Zhang Jie, Tan Jie, Wang Mengke, Wang Yifen, Dong Mengzhen, Ma Xuefeng, Sun Baokai, Liu Shousheng, Zhao Zhenzhen, Chen Lizhen, Liu Kai, Xin Yongning, Zhuang Likun
Department of Infectious Diseases, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, China.
Clinical Research Center, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, China.
Sci Adv. 2021 Nov 5;7(45):eabh1541. doi: 10.1126/sciadv.abh1541. Epub 2021 Nov 3.
The biogenesis and diagnostic value of exosomes in nonalcoholic fatty liver disease (NAFLD) are unclear. In this study, we revealed that the plasma exosome level was higher in patients with NAFLD than that in healthy controls. was identified as one of the genes related to exosome secretion in patients with NAFLD. Then, loss or knockdown of DRAM down-regulated exosome secretion from hepatic cells using a knockout mouse model and a knockdown cell model. knockout reversed high-fat diet–induced increase of secreted exosomes. Furthermore, DRAM knockdown inhibited fatty acid (FA)–induced lysosomal membrane permeabilization and lysosome inhibitor reversed the down-regulation of exosome release in knockout mice. Last, FA-induced DRAM interacted with stomatin and promoted its lysosomal localization to enhance exosome secretion from hepatic cells. We revealed a DRAM-mediated mechanism for exosome secretion and provided the foundation for plasma exosomes as a potential biomarker for NAFLD.
非酒精性脂肪性肝病（NAFLD）中外泌体的生物发生及其诊断价值尚不清楚。在本研究中，我们发现NAFLD患者血浆外泌体水平高于健康对照。被确定为NAFLD患者中与外泌体分泌相关的基因之一。然后，使用基因敲除小鼠模型和基因敲低细胞模型，DRAM的缺失或敲低下调了肝细胞的外泌体分泌。基因敲除逆转了高脂饮食诱导的分泌外泌体增加。此外，DRAM敲低抑制了脂肪酸（FA）诱导的溶酶体膜通透性，溶酶体抑制剂逆转了基因敲除小鼠中外泌体释放的下调。最后，FA诱导的DRAM与胃动蛋白相互作用并促进其溶酶体定位，以增强肝细胞的外泌体分泌。我们揭示了一种DRAM介导的外泌体分泌机制，并为血浆外泌体作为NAFLD潜在生物标志物提供了基础。
