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• W2983129301 abstract "Abstract mTORC1 is a protein kinase important for metabolism and is regulated by growth factor and nutrient signaling pathways, mediated by the Rheb and Rag GTPases, respectively. Here we provide the first animal model in which both pathways were upregulated through concurrent mutations in their GTPase-activating proteins, Tsc1 and Depdc5 . Unlike former models that induced limited mTORC1 upregulation, hepatic deletion of both Tsc1 and Depdc5 (DKO) produced strong, synergistic activation of the mTORC1 pathway and provoked pronounced and widespread hepatocyte damage, leading to externally visible liver failure phenotypes, such as jaundice and systemic growth defects. The transcriptome profile of DKO was different from single knockout mutants but similar to those of diseased human livers with severe hepatitis and mouse livers challenged with oxidative stress-inducing chemicals. In addition, DKO liver cells exhibited prominent molecular pathologies associated with excessive endoplasmic reticulum (ER) stress, oxidative stress, DNA damage and inflammation. Although DKO liver pathologies were ameliorated by mTORC1 inhibition, ER stress suppression unexpectedly aggravated them, suggesting that ER stress signaling is not the major conduit of how hyperactive mTORC1 produces liver damage. Interestingly, superoxide scavengers N-acetylcysteine (NAC) and Tempol, chemicals that reduce oxidative stress, were able to recover liver phenotypes, indicating that mTORC1 hyperactivation induced liver damage mainly through oxidative stress pathways. Our study provides a new model of unregulated mTORC1 activation through concomitant upregulation of growth factor and nutrient signaling axes and shows that mTORC1 hyperactivation alone can provoke oxidative tissue injury." @default.
• W2983129301 created "2019-11-22" @default.
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• W2983129301 date "2019-11-19" @default.
• W2983129301 modified "2023-10-15" @default.
• W2983129301 title "Concurrent activation of growth factor and nutrient arms of mTORC1 induces oxidative liver injury" @default.
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• W2983129301 cites W2008781245 @default.
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• W2983129301 cites W2087614405 @default.
• W2983129301 cites W2094399892 @default.
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• W2983129301 cites W2111352469 @default.
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• W2983129301 cites W2126214983 @default.
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• W2983129301 doi "https://doi.org/10.1038/s41421-019-0131-9" @default.
• W2983129301 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6868011" @default.
• W2983129301 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/31754457" @default.
• W2983129301 hasPublicationYear "2019" @default.
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