癌症消瘦（cancer cachexia）是一种由全身性炎症驱动的综合征，以肌肉萎缩和脂肪组织浪费为特征，伴随着逐渐减重，导致生理功能严重受损。癌细胞源性的细胞外囊泡（extracellular vesicles，EVs）在脂肪细胞脂解中起到重要作用，但其机制尚未阐明。本研究提取和鉴定了来源于Lewis肺癌（LLC）细胞的EVs。将3T3-L1和HIB1B脂肪细胞培养于LLC的条件培养液或EVs中，并使用LLC细胞建立了癌症消瘦小鼠模型。LLC细胞源性的EVs被3T3-L1和HIB1B脂肪细胞摄取，进而由外泌体中的EIF5A蛋白引起脂肪细胞脂解。LLC细胞的EVs中表达了高水平的EIF5A，外泌体中的EIF5A与脂代谢有关。EIF5A的表达增高与肺癌患者较短的总生存期相关。西方印迹、甘油释放和Oil red O染色法被用于评估脂肪细胞脂解。通过在体外沉默EIF5A或使用药物抑制剂GC7处理，可以实现对3T3-L1和HIB1B脂肪细胞脂解的减少，并且通过感染shRNA或GC7处理抑制LLC细胞中的EIF5A表达，部分缓解了癌症消瘦模型中的白色和棕色脂肪组织脂解。在机制上，EIF5A直接结合G蛋白偶联胆酸受体1（GPBAR1）mRNA以促进其翻译，然后激活cAMP反应元件结合蛋白（CREB）信号通路诱导脂肪细胞脂解。本研究证明LLC细胞外泌体中含有儿茶酚胺变性的EIF5A具有对脂肪细胞和脂肪组织的脂解作用，且外泌体中的EIF5A可能参与脂解，这些发现表明EIF5A是癌症消瘦治疗的一种新调控因子和潜在靶点。 © 2023 Elsevier Inc. 发表。

Cancer cachexia is a systemic inflammation-driven syndrome, characterized by muscle atrophy and adipose tissue wasting, with progressive weight loss leading to serious impairment of physiological function. Extracellular vesicles (EVs) derived from cancer cells play a significant role in adipocyte lipolysis, yet the mechanism remain uneclucidated. In this study, EVs derived from Lewis lung carcinoma (LLC) cells were extracted and characterized. 3 T3-L1 and HIB1B adipocytes were cultured with conditioned medium or EVs from LLC, and LLC cells were used to establish a cancer cachexia mouse model. EVs derived from LLC cells were taken up by 3 T3-L1 and HIB1B adipocytes, and derived exosomal EIF5A protein-induced lipolysis of adipocytes. High level of EIF5A was expressed in EVs from LLC cells, exosomal EIF5A is linked to lipid metabolism. Elevated expression of EIF5A is associated with shorter overall survival in lung cancer patients. Western blots, glycerol release and Oil red O staining assays were used to evaluate lipolysis of adipocytes. The reduction of lipolysis in 3 T3-L1 and HIB1B adipocytes is achieved through silencing EIF5A or treating with pharmacologic inhibitor GC7 in vitro, and suppressing the expression of EIF5A in LLC cells by infected with shRNA or GC7 treatment partly alleviated white and brown adipose tissue lipolysis in vivo. Mechanistically, EIF5A directly binds with G protein-coupled bile acid receptor 1 (GPBAR1) mRNA to promote its translation and then activates cAMP response element binding protein (CREB) signaling pathway to induce lipolysis. This study demonstrates that exosomal EIF5A from LLC cells, with hypusinated EIF5A, has a lipolytic effect on adipocyte and adipose tissues in cancer cachexia model. Exosomal EIF5A could be involved in lipolysis and these findings indicate that a novel regulator and potential target for cachexia treatment.Copyright © 2023. Published by Elsevier Inc.