Ou Xiang, Liu Meilian, Luo Hairong, Dong Lily Q, Liu Feng
Metabolic Syndrome Research Center and Diabetes Center, Key Laboratory of Diabetes Immunology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Pharmacology University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
Metabolic Syndrome Research Center and Diabetes Center, Key Laboratory of Diabetes Immunology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
PLoS One. 2014 Apr 16;9(4):e95393. doi: 10.1371/journal.pone.0095393. eCollection 2014.
Ursolic acid (UA), a pentacyclic triterpenoid widely found in medicinal herbs and fruits, has been reported to possess a wide range of beneficial properties including anti-hyperglycemia, anti-obesity, and anti-cancer. However, the molecular mechanisms underlying the action of UA remain largely unknown. Here we show that UA inhibits leucine-induced activation of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway in C2C12 myotubes. The UA-mediated inhibition of mTORC1 is independent of Akt, tuberous sclerosis complex 1/2 (TSC1/2), and Ras homolog enriched in brain (Rheb), suggesting that UA negatively regulates mTORC1 signaling by targeting at a site downstream of these mTOR regulators. UA treatment had no effect on the interaction between mTOR and its activator Raptor or inhibitor Deptor, but suppressed the binding of RagB to Raptor and inhibited leucine-induced mTOR lysosomal localization. Taken together, our study identifies UA as a direct negative regulator of the mTORC1 signaling pathway and suggests a novel mechanism by which UA exerts its beneficial function.
熊果酸（UA）是一种广泛存在于草药和水果中的五环三萜类化合物，据报道具有多种有益特性，包括抗高血糖、抗肥胖和抗癌作用。然而，UA作用的分子机制在很大程度上仍不清楚。在此，我们表明UA可抑制亮氨酸诱导的C2C12肌管中雷帕霉素复合物1（mTORC1）信号通路的激活。UA介导的对mTORC1的抑制作用不依赖于Akt、结节性硬化复合物1/2（TSC1/2）和富含脑的Ras同源物（Rheb），这表明UA通过靶向这些mTOR调节因子下游的位点来负调控mTORC1信号通路。UA处理对mTOR与其激活剂Raptor或抑制剂Deptor之间的相互作用没有影响，但抑制了RagB与Raptor的结合，并抑制了亮氨酸诱导的mTOR溶酶体定位。综上所述，我们的研究确定UA是mTORC1信号通路的直接负调节因子，并提出了一种UA发挥其有益功能的新机制。
