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J Biol Chem, Vol. 274, Issue 49, 35219-35226, December 3, 1999

An Extrahepatic Receptor-associated Protein-sensitive Mechanism Is Involved in the Metabolism of Triglyceride-rich Lipoproteins

Bart J. M. van Vlijmen^§, Astrid Rohlmann^¶, Shallee T. Page, André Bensadoun, I. Sophie T. Bos^§, Theo J. C. van Berkel, Louis M. Havekes^§**, and Joachim Herz^¶

From the  Department of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden 2300 RA, The Netherlands, ^§ TNO Prevention and Health, Gaubius Laboratory, Leiden 2300 RA, The Netherlands, the ^¶ Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75235, the  Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853, and ^** Departments of Cardiology and Internal Medicine, Leiden University Medical Center, Leiden 2300 RA, The Netherlands

We have used adenovirus-mediated gene transfer in mice to investigate low density lipoprotein receptor (LDLR) and LDLR-related protein (LRP)-independent mechanisms that control the metabolism of chylomicron and very low density lipoprotein (VLDL) remnants in vivo. Overexpression of receptor-associated protein (RAP) in mice that lack both LRP and LDLR (MX1cre⁺LRP^flox/floxLDLR^/) in their livers elicited a marked hypertriglyceridemia in addition to the pre-existing hypercholesterolemia in these animals, resulting in a shift in the distribution of plasma lipids from LDL-sized lipoproteins to large VLDL-sized particles. This dramatic increase in plasma lipids was not due to a RAP-mediated inhibition of a unknown hepatic high affinity binding site involved in lipoprotein metabolism, because no RAP binding could be detected in livers of MX1cre⁺LRP^flox/floxLDLR^/ mice using both membrane binding studies and ligand blotting experiments. Remarkably, RAP overexpression also resulted in a 7-fold increase (from 13.6 to 95.6 ng/ml) of circulating, but largely inactive, lipoprotein lipase (LPL). In contrast, plasma hepatic lipase levels and activity were unaffected. In vitro studies showed that RAP binds to LPL with high affinity (K_d = 5 nM) but does not affect its catalytic activity, in vitro or in vivo. Our findings suggest that an extrahepatic RAP-sensitive process that is independent of the LDLR or LRP is involved in metabolism of triglyceride-rich lipoproteins. There, RAP may affect the functional maturation of LPL, thus causing the accumulation of triglyceride-rich lipoproteins in the circulation.

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