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00925njm 22002777a 4500 dc Malehmir, Mohsen author Pfister, Dominik author Gallage, Suchira author Szydlowska, Marta author Inverso, Donato author Kotsiliti, Elena author Leone, Valentina author Peiseler, Moritz author Surewaard, Bas G J author Rath, Dominik author Ali, Adnan author Wolf, Monika Julia author Drescher, Hannah author Healy, Marc E author Dauch, Daniel author Kroy, Daniela author Krenkel, Oliver author Kohlhepp, Marlene author Engleitner, Thomas author Olkus, Alexander author Sijmonsma, Tjeerd author Volz, Julia author Deppermann, Carsten author Stegner, David author Helbling, Patrick author Nombela-Arrieta, César author Rafiei, Anahita author Hinterleitner, Martina author Rall, Marcel author Baku, Florian author Borst, Oliver author Wilson, Caroline L author Leslie, Jack author O'Connor, Tracy author Weston, Christopher J author Chauhan, Abhishek author Adams, David H author Sheriff, Lozan author Teijeiro, Ana author Prinz, Marco author Bogeska, Ruzhica author Anstee, Natasha author Bongers, Malte N author Notohamiprodjo, Mike author Geisler, Tobias author Withers, Dominic J author Ware, Jerry author Mann, Derek A author Augustin, Hellmut G author Vegiopoulos, Alexandros author Milsom, Michael D author Rose, Adam J author Lalor, Patricia F author Llovet, Josep M author Pinyol, Roser author Tacke, Frank author Rad, Roland author Matter, Matthias author Djouder, Nabil author Kubes, Paul author Knolle, Percy A author Unger, Kristian author Zender, Lars author Nieswandt, Bernhard author Gawaz, Meinrad author Weber, Achim author Heikenwalder, Mathias author 2019-04 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. Nat Med . 2019 ;25(4):641-655. 10.1038/s41591-019-0379-5 1546-170X Nature medicine 30936549 http://hdl.handle.net/20.500.12105/17957 Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer.