Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer
Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer
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DOI：
10.1038/s41591-019-0379-5
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发表时间：
2019-04-01
期刊：
影响因子：
82.9
通讯作者：
Heikenwalder, Mathias
中科院分区：
文献类型：
--
作者：
Malehmir, Mohsen;Pfister, Dominik;Heikenwalder, Mathias
非酒精性脂肪肝疾病范围从脂肪变性到非酒精性脂肪性肝炎 (NASH)，可能进展为肝硬化和肝细胞癌 (HCC)。在这里，我们发现 NASH 中血小板数量、血小板活化和血小板聚集增加，但在脂肪变性或胰岛素抵抗中则没有增加。抗血小板治疗（APT；阿司匹林/氯吡格雷、替格瑞洛）可预防 NASH 和随后的 HCC 发展，但使用舒林酸的非甾体类抗炎药 (NSAID) 治疗则不能。活体显微镜显示，在NASH早期和晚期，血小板在肝脏的定植主要依赖于库普弗细胞，涉及透明质酸-CD44结合。 APT 减少肝内血小板积聚和血小板与免疫细胞相互作用的频率，从而限制肝免疫细胞运输。因此，肝内细胞因子和趋化因子的释放、大泡性脂肪变性和肝损伤均得到减轻。血小板货物、血小板粘附和血小板激活（但不是血小板聚集）被认为是 NASH 和随后的肝癌发生的关键。特别是，血小板衍生的 GPIb α 被证明对于 NASH 和随后的 HCC 的发展至关重要，独立于其报道的同源配体 vWF、P-选择素或 Mac-1，提供了对抗 NASH 的潜在靶点。
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 GPIb alpha 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.