Background & Aims: Immune system activation along with lipotoxicity due to excessive lipid droplet (LD) accumulation in the liver are key drivers of non-alcoholic steatohepatitis (NASH). Extracellular vesicles (EVs) released by cells that carry biological signals to contribute intercellular communication. But the roles of immune cells-derived EVs in pathogenesis of NASH are unclear. Approach & Results: Platelets are abundant in blood. We explored the role of platelet-derived EVs (pEVs) in LD accumulation from 30 patients with non-alcoholic fatty liver disease of different severity as well as 20 healthy subjects, a rat model, and an in vitro cell-based assay. There was increased platelet activation, accompanied by pEVs release, in NASH patients/rat model, and palmitate-treated cells. The mitochondria in the platelets and pEVs from NASH patients/rats were increased but dysfunctional, including a reduction in fatty acid β-oxidation, inactivated ACC2, and suppressed oxidative phosphorylation system complex II/III/IV activity. These damaged mitochondria could be transferred to hepatocytes via pEVs to increase the number of lipid droplet–bound mitochondria (LDM). An increase in dysfunctional LDM in hepatocytes affects lipid metabolism, resulting in excessive LD accumulation, elevated mitochondrial ROS production, and apoptosis. Conclusions: We offer a novel molecular mechanism that connects platelets, pEVs, and excessive LD accumulation to the development of NASH. Our results suggest that NASH progression may be alleviated by specifically inhibiting the production and release of pEVs, or by targeting pEVs components and inhibiting their uptake. Additional experiments are required to confirm this potentiality.

中文翻译：

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血小板来源的线粒体通过细胞外囊泡调节非酒精性脂肪性肝炎的脂质代谢


背景和目标：免疫系统激活以及由于肝脏中过多的脂滴（LD）积累而导致的脂毒性是非酒精性脂肪性肝炎（NASH）的关键驱动因素。携带生物信号以促进细胞间通讯的细胞释放的细胞外囊泡 （EV）。但免疫细胞来源的 EV 在 NASH 发病机制中的作用尚不清楚。方法和结果：血小板在血液中含量丰富。我们探讨了血小板衍生的 EVs （pEVs） 在 30 例不同严重程度的非酒精性脂肪性肝病患者以及 20 例健康受试者、大鼠模型和体外细胞测定的 LD 积累中的作用。在 NASH 患者/大鼠模型和棕榈酸酯处理的细胞中，血小板活化增加，伴有 pEVs 释放。NASH 患者/大鼠血小板和 pEVs 中的线粒体增加但功能失调，包括脂肪酸β氧化减少、ACC2 灭活和氧化磷酸化系统复合物 II/III/IV 活性抑制。这些受损的线粒体可以通过 pEVs 转移到肝细胞，以增加脂滴结合的线粒体 （LDM） 的数量。肝细胞中功能失调的 LDM 的增加会影响脂质代谢，导致 LD 过度积累、线粒体 ROS 产生增加和细胞凋亡。结论： 我们提供了一种新的分子机制，将血小板、 pEVs 和过度的 LD 积累与 NASH 的发展联系起来。我们的结果表明，通过特异性抑制 pEVs 的产生和释放，或通过靶向 pEVs 成分并抑制其摄取，可以缓解 NASH 进展。需要额外的实验来证实这种可能性。