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

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Title: Platelet GPIb alpha is a mediator and potential interventional target for NASH and subsequent liver cancer
Authors: Malehmir, M
Pfister, D
Gallage, S
Szydlowska, M
Inverso, D
Kotsiliti, E
Leone, V
Peiseler, M
Surewaard, BGJ
Rath, D
Ali, A
Wolf, MJ
Drescher, H
Healy, ME
Dauch, D
Kroy, D
Krenkel, O
Kohlhepp, M
Engleitner, T
Olkus, A
Sijmonsma, T
Volz, J
Deppermann, C
Stegner, D
Helbling, P
Nombela-Arrieta, C
Rafiei, A
Hinterleitner, M
Rall, M
Baku, F
Borst, O
Wilson, CL
Leslie, J
O'Connor, T
Weston, CJ
Adams, DH
Sheriff, L
Teijeiro, A
Prinz, M
Bogeska, R
Anstee, N
Bongers, MN
Notohamiprodjo, M
Geisler, T
Withers, DJ
Ware, J
Mann, DA
Augustin, HG
Vegiopoulos, A
Milsom, MD
Rose, AJ
Lalor, PF
Llovet, JM
Pinyol, R
Tacke, F
Rad, R
Matter, M
Djouder, N
Kubes, P
Knolle, PA
Unger, K
Zender, L
Nieswandt, B
Gawaz, M
Weber, A
Heikenwalder, M
Item Type: Journal Article
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.
Issue Date: 1-Apr-2019
Date of Acceptance: 28-Jan-2019
URI: http://hdl.handle.net/10044/1/70687
DOI: https://doi.org/10.1038/s41591-019-0379-5
ISSN: 1078-8956
Publisher: Nature Research
Start Page: 641
End Page: 655
Journal / Book Title: Nature Medicine
Volume: 25
Issue: 4
Copyright Statement: ©2019 The Author(s), under exclusive licence to Springer Nature America, Inc.
Sponsor/Funder: Medical Research Council
Wellcome Trust
Funder's Grant Number: MC-A654-5QB40
511377
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Cell Biology
Medicine, Research & Experimental
Research & Experimental Medicine
CAUSES NONALCOHOLIC STEATOHEPATITIS
SET ENRICHMENT ANALYSIS
IN-VIVO DEPLETION
NF-KAPPA-B
GLYCOPROTEIN-VI
HEPATOCELLULAR-CARCINOMA
ANTIPLATELET THERAPY
FACTOR BINDING
MOUSE MODEL
INFLAMMATION
Animals
Blood Platelets
Body Weight
Cytokines
Cytoplasmic Granules
Endothelium
Hepatocytes
Humans
Hyaluronan Receptors
Hyaluronic Acid
Kupffer Cells
Liver
Liver Neoplasms
Mice, Transgenic
Non-alcoholic Fatty Liver Disease
Platelet Aggregation
Platelet Aggregation Inhibitors
Platelet Count
Platelet Glycoprotein GPIb-IX Complex
Liver
Endothelium
Blood Platelets
Cytoplasmic Granules
Kupffer Cells
Hepatocytes
Animals
Mice, Transgenic
Humans
Liver Neoplasms
Body Weight
Hyaluronic Acid
Platelet Glycoprotein GPIb-IX Complex
Platelet Aggregation Inhibitors
Cytokines
Platelet Count
Platelet Aggregation
Non-alcoholic Fatty Liver Disease
Hyaluronan Receptors
Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Cell Biology
Medicine, Research & Experimental
Research & Experimental Medicine
CAUSES NONALCOHOLIC STEATOHEPATITIS
SET ENRICHMENT ANALYSIS
IN-VIVO DEPLETION
NF-KAPPA-B
GLYCOPROTEIN-VI
HEPATOCELLULAR-CARCINOMA
ANTIPLATELET THERAPY
FACTOR BINDING
MOUSE MODEL
INFLAMMATION
11 Medical and Health Sciences
Immunology
Publication Status: Published
Online Publication Date: 2019-04-01
Appears in Collections:Clinical Sciences
Molecular Sciences



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