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. Abbreviations: Atg5: autophgy related 5; DKO: double-knockout; HCC: hepatocellular carcinoma; INS: insulin; INSR: insulin receptor; KEAP1: kelch-like ECH-associated protein 1; KO: knockout; MTOR: mechanistic target of rapamycin kinase; NFE2L2: nuclear factor, erythroid 2 like 2; raptor: regulatory associated protein of MTOR, complex 1; SQSTM1: sequestosome 1: tsc1: TSC complex subunit 1.
Keywords: AKT; Atg5; Nrf2; hepatocellular carcinoma; proteotoxicity.