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PLoS One. 2014 Apr 16;9(4):e95393. doi: 10.1371/journal.pone.0095393. eCollection 2014.

Ursolic acid inhibits leucine-stimulated mTORC1 signaling by suppressing mTOR localization to lysosome.

Author information

1
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.
2
Metabolic Syndrome Research Center and Diabetes Center, Key Laboratory of Diabetes Immunology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
3
Department of Cellular & Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.

Abstract

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.

PMID:
24740400
PMCID:
PMC3989317
DOI:
10.1371/journal.pone.0095393
[Indexed for MEDLINE]
Free PMC Article

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