Journal
AUTOPHAGY
Volume 15, Issue 9, Pages 1671-1673Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2019.1634445
Keywords
AKT; Atg5; hepatocellular carcinoma; Nrf2; proteotoxicity
Categories
Funding
- NIAAA [R01 AA020518, U01 AA024733, R21 AA027250, R21 AA026904]
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Liver-specific deletion of autophagy-related genes in mice leads to hepatomegaly, liver injury and spontaneous liver tumorigenesis. Accumulating evidence indicates that p62/SQSTM1-mediated NFE2L2/Nrf2/(nuclear factor, erythroid 2 like 2) activation plays a critical role in promoting liver injury and tumorigenesis in autophagy-defective livers. However, the mechanisms of how persistent NFE2L2 activation induces liver injury and tumorigenesis are unknown. In a recent study, it was found that deletion of Mtor (mechanistic target of rapamycin kinase) or Rptor/Raptor attenuates hepatomegaly and liver injury in young liver-specific atg5 knockout mice but accelerates liver tumorigenesis in old mice likely due to feedback AKT activation. Overall, these findings suggest that both hyper- and hypo-activation of MTOR are detrimental to the liver resulting in the development of liver tumors. A balanced MTOR activity is critical to maintain the normal physiological functions of the liver, and caution should be exercised when treating hepatocellular carcinomas using MTOR inhibitors.
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