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Malehmir, M.* ; Pfister, D.* ; Gallage, S.* ; Szydlowska, M.* ; Inverso, D.* ; Kotsiliti, E. ; Leone, V. ; Peiseler, M.* ; Surewaard, B.G.J.* ; Rath, D.* ; Ali, A.* ; Wolf, M.J.* ; Drescher, H.* ; Healy, M.E.* ; 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, C.L.* ; Leslie, J.* ; O'Connor, T. ; Weston, C.J.* ; Adams, D.H.* ; Sheriff, L.* ; Teijeiro, A.* ; Prinz, M.* ; Bogeska, R.* ; Anstee, N.* ; Bongers, M.N.* ; Notohamiprodjo, M.* ; Geisler, T.* ; Withers, D.J.* ; Ware, J.* ; Mann, D.A.* ; Augustin, H.G.* ; Vegiopoulos, A.* ; Milsom, M.D.* ; Rose, A.J.* ; Lalor, P.F.* ; Llovet, J.M.* ; Pinyol, R.* ; Tacke, F.* ; Rad, R.* ; Matter, M.* ; Djouder, N.* ; Kubes, P.* ; Knolle, P.A.* ; Unger, K. ; Zender, L.* ; Nieswandt, B.* ; Gawaz, M.* ; Weber, A.* ; Heikenwälder, M.

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

Nat. Med. 25, 641-655 (2019)
Postprint DOI PMC
Open Access Green
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Causes Nonalcoholic Steatohepatitis; Set Enrichment Analysis; In-vivo Depletion; Nf-kappa-b; Glycoprotein-vi; Hepatocellular-carcinoma; Antiplatelet Therapy; Factor Binding; Mouse Model; Inflammation
ISSN (print) / ISBN 1078-8956
e-ISSN 1546-170X
Zeitschrift Nature medicine
Quellenangaben Band: 25, Heft: 4, Seiten: 641-655 Artikelnummer: , Supplement: ,
Verlag Nature Publishing Group
Verlagsort New York, NY
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Virology (VIRO)
Translational Metabolic Oncology (TMO)