Einfluss der antithrombozytären Therapie auf den klinischen Verlauf der Steatosis hepatis

Die NAFLD stellt die häufigste chronische Lebererkrankung in Industrienationen dar (Loomba and Sanyal, 2013). Neben diätetischen Therapiemaßnahmen sind medikamentöse Therapieoptionen dringend erforderlich. Die Arbeit beschäftigt sich hierbei mit dem möglichen Einfluss einer antithrombozytären Therapie auf den klinischen Verlauf der Steatosis hepatis

Einfluss der antithrombozytären Therapie auf den klinischen Verlauf der Steatosis hepatis

Die NAFLD stellt die häufigste chronische Lebererkrankung in Industrienationen dar (Loomba and Sanyal, 2013). Neben diätetischen Therapiemaßnahmen sind medikamentöse Therapieoptionen dringend erforderlich. Die Arbeit beschäftigt sich hierbei mit dem möglichen Einfluss einer antithrombozytären Therapie auf den klinischen Verlauf der Steatosis hepatis

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 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

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 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.We thank D. Heide, J. Hetzer, R. Hillermann, C. Gropp, F. Muller, S. Prokosch, D. Kull, R. Dunkl, O. Seelbach, M. Bawohl, R. Maire, M. Bieri, C. Mittmann, H. HoncharovaBiletska, A. Fitsche, A. Adili, P. Munzer, T. Nussbaumer, F. Prutek, G. Dharmalingam and I. Singh for excellent technical assistance. We thank K. Nikolaou for the help with the human cohort recruitment and analysis. M. Malehmir was partially supported by grants from the University Zurich (Zurich Integrative Human Physiology (ZHIP) Sprint Fellowship) and from the Hartmann Muller Stiftung, Zurich. A.W. was supported by a grant from the Swiss National Science Foundation (320030_182764/1). M. Heikenwaelder was supported by an ERC Consolidator grant (HepatoMetaboPath), an EOS grant, SFBTR 209, SFBTR179, Research Foundation Flanders (FWO) under grant 30826052 (EOS Convention MODEL-IDI), Deutsche Krebshilfe projects 70113166 and 70113167, and the Helmholtz-Gemeinschaft, Zukunftsthema 'Immunology and Inflammation' (ZT-0027). This project has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement 667273 and the DFG (SFB/TR 240 (project 374031971) to B.N. and D. S.), ERC Consolidator grant 'CholangioConcept' (to L.Z.), and the German Research Foundation (DFG): grants FOR2314, SFB685 and the Gottfried Wilhelm Leibniz Program (to L.Z.). Further funding was provided by the German Ministry for Education and Research (BMBF) (eMed/Multiscale HCC), the German Universities Excellence Initiative (third funding line: 'future concept'), the German Center for Translational Cancer Research (DKTK) and the German-Israeli Cooperation in Cancer Research (DKFZ-MOST) (to L.Z. and M. Heikenwaelder). D. I. was supported by an EMBO Long-term Fellowship. J.M.L. is supported by Asociacion Espanola Contra el Cancer (Accelerator award: HUNTER), Spanish National Health Institute (SAF2013-41027), Generalitat de Catalunya (SGR 1162 and AGAUR, SGR-1358), the Samuel Waxman Cancer Research Foundation, the US Department of Defense (CA150272P3), the European Commission Horizon 2020 Program (HEPCAR, proposal number 667273-2), and the National Cancer Institute (P30 CA196521). D. A. M. is supported by CRUK grant C18342/A23390 and MRC grant MR/K001949/1. M. P. is supported by the German Research Foundation (DFG). M. G., T. G. and D. R. was supported by grants from the German Research Foundation (KFO274 and SFB/TR240 (project 374031971)). D. J. W. received a Wellcome Trust Strategic Award (098565/Z/12/Z) and funding from the Medical Research Council (MC-A654-5QB40). C.L.W. was funded by CRUK project Cancer Research UK Programme Grant C18342/A23390. H. G. A. has been supported by the Deutsche Forschungsgemeinschaft (SFB-TR209 'Liver Cancer').S