Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Medical Science, China-Japan Friendship Hospital, No. 2 Yinghua East Street, Chaoyang District, Beijing 100029, China; School of Basic Medical Sciences, North China University of Science and Technology, No. 21 Bohai Road, Caofeidian District, Tangshan, Hebei 063210, China.
Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Medical Science, China-Japan Friendship Hospital, No. 2 Yinghua East Street, Chaoyang District, Beijing 100029, China; Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China.
Pharmacol Res. 2021 Dec;174:105964. doi: 10.1016/j.phrs.2021.105964. Epub 2021 Oct 31.
Lipophagy is the autophagic degradation of lipid droplets. Dysregulated lipophagy has been implicated in the development of non-alcoholic fatty liver disease (NAFLD). Ajugol is an active alkaloid isolated from the root of Rehmannia glutinosa which is commonly used to treat various inflammatory and metabolic diseases. This study aimed to investigate the effect of ajugol on alleviating hepatic steatosis and sought to determine whether its potential mechanism via the key lysosome-mediated process of lipophagy. Our findings showed that ajugol significantly improved high-fat diet-induced hepatic steatosis in mice and inhibited palmitate-induced lipid accumulation in hepatocytes. Further analysis found that hepatic steatosis promoted the expression of LC3-II, an autophagosome marker, but led to autophagic flux blockade due to a lack of lysosomes. Ajugol also enhanced lysosomal biogenesis and promoted the fusion of autophagosome and lysosome to improve impaired autophagic flux and hepatosteatosis. Mechanistically, ajugol inactivated mammalian target of rapamycin and induced nuclear translocation of the transcription factor EB (TFEB), an essential regulator of lysosomal biogenesis. siRNA-mediated knockdown of TFEB significantly abrogated ajugol-induced lysosomal biogenesis as well as autophagosome-lysosome fusion and lipophagy. We conclude that lysosomal deficit is a critical mediator of hepatic steatosis, and ajugol may alleviate NAFLD via promoting the TFEB-mediated autophagy-lysosomal pathway and lipophagy.
脂噬作用是指脂质滴的自噬降解。脂噬作用失调与非酒精性脂肪性肝病（NAFLD）的发展有关。梓醇是从地黄根中分离得到的一种活性生物碱，常用于治疗各种炎症和代谢性疾病。本研究旨在探讨梓醇缓解肝脂肪变性的作用，并确定其是否通过关键溶酶体介导的脂噬作用过程发挥潜在作用。我们的研究结果表明，梓醇可显著改善高脂肪饮食诱导的小鼠肝脂肪变性，并抑制棕榈酸诱导的肝细胞脂质堆积。进一步分析发现，肝脂肪变性促进了自噬体标志物 LC3-II 的表达，但由于缺乏溶酶体导致自噬流阻滞。梓醇还增强了溶酶体的生物发生，并促进了自噬体与溶酶体的融合，以改善受损的自噬流和肝脂肪变性。在机制上，梓醇使哺乳动物雷帕霉素靶蛋白失活，并诱导转录因子 EB（TFEB）的核转位，TFEB 是溶酶体生物发生的关键调节因子。siRNA 介导的 TFEB 敲低显著阻断了梓醇诱导的溶酶体生物发生以及自噬体-溶酶体融合和脂噬作用。我们得出结论，溶酶体缺陷是肝脂肪变性的关键介导因素，梓醇可能通过促进 TFEB 介导的自噬-溶酶体途径和脂噬作用来缓解 NAFLD。
