雷帕霉素靶点蛋白(target of rapamycin,TOR)作为细胞内重要的生长和代谢调节中枢,主要通过形成两种复合物TORC1与TORC2发挥其功能。其中TORC1接收广泛的细胞内信号,如氨基酸水平、生长因子、能量以及缺氧状态等,通过调控蛋白质合成来...雷帕霉素靶点蛋白(target of rapamycin,TOR)作为细胞内重要的生长和代谢调节中枢,主要通过形成两种复合物TORC1与TORC2发挥其功能。其中TORC1接收广泛的细胞内信号,如氨基酸水平、生长因子、能量以及缺氧状态等,通过调控蛋白质合成来促进细胞的增殖与生长。在这些信号当中,氨基酸不仅能够激活TORC1通路,还同时作为其他信号激活TORC1的必需条件。目前,对于生长因子和能量水平激活TORC1过程的分子机制已有较深入的认识,而对于氨基酸信号如何转导至TORC1的分子机制直到近年来才有了新的突破。该文通过梳理已发表的哺乳动物细胞中氨基酸信号调控mTORC1分子机制的相关实验结论,对该领域的研究方向进行了总结和展望。展开更多
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 ...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.展开更多
文摘雷帕霉素靶点蛋白(target of rapamycin,TOR)作为细胞内重要的生长和代谢调节中枢,主要通过形成两种复合物TORC1与TORC2发挥其功能。其中TORC1接收广泛的细胞内信号,如氨基酸水平、生长因子、能量以及缺氧状态等,通过调控蛋白质合成来促进细胞的增殖与生长。在这些信号当中,氨基酸不仅能够激活TORC1通路,还同时作为其他信号激活TORC1的必需条件。目前,对于生长因子和能量水平激活TORC1过程的分子机制已有较深入的认识,而对于氨基酸信号如何转导至TORC1的分子机制直到近年来才有了新的突破。该文通过梳理已发表的哺乳动物细胞中氨基酸信号调控mTORC1分子机制的相关实验结论,对该领域的研究方向进行了总结和展望。
基金supported by the National Natural Science Foundation of China (Beijing, Chinagrant Nos. U20A2062, 32022084, and 32002349)+1 种基金Jilin Province Science and Technology Development Project (Changchun, Chinagrant No. 20210508011RQ)
文摘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.
