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Insulin stimulates hepatic low density lipoprotein receptor-related protein 1 (LRP1) to increase postprandial lipoprotein clearance

  • Alexander Laatsch
    Correspondence
    Corresponding author at: IBMII: Molekulare Zellbiologie, Universitätsklinikum Hamburg-Eppendorf, 20246 Hamburg, Germany. Tel.: +49 40 42803 3917; fax: +49 40 42803 4592.
    Affiliations
    Department of Biochemistry and Molecular Biology II: Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
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  • Martin Merkel
    Affiliations
    III. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
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  • Philippa J. Talmud
    Affiliations
    Division of Cardiovascular Genetics, Department of Medicine, Royal Free and University College Medical School, 5 University Street, London WC1E 6JF, UK
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  • Thomas Grewal
    Affiliations
    Faculty of Pharmacy, The University of Sydney, Sydney, NSW 2006, Australia
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  • Ulrike Beisiegel
    Affiliations
    Department of Biochemistry and Molecular Biology II: Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
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  • Joerg Heeren
    Correspondence
    Corresponding author at: IBMII: Molekulare Zellbiologie, Universitätsklinikum Hamburg-Eppendorf, 20246 Hamburg, Germany. Tel.: +49 40 42803 4745; fax: +49 40 42803 4592.
    Affiliations
    Department of Biochemistry and Molecular Biology II: Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
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      Abstract

      Background

      While the role of insulin in glucose uptake and its aberration in diabetes are well established, the effect of insulin on lipoprotein clearance in the postprandial phase is not yet fully understood. The dietary lipids are carried in chylomicron remnants (CR) which are taken up into the liver mainly via LDLR-related protein 1 (LRP1). In this study, the effect of insulin on LRP1-mediated hepatic CR uptake was investigated.

      Methods

      The study was based on determining the subcellular localisation of LRP1 by subcellular fractionation and immunofluorescence microscopy and correlating those findings with the hepatic uptake of fluorescently or radioactively labelled LRP1-specific ligands and CR in hepatoma cells, primary hepatocytes and mouse models.

      Results and conclusion

      In vitro and in vivo, insulin stimulated the translocation of hepatic LRP1 from intracellular vesicles to the plasma membrane, which correlates with an increased uptake of LRP1-specific ligands. In wild-type mice, a glucose-induced insulin response increased the hepatic uptake of LRP1 ligands while in leptin-deficient obese mice (ob/ob), which are characterised by hepatic insulin resistance, insulin-inducible LRP1 ligand uptake was abolished. Finally, upon hepatic LRP1 knockdown, insulin no longer significantly enhanced CR uptake into the liver. The insulin-induced LRP1-mediated CR uptake, as demonstrated here, suggests that impaired hepatic LRP1 translocation can contribute to the postprandial lipaemia in insulin resistance.

      Keywords

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