An extrahepatic receptor-associated protein-sensitive mechanism is involved in the metabolism of triglyceride-rich lipoproteins.
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.
van Vlijmen
B J
BJ
Department of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden 2300 RA, The Netherlands.
Rohlmann
A
A
Page
S T
ST
Bensadoun
A
A
Bos
I S
IS
van Berkel
T J
TJ
Havekes
L M
LM
Herz
J
J
D000818:Animals; D001665:Binding Sites; D002784:Cholesterol / Q000097:blood; D002914:Chylomicrons / Q000378:metabolism; D003902:Detergents / Q000494:pharmacology; D018014:Gene Transfer Techniques; D026541:Heymann Nephritis Antigenic Complex; D015151:Immunoblotting; D008049:Lipase / Q000097:blood; D008071:Lipoprotein Lipase / Q000097:blood; D008099:Liver / Q000378:metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D011092:Polyethylene Glycols / Q000494:pharmacology; D051381:Rats; D011971:Receptors, Immunologic / Q000172:deficiency; D011973:Receptors, LDL / Q000172:deficiency / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D014280:Triglycerides / Q000378:metabolism*
D002914:Chylomicrons; D003902:Detergents; D026541:Heymann Nephritis Antigenic Complex; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; D011973:Receptors, LDL; D014280:Triglycerides; D011092:Polyethylene Glycols; D002784:Cholesterol; D008049:Lipase; D008071:Lipoprotein Lipase; C016811:tyloxapol