-rich lipoproteins from plasma. Whereas LDLR deficiency in mice results in the accumulation of plasma LDL-sized lipoproteins, VLDLR or LRP deficiency alone only minimally affects plasma lipoproteins. To investigate the combined effect of the absence of these receptors on TG-rich lipoprotein levels, we have generated unique VLDLR, LDLR, and LRP triple-deficient mice. Compared with wild-type mice, these mice markedly accumulated plasma lipids and lipases. These mice did not show aggravated hyperlipidemia compared with LDLR and LRP double-deficient mice, but plasma TG was increased after high-fat diet feeding. In addition, these mice showed a severely decreased postprandial TG clearance typical of VLDLR-deficient (VLDLR^–/–) mice.

Collectively, although VLDLR deficiency in LRP^– and LDLR^–/– mice does not aggravate hyperlipidemia, these triple-deficient mice represent a unique model of markedly delayed TG clearance on a hyperlipidemic background.

Abbreviations: apoE, apolipoprotein E; AUC, area under the curve; HFD, high-fat diet; LDLR, low density lipoprotein receptor; LRP, low density lipoprotein receptor-related protein; RAP, receptor-associated protein; TG, triglyceride; VLDLR, very low density lipoprotein receptor

Supplementary key words apolipoprotein E • hepatic lipase • hyperlipidemia • lipid metabolism • lipoprotein lipase • postprandial response • transgenic mice • very low density lipoproteins • very low density lipoprotein receptor • low density lipoprotein receptor • low density lipoprotein receptor-related protein

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