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

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 ins...

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Autores: Malehmir, Mohsen, Pfister, Dominik, Gallage, Suchira, Szydlowska, Marta, Inverso, Donato, Kotsiliti, Elena, Leone, Valentina, Peiseler, Moritz, Surewaard, Bas G J, Rath, Dominik, Ali, Adnan, Wolf, Monika Julia, Drescher, Hannah, Healy, Marc E, Dauch, Daniel, Kroy, Daniela, Krenkel, Oliver, Kohlhepp, Marlene, Engleitner, Thomas, Olkus, Alexander, Sijmonsma, Tjeerd, Volz, Julia, Deppermann, Carsten, Stegner, David, Helbling, Patrick, Nombela-Arrieta, César, Rafiei, Anahita, Hinterleitner, Martina, Rall, Marcel, Baku, Florian, Borst, Oliver, Wilson, Caroline L, Leslie, Jack, O'Connor, Tracy, Weston, Christopher J, Chauhan, Abhishek, Adams, David H, Sheriff, Lozan, Teijeiro, Ana, Prinz, Marco, Bogeska, Ruzhica, Anstee, Natasha, Bongers, Malte N, Notohamiprodjo, Mike, Geisler, Tobias, Withers, Dominic J, Ware, Jerry, Mann, Derek A, Augustin, Hellmut G, Vegiopoulos, Alexandros, Milsom, Michael D, Rose, Adam J, Lalor, Patricia F, Llovet, Josep M, Pinyol, Roser, Tacke, Frank, Rad, Roland, Matter, Matthias, Djouder, Nabil, Kubes, Paul, Knolle, Percy A, Unger, Kristian, Zender, Lars, Nieswandt, Bernhard, Gawaz, Meinrad, Weber, Achim, Heikenwalder, Mathias
Tipo de recurso: artículo
Fecha de publicación:2019
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/17957
Acceso en línea:http://hdl.handle.net/20.500.12105/17957
Access Level:acceso abierto
Palabra clave: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
Descripción
Sumario: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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