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An extrahepatic receptor-associated protein-sensitive mechanism is involved in the metabolism of triglyceride-rich lipoproteins

Author: Vlijmen, B.J.M. van · Rohlmann, A. · Page, S.T. · Bensadoun, A. · Bos, I.S.T. · Berkel, T.J.C. van · Havekes, L.M. · Herz, J.
Type:article
Date:1999
Institution: Gaubius instituut TNO
Source:Journal of Biological Chemistry, 49, 274, 35219-35226
Identifier: 235347
doi: doi:10.1074/jbc.274.49.35219
Keywords: Animals · Binding Sites · Cholesterol · Chylomicrons · Detergents · Gene Transfer Techniques · Heymann Nephritis Antigenic Complex · Immunoblotting · LDL-Receptor Related Protein 1 · Lipase · Lipoprotein Lipase · Liver · Membrane Glycoproteins · Mice · Mice, Transgenic · Polyethylene Glycols · Rats · Receptors, Immunologic · Receptors, LDL · Time Factors · Transfection · Triglycerides

Abstract

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/flox)LDLR(-/-)) 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/flox)LDLR(-/-) 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. Chemicals/CAS: Cholesterol, 57-88-5; Chylomicrons; Detergents; Heymann Nephritis Antigenic Complex; LDL-Receptor Related Protein 1; Lipase, EC 3.1.1.3; Lipoprotein Lipase, EC 3.1.1.34; Membrane Glycoproteins; Polyethylene Glycols; Receptors, Immunologic; Receptors, LDL; Triglycerides; tyloxapol, 25301-02-4