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, Joachim Herz

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)35219-35226
Number of pages8
JournalJournal of Biological Chemistry
Volume274
Issue number49
DOIs
StatePublished - Dec 3 1999

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Metabolism
Lipoproteins
Triglycerides
LDL Receptors
Proteins
Lipoprotein Lipase
VLDL Lipoproteins
Liver
Plasmas
LDL-Receptor Related Proteins
Gene transfer
Lipids
Chylomicrons
Hypertriglyceridemia
Hypercholesterolemia
Lipase
LDL Lipoproteins
Protein Binding
Adenoviridae
Catalyst activity

ASJC Scopus subject areas

  • Biochemistry

Cite this

An extrahepatic receptor-associated protein-sensitive mechanism is involved in the metabolism of triglyceride-rich lipoproteins. / Van Vlijmen, Bart J M; Rohlmann, Astrid; Page, Shallee T.; Bensadoun, André; Bos, I. Sophie T; Van Berkel, Theo J C; Havekes, Louis M.; Herz, Joachim.

In: Journal of Biological Chemistry, Vol. 274, No. 49, 03.12.1999, p. 35219-35226.

Research output: Contribution to journalArticle

Van Vlijmen, BJM, Rohlmann, A, Page, ST, Bensadoun, A, Bos, IST, Van Berkel, TJC, Havekes, LM & Herz, J 1999, 'An extrahepatic receptor-associated protein-sensitive mechanism is involved in the metabolism of triglyceride-rich lipoproteins', Journal of Biological Chemistry, vol. 274, no. 49, pp. 35219-35226. https://doi.org/10.1074/jbc.274.49.35219
Van Vlijmen, Bart J M ; Rohlmann, Astrid ; Page, Shallee T. ; Bensadoun, André ; Bos, I. Sophie T ; Van Berkel, Theo J C ; Havekes, Louis M. ; Herz, Joachim. / An extrahepatic receptor-associated protein-sensitive mechanism is involved in the metabolism of triglyceride-rich lipoproteins. In: Journal of Biological Chemistry. 1999 ; Vol. 274, No. 49. pp. 35219-35226.
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AU - Bensadoun, André

AU - Bos, I. Sophie T

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AU - Herz, Joachim

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