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Nat Med. 2019 Apr;25(4):641-655. doi: 10.1038/s41591-019-0379-5. Epub 2019 Apr 1.

Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer.

Author information

1
Department of Pathology and Molecular Pathology, University and University Hospital Zurich, Zurich, Switzerland.
2
Division of Chronic Inflammation and Cancer, German Cancer Research Center Heidelberg (DKFZ), Heidelberg, Germany.
3
Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany.
4
European Center of Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
5
Institute for Virology, Technische Universität München/Helmholtz Zentrum München, Munich, Germany.
6
Research Unit of Radiation Cytogenetics, Helmholtz Zentrum München, Neuherberg, Germany.
7
Calvin Phoebe & Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
8
Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
9
Department of Microbiology, Immunology & Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
10
Department of Medical Microbiology, University Medical Center, Utrmeecht, the Netherlands.
11
Department of Cardiology and Circulatory Diseases, Internal Medicine Clinic III, Eberhard Karls University Tübingen, Tübingen, Germany.
12
Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
13
Department of Internal Medicine VIII, University Hospital Tübingen, Tübingen, Germany.
14
Department of Physiology I, Institute of Physiology, Eberhard Karls University Tübingen, Tübingen, Germany.
15
Center for Translational Cancer Research (TranslaTUM), Technische Universität München, Munich, Germany.
16
Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
17
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
18
Medical Faculty, University of Heidelberg, Heidelberg, Germany.
19
Institute of Experimental Biomedicine, University Hospital and Rudolf Virchow Center, University of Würzburg, Würzburg, Germany.
20
Hematology, University Hospital and University of Zurich, Zurich, Switzerland.
21
Newcastle Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK.
22
Institute of Molecular Immunology and Experimental Oncology, Technical University of Munich, Munich, Germany.
23
Centre for Liver Research and National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit, Birmingham, UK.
24
Liver Unit, University Hospitals Birmingham NHS Trust, Birmingham, UK.
25
Institute for Cardiovascular Sciences, University of Birmingham, Birmingham, UK.
26
Cancer Cell Biology Programme, Growth Factors, Nutrients and Cancer Group, Spanish National Cancer Research Centre, CNIO, Madrid, Spain.
27
Institute of Neuropathology, Medical Faculty, University of Freiburg, Freiburg, Germany.
28
Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany.
29
Center for NeuroModulation, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
30
Division of Experimental Hematology, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany.
31
DKFZ-ZMBH Alliance, Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH) Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany.
32
Department of Diagnostic and Interventional Radiology, University Hospital of Tübingen, Tübingen, Germany.
33
Department of Cardiovascular Medicine, University Hospital, Eberhard Karls University of Tübingen, Tübingen, Germany.
34
Metabolic Signalling Group, MRC London Institute of Medical Sciences, London, UK.
35
Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK.
36
Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
37
DKFZ Junior Group Metabolism and Stem Cell Plasticity, German Cancer Research Center (DKFZ), Heidelberg, Germany.
38
Nutrient Metabolism and Signalling Lab, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, and Metabolism, Diabetes and Obesity Program, Biomedicine Discovery Institute, Monash University, Clayton, Australia.
39
Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Medicine, Department of Pathology, Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
40
Liver Cancer Translational Research Laboratory, IDIBAPS, Liver Unit, Hospital Clinic, University of Barcelona, Barcelona, Catalonia, Spain.
41
Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain.
42
Institute of Pathology, University Hospital of Basel, Basel, Switzerland.
43
Translational Gastrointestinal Oncology Group, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
44
Department of Pathology and Molecular Pathology, University and University Hospital Zurich, Zurich, Switzerland. achim.weber@usz.ch.
45
Division of Chronic Inflammation and Cancer, German Cancer Research Center Heidelberg (DKFZ), Heidelberg, Germany. heikenwaelder@helmholtz-muenchen.de.
46
Institute for Virology, Technische Universität München/Helmholtz Zentrum München, Munich, Germany. heikenwaelder@helmholtz-muenchen.de.

Abstract

Non-alcoholic fatty liver disease ranges from steatosis to non-alcoholic steatohepatitis (NASH), potentially progressing to cirrhosis and hepatocellular carcinoma (HCC). Here, we show that platelet number, platelet activation and platelet aggregation are increased in NASH but not in steatosis or insulin resistance. Antiplatelet therapy (APT; aspirin/clopidogrel, ticagrelor) but not nonsteroidal anti-inflammatory drug (NSAID) treatment with sulindac prevented NASH and subsequent HCC development. Intravital microscopy showed that liver colonization by platelets depended primarily on Kupffer cells at early and late stages of NASH, involving hyaluronan-CD44 binding. APT reduced intrahepatic platelet accumulation and the frequency of platelet-immune cell interaction, thereby limiting hepatic immune cell trafficking. Consequently, intrahepatic cytokine and chemokine release, macrovesicular steatosis and liver damage were attenuated. Platelet cargo, platelet adhesion and platelet activation but not platelet aggregation were identified as pivotal for NASH and subsequent hepatocarcinogenesis. In particular, platelet-derived GPIbα proved critical for development of NASH and subsequent HCC, independent of its reported cognate ligands vWF, P-selectin or Mac-1, offering a potential target against NASH.

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PMID:
30936549
DOI:
10.1038/s41591-019-0379-5
[Indexed for MEDLINE]
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