Title
An extrahepatic receptor-associated protein-sensitive mechanism is involved in the metabolism of triglyceride-rich lipoproteins
Author
Gaubius instituut TNO
van Vlijmen, B.J.M.
Rohlmann, A.
Page, S.T.
Bensadoun, A.
Bos, I.S.T.
van Berkel, T.J.C.
Havekes, L.M.
Herz, J.
Publication year
1999
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
Subject
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
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DOI
https://doi.org/10.1074/jbc.274.49.35219
TNO identifier
235347
ISSN
0021-9258
Source
Journal of Biological Chemistry, 274 (274), 35219-35226
Document type
article