Nuciferine protects against high-fat diet-induced hepatic steatosis and insulin resistance via activating TFEB-mediated autophagy——lysosomal pathway  

作　　者：Xiliang Du Chiara Di Malta Zhiyuan Fang Taiyu Shen Xiaodi Niu Meng Chen Bo Jin Hao Yu Lin Lei Wenwen Gao Yuxiang Song Zhe Wang Chuang Xu Zhijun Cao Guowen Liu Xinwei Li 

机构地区：[1]Key Laboratory of Zoonosis,Ministry of Education,College of Veterinary Medicine,Jilin University,Changchun 130062,China [2]Telethon Institute of Genetics and Medicine(TIGEM)Via Campi Flegrei 34,Pozzuoli,NA 80078,Italy [3]Medical Genetics Unit,Department of Medical and Translational Science,Federico Ⅱ University,Naples 80131,Italy [4]College of Food Science and Engineering,Jilin University,Changchun 130062,China [5]College of Animal Science and Veterinary Medicine,Heilongjiang Bayi Agricultural University,Daqing 163319,China [6]State Key Laboratory of Animal Nutrition,Beijing Engineering Technology Research Center of Raw Milk Quality and Safety Control,College of Animal Science and Technology,China Agricultural University,Beijing 100193,China

出　　处：《Acta Pharmaceutica Sinica B》2022年第6期2869-2886,共18页药学学报（英文版）

基　　金：supported by the National Natural Science Foundation of China (Beijing, China;grant Nos. U20A2062, 32022084, and 32002349);Jilin Province Science and Technology Development Project (Changchun, China;grant No. 20210508011RQ)

摘　　要：Nonalcoholic fatty liver disease(NAFLD) is characterized by hepatic steatosis and insulin resistance and there are currently no approved drugs for its treatment.Hyperactivation of mTOR complex1(mTORCl) and subsequent impairment of the transcription factor EB(TFEB)-mediated autophagy-lysosomal pathway(ALP) are implicated in the development of NAFLD.Accordingly,agents that augment hepatic TFEB transcriptional activity may have therapeutic potential against NAFLD.The objective of this study was to investigate the effects of nuciferine,a major active component from lotus leaf,on NAFLD and its underlying mechanism of action.Here we show that nuciferine activated ALP and alleviated steatosis,insulin resistance in the livers of NAFLD mice and palmitic acid-challenged hepatocytes in a TFEB-dependent manner.Mechanistic investigation revealed that nuciferine interacts with the Ragulator subunit hepatitis B X-interacting protein and impairs the interaction of the Ragulator complex with Rag GTPases,thereby suppressing lysosomal localization and activity of mTORC1,which activates TFEB-mediated ALP and further ameliorates hepatic steatosis and insulin resistance.Our present results indicate that nuciferine may be a potential agent for treating NAFLD and that regulation of the mTORCl-TFEB-ALP axis could represent a novel pharmacological strategy to combat NAFLD.

关 键 词：AUTOPHAGY Fatty liver Lotus leaf LYSOSOME MiT/TFE mTORC1 Ragulator TFEB 

分 类 号：R575[医药卫生—消化系统]