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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 VlijmenDagger §, Astrid Rohlmann, Shallee T. Pageparallel , André Bensadounparallel , I. Sophie T. BosDagger §, Theo J. C. van BerkelDagger , Louis M. Havekes§**, and Joachim Herz

From the Dagger  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 parallel  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+LRPflox/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+LRPflox/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 (Kd = 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.

Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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