Trapping of oxidized LDL in lysosomes of Kupffer cells is a trigger for hepatic inflammation

Authors

  • Veerle Bieghs,

    1. Department of Molecular Genetics, Maastricht University, Maastricht, the Netherlands
    2. Department of Internal Medicine, University Hospital (RWTH), Aachen, Germany
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  • Sofie M. A. Walenbergh,

    1. Department of Molecular Genetics, Maastricht University, Maastricht, the Netherlands
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  • Tim Hendrikx,

    1. Department of Molecular Genetics, Maastricht University, Maastricht, the Netherlands
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  • Patrick J. van Gorp,

    1. Department of Molecular Genetics, Maastricht University, Maastricht, the Netherlands
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  • Fons Verheyen,

    1. Department of Electron Microscopy Unit, CRISP, Department of Molecular Cell Biology, Maastricht University, Maastricht, the Netherlands
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  • Steven W. Olde Damink,

    1. Department of General Surgery, Maastricht University, Maastricht, the Netherlands
    2. Department of HPB and Liver Transplantation Surgery, UCL Institute for Liver and Digestive Health, University College London Medical School, Royal Free Campus, London, UK
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  • Ad A. Masclee,

    1. Department of Internal Medicine, Division of Gastroenterology and Hepatology, Maastricht University Medical Centre (MUMC), Maastricht, the Netherlands
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  • Ger H. Koek,

    1. Department of Internal Medicine, Division of Gastroenterology and Hepatology, Maastricht University Medical Centre (MUMC), Maastricht, the Netherlands
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  • Marten H. Hofker,

    1. Department of Pathology & Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
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  • Christoph J. Binder,

    1. Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
    2. Center for Molecular Medicine, Austrian Academy of Sciences, Vienna, Austria
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  • Ronit Shiri-Sverdlov

    Corresponding author
    • Department of Molecular Genetics, Maastricht University, Maastricht, the Netherlands
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Correspondence

Ronit Shiri-Sverdlov, Department of Molecular Genetics, Maastricht University, P.O. Box 616, 6200 MD Maastricht, the Netherlands

Tel: +31 43 388 1746

Fax: +31 43 388 4574

e-mail: r.sverdlov@maastrichtuniversity.nl

Abstract

Background & Aims

Non-alcoholic steatohepatitis (NASH) is characterized by steatosis and inflammation. The transition from steatosis towards NASH represents a key step in pathogenesis, as it will set the stage for further severe liver damage. Under normal conditions, lipoproteins that are endocytosed by Kupffer cells (KCs) are easily transferred from the lysosomes into the cytoplasm. Oxidized LDL (oxLDL) that is taken up by the macrophages in vitro is trapped within the lysosomes, while acetylated LDL (acLDL) is leading to normal lysosomal hydrolysis, resulting in cytoplasmic storage. We have recently demonstrated that hepatic inflammation is correlated with lysosomal trapping of lipids. So far, a link between lysosomal trapping of oxLDL and inflammation was not established. We hypothesized that lysosomal trapping of oxLDL in KCs will lead to hepatic inflammation.

Methods

Ldlr−/− mice were injected with LDL, acLDL and oxLDL and sacrificed after 2, 6 and 24 h.

Results

Electron microscopy of KCs demonstrated that after oxLDL injection, small lipid inclusions were present inside the lysosomes after all time points and were mostly pronounced after 6 and 24 h. In contrast, no lipid inclusions were present inside KCs after LDL or acLDL injection. Hepatic expression of several inflammatory genes and scavenger receptors was higher after oxLDL injections compared with LDL or acLDL.

Conclusions

These data suggest that trapping of oxLDL inside lysosomes of KCs in vivo is causally linked to increased hepatic inflammatory gene expression. Our novel observations provide new bases for prevention and treatment of NASH.

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