State Key Laboratory of Pharmaceutical Biotechnology, Medical School, School of Life Science, Nanjing University, Nanjing , 210093, China; Institute of Drug R&D, Medical School, Nanjing University, Nanjing, 210093, China.
Affiliated Drum Tower Hospital, Medical School, Nanjing University, Nanjing, 210008, China.
Biomaterials. 2023 Oct;301:122291. doi: 10.1016/j.biomaterials.2023.122291. Epub 2023 Aug 20.
Non-alcoholic fatty liver disease (NAFLD) is the most prevalent hepatic disease characterized as lipid accumulation, yet without any approved drug. And development of therapeutic molecules is obstructed by low efficiency and organ toxicity. Herein, we develop a long-term, low-toxic and liver-selected nano candidate, nabCK, to alleviate NAFLD. NabCK is simply composed by natural compound ginsenoside compound K (CK) and albumin. As a major metabolite of ginseng, ginsenoside CK has excellently modulating functions for lipid metabolism, but accompanied by an extremely poor bioavailability <1%. Albumin is a key lipid carrier secreted and metabolized by livers. Thereby, it can improve solubility and liver-localization of CK. In adipocytes and hepatocytes, nabCK prevents lipid deposition and eliminates lipid droplets. Transcriptomic analysis reveals that nabCK rectifies various pathways that involved in steatosis development, including lipid absorption, lipid export, fatty acid biosynthesis, lipid storage and inflammation. All these pathways are modulated by mTOR, the pivotal feedback sensor that is hyperactive in NAFLD. NabCK suppresses mTOR activation to restores lipid homeostasis. In high-fat diet (HFD) induced NAFLD mice, nabCK retards development of steatosis and fibrosis, coupling a protective effect on cardiac tissues from lipotoxicity. Together, nabCK is a safe and potent candidate to offer benefits for NAFLD treatment.
非酒精性脂肪性肝病 (NAFLD) 是最常见的肝脏疾病，其特征是脂质积累，但目前尚无任何批准的药物。由于效率低和器官毒性，治疗分子的开发受到阻碍。在此，我们开发了一种长效、低毒且肝脏选择性的纳米候选药物 nabCK，以缓解 NAFLD。nabCK 由天然化合物人参皂苷 CK 和白蛋白简单组成。作为人参的主要代谢物，人参皂苷 CK 对脂质代谢具有极好的调节功能，但生物利用度极低，<1%。白蛋白是肝脏分泌和代谢的关键脂质载体。因此，它可以提高 CK 的溶解度和肝脏定位。在脂肪细胞和肝细胞中，nabCK 可防止脂质沉积并消除脂质滴。转录组分析显示，nabCK 纠正了参与脂肪变性发展的各种途径，包括脂质吸收、脂质输出、脂肪酸生物合成、脂质储存和炎症。所有这些途径都由 mTOR 调节，mTOR 是在 NAFLD 中过度活跃的关键反馈传感器。nabCK 抑制 mTOR 激活以恢复脂质稳态。在高脂肪饮食 (HFD) 诱导的 NAFLD 小鼠中，nabCK 可延缓脂肪变性和纤维化的发展，并对心脏组织的脂毒性起到保护作用。总之，nabCK 是一种安全有效的候选药物，可为 NAFLD 治疗带来益处。
