We have shown previously that human apolipoprotein (apo)C1 transgenic mice exhibit hyperlipidaemia, due primarily to an impaired clearance of very-low-density lipoprotein (VLDL) particles from the circulation. In the absence of at least the low-density-lipoprotein receptor (LDLR), it was shown that APOC1 overexpression in transgenic mice inhibited the hepatic uptake of VLDL via the LDLR-related protein. In the present study, we have now examined the effect of apoC1 on the binding of lipoproteins to both the VLDL receptor (VLDLR) and the LDLR. The binding specificity of the VLDLR and LDLR for apoC1-enriched lipoprotein particles was examined in vivo through adenovirus-mediated gene transfer of the VLDLR and the LDLR [giving rise to adenovirus-containing (Ad)-VLDLR and Ad-LDLR respectively] in APOC1 transgenic mice, LDLR-deficient (LDLR-/-) mice and wild-type mice. Remarkably, Ad-VLDLR treatment did not reduce hyperlipidaemia in transgenic mice overexpressing human APOC1, irrespective of both the level of transgenic expression and the presence of the LDLR, whereas Ad-VLDLR treatment did reverse hyperlipidaemia in LDLR-/- and wild-type mice. On the other hand, Ad-LDLR treatment strongly decreased plasma lipid levels in these APOC1 transgenic mice. These results suggest that apoC1 inhibits the clearance of lipoprotein particles via the VLDLR, but not via the LDLR. This hypothesis is corroborated by in vitro binding studies. Chinese hamster ovary (CHO) cells expressing the VLDLR (CHO-VLDLR) or LDLR (CHO-LDLR) bound less APOC1 transgenic VLDL than wild-type VLDL. Intriguingly, however, enrichment with apoE enhanced dose-dependently the binding of wild-type VLDL to CHO-VLDLR cells (up to 5-fold), whereas apoE did not enhance the binding of APOC1 transgenic VLDL to these cells. In contrast, for binding to CHO-LDLR cells, both wild-type and APOC1 transgenic VLDL were stimulated upon enrichment with apoE. From these studies, we conclude that apoC1 specifically inhibits the apoE-mediated binding of triacylglycerol-rich lipoprotein particles to the VLDLR, whereas apoC1-enriched lipoproteins can still bind to the LDLR. The variability in specificity of these lipoprotein receptors for apoC1-containing lipoprotein particles provides further evidence for a regulatory role of apoC1 in the delivery of lipoprotein constituents to different tissues on which these receptors are located.
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Research Article|
February 22 1999
Reversal of hyperlipidaemia in apolipoprotein C1 transgenic mice by adenovirus-mediated gene delivery of the low-density-lipoprotein receptor, but not by the very-low-density-lipoprotein receptor
Miek C. JONG;
Miek C. JONG
*TNO-Prevention and Health, Gaubius Laboratory, 2301 CE Leiden, The Netherlands
║Centre du Médicament et Centre de Médicine Préventive, BP7 54501 Nancy, France
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Ko WILLEMS Van DIJK;
Ko WILLEMS Van DIJK
†MGC-Department of Human Genetics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
║Centre du Médicament et Centre de Médicine Préventive, BP7 54501 Nancy, France
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Vivian E.H. DAHLMANS;
Vivian E.H. DAHLMANS
*TNO-Prevention and Health, Gaubius Laboratory, 2301 CE Leiden, The Netherlands
║Centre du Médicament et Centre de Médicine Préventive, BP7 54501 Nancy, France
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Hans Van Der BOOM;
Hans Van Der BOOM
*TNO-Prevention and Health, Gaubius Laboratory, 2301 CE Leiden, The Netherlands
║Centre du Médicament et Centre de Médicine Préventive, BP7 54501 Nancy, France
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Kunisha KOBAYASHI;
Kunisha KOBAYASHI
‡Departments of Cell Biology and Medicine, Baylor College of Medicine, Children's Nutrition Research Center, Houston, Texas 77030, U.S.A.
§USDA/ARS Children's Nutrition Research Center, Houston, Texas 77030, U.S.A.
║Centre du Médicament et Centre de Médicine Préventive, BP7 54501 Nancy, France
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Kazuhito OKA;
Kazuhito OKA
‡Departments of Cell Biology and Medicine, Baylor College of Medicine, Children's Nutrition Research Center, Houston, Texas 77030, U.S.A.
║Centre du Médicament et Centre de Médicine Préventive, BP7 54501 Nancy, France
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Gerard SIEST;
Gerard SIEST
§USDA/ARS Children's Nutrition Research Center, Houston, Texas 77030, U.S.A.
║Centre du Médicament et Centre de Médicine Préventive, BP7 54501 Nancy, France
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Lawrence CHAN;
Lawrence CHAN
‡Departments of Cell Biology and Medicine, Baylor College of Medicine, Children's Nutrition Research Center, Houston, Texas 77030, U.S.A.
║Centre du Médicament et Centre de Médicine Préventive, BP7 54501 Nancy, France
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Marten H. HOFKER;
Marten H. HOFKER
†MGC-Department of Human Genetics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
║Centre du Médicament et Centre de Médicine Préventive, BP7 54501 Nancy, France
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Louis M. HAVEKES
Louis M. HAVEKES
1
*TNO-Prevention and Health, Gaubius Laboratory, 2301 CE Leiden, The Netherlands
¶Departments of Cardiology and Internal Medicine, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
║Centre du Médicament et Centre de Médicine Préventive, BP7 54501 Nancy, France
1To whom correspondence should be addressed (e-mail LM.HAVEKES@PG.TNO.NL).
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Biochem J (1999) 338 (2): 281–287.
Article history
Received:
May 01 1998
Revision Received:
October 22 1998
Accepted:
November 20 1998
Citation
Miek C. JONG, Ko WILLEMS Van DIJK, Vivian E.H. DAHLMANS, Hans Van Der BOOM, Kunisha KOBAYASHI, Kazuhito OKA, Gerard SIEST, Lawrence CHAN, Marten H. HOFKER, Louis M. HAVEKES; Reversal of hyperlipidaemia in apolipoprotein C1 transgenic mice by adenovirus-mediated gene delivery of the low-density-lipoprotein receptor, but not by the very-low-density-lipoprotein receptor. Biochem J 1 March 1999; 338 (2): 281–287. doi: https://doi.org/10.1042/bj3380281
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