Z Gastroenterol 2019; 57(01): e47-e48
DOI: 10.1055/s-0038-1677172
3. Metabolism (incl. NAFLD)
Georg Thieme Verlag KG Stuttgart · New York

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

M Malehmir
1   Department of Pathology and Molecular Pathology, University and University Hospital Zurich, Zurich, Switzerland
,
D Pfister
2   Division of Chronic Inflammation and Cancer, German Cancer Research Center Heidelberg (DKFZ), Heidelberg, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
,
S Gallage
2   Division of Chronic Inflammation and Cancer, German Cancer Research Center Heidelberg (DKFZ), Heidelberg, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
,
M Szydlowska
2   Division of Chronic Inflammation and Cancer, German Cancer Research Center Heidelberg (DKFZ), Heidelberg, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
,
D Inverso
3   Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
,
E Kotsiliti
2   Division of Chronic Inflammation and Cancer, German Cancer Research Center Heidelberg (DKFZ), Heidelberg, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
4   Institute for Virology, Technische Universität München/Helmholtz Zentrum München, Munich, Germany
,
V Leone
2   Division of Chronic Inflammation and Cancer, German Cancer Research Center Heidelberg (DKFZ), Heidelberg, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
5   Research Unit of Radiation Cytogenetics, Helmholtz Zentrum München, Neuherberg Germany
,
M Peiseler
6   Calvin Phoebe & Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
7   Department of Physiology and Pharmacology Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
,
BGJ Surewaard
6   Calvin Phoebe & Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
7   Department of Physiology and Pharmacology Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
9   Department of Medical Microbiology, University Medical Center, Utrecht, the Netherlands.
,
D Rath
10   Department of Cardiology and Circulatory Diseases, Internal Medicine Clinic III, Eberhard Karls University Tübingen, Tübingen, Germany
,
M Prinz
11   Institute of Neuropathology, Medical Faculty, University of Freiburg, Freiburg, Germany
12   BIOSS Centre for Biological Signalling Studies, University of Freiburg, Germany
13   CIBSS Centre for Integrative Biological Signalling Studies, University of Freiburg, Germany
,
H Augustin
3   Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
14   Department of Vascular Biology and Tumor Angiogenesis, Medical Faculty Mannheim (CBTM), Heidelberg University, Mannheim, Germany.
,
JM Llovet
15   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, USA
16   Liver Cancer Translational Research Laboratory, IDIBAPS, Liver Unit, Hospital Clinic, University of Barcelona, Barcelona, Catalonia, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain
,
R Pinyol
16   Liver Cancer Translational Research Laboratory, IDIBAPS, Liver Unit, Hospital Clinic, University of Barcelona, Barcelona, Catalonia, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain
,
F Tacke
17   Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
,
R Rad
18   Center for Translational Cancer Research (TranslaTUM), Technische Universität München, 81675 Munich, Germany
19   Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
20   German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
,
N Djouder
21   Cancer Cell Biology Programme, Growth Factors, Nutrients and Cancer Group, Spanish National Cancer Research Centre, CNIO, Madrid, Spain.
,
P Kubes
6   Calvin Phoebe & Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
7   Department of Physiology and Pharmacology Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
8   Department of Microbiology, Immunology & Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
,
PA Knolle
22   Institute of Molecular Immunology and Experimental Oncology, Technical University of Munich, Ismaningerstraße 22, 81675 Munich, Germany
,
K Unger
5   Research Unit of Radiation Cytogenetics, Helmholtz Zentrum München, Neuherberg Germany
,
L Zender
23   Department of Internal Medicine VIII, University Hospital Tübingen, 72076 Tübingen, Germany
24   Department of Physiology I, Institute of Physiology, Eberhard Karls University Tübingen, 72076 Tübingen, Germany
25   Translational Gastrointestinal Oncology Group, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
,
B Nieswandt
26   Institute of Experimental Biomedicine, University Hospital and Rudolf Virchow Center, University of Würzburg, Würzburg, Germany
,
M Gawaz
10   Department of Cardiology and Circulatory Diseases, Internal Medicine Clinic III, Eberhard Karls University Tübingen, Tübingen, Germany
,
A Weber
1   Department of Pathology and Molecular Pathology, University and University Hospital Zurich, Zurich, Switzerland
,
M Heikenwälder
2   Division of Chronic Inflammation and Cancer, German Cancer Research Center Heidelberg (DKFZ), Heidelberg, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
4   Institute for Virology, Technische Universität München/Helmholtz Zentrum München, Munich, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
04 January 2019 (online)

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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 murine/human NASH, but not in steatosis or steatotic, insulin resistance. Antiplatelet therapy (APT – Aspirin/Clopidogrel; Ticagrelor) but not NSAIDs (Sulindac) prevented NASH and subsequent HCC development. Intravital microscopy showed that efficient liver colonization by platelets depends primarily on Kupffer cells at early and late stages of NASH, involving hyaluronan-CD44 binding. APT reduced intrahepatic platelet-accumulation and frequency of platelet-immune cell interaction, thereby limiting hepatic immune-cell trafficking. Consequently, cytokine/chemokine release, macrovesicular steatosis and liver damage were attenuated. Analyses of distinct animal models (e.g. Nbeal2-/-, Itga2b-/-, Gp6-/-) identified platelet-cargo, platelet-adhesion and platelet-activation but not platelet-aggregation as pivotal for NASH and subsequent HCC pathogenesis. In particular, platelet-derived GPIbα is critical for development of NASH and subsequent HCC, independent of its reported cognate ligands vWF, P-Selectin or Mac-1, offering a potential interventional target against NASH.