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. 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

Mohsen Malehmir  1 Dominik Pfister  2 Suchira Gallage  2 Marta Szydlowska  2 Donato Inverso  3   4 Elena Kotsiliti  2   5 Valentina Leone  2   6 Moritz Peiseler  7   8 Bas G J Surewaard  8   9   10 Dominik Rath  11 Adnan Ali  2 Monika Julia Wolf  1 Hannah Drescher  12 Marc E Healy  1 Daniel Dauch  13   14 Daniela Kroy  12 Oliver Krenkel  12 Marlene Kohlhepp  12 Thomas Engleitner  15   16   17 Alexander Olkus  2   18 Tjeerd Sijmonsma  2 Julia Volz  19 Carsten Deppermann  19 David Stegner  19 Patrick Helbling  20 César Nombela-Arrieta  20 Anahita Rafiei  20 Martina Hinterleitner  13   14 Marcel Rall  11 Florian Baku  11 Oliver Borst  11 Caroline L Wilson  21 Jack Leslie  21 Tracy O'Connor  5   22 Christopher J Weston  23 David H Adams  23   24 Lozan Sheriff  25 Ana Teijeiro  26 Marco Prinz  27   28   29 Ruzhica Bogeska  30   31 Natasha Anstee  30   31 Malte N Bongers  32 Mike Notohamiprodjo  32 Tobias Geisler  33 Dominic J Withers  34   35 Jerry Ware  36 Derek A Mann  21 Hellmut G Augustin  3   4 Alexandros Vegiopoulos  37 Michael D Milsom  30   31 Adam J Rose  38 Patricia F Lalor  23 Josep M Llovet  39   40   41 Roser Pinyol  40 Frank Tacke  12 Roland Rad  15   16   17 Matthias Matter  42 Nabil Djouder  26 Paul Kubes  7   8   9 Percy A Knolle  22 Kristian Unger  6 Lars Zender  13   14   43 Bernhard Nieswandt  19 Meinrad Gawaz  11 Achim Weber  44 Mathias Heikenwalder  45   46
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Free article

Platelet GPIbα Is a Mediator and Potential Interventional Target for NASH and Subsequent Liver Cancer

Mohsen Malehmir et al. Nat Med. .
Free 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.

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