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Autophagy is a lysosomal degradation pathway that degrades cytoplasmic proteins and organelles. Absence of autophagy in hepatocytes has been linked to promoting liver injury and tumorigenesis, however the mechanisms behind why a lack of autophagy induces these complications is not fully understood. The role of mammalian target of rapamycin (mTOR) in impaired autophagy-induced liver pathogenesis and tumorigenesis was investigated by using liver-specific Atg5 knockout (L-Atg5 KO) mice, L-Atg5/mTOR, and L-Atg5/Raptor double knockout (DKO) mice. At two months of age, we found that deletion of mTOR or Raptor in L-Atg5 KO mice attenuated hepatomegaly, cell death and inflammation but not fibrosis. Surprisingly, at six months of age, L-Atg5/mTOR DKO and L-Atg5/Raptor DKO mice also had increased hepatic inflammation, fibrosis, and liver injury, similar to the L-Atg5 KO mice. Moreover, more than 50% of L-Atg5/mTOR DKO and L-Atg5/Raptor DKO mice already developed spontaneous tumors but none of the L-Atg5 KO mice had developed any tumors at six months of age. At nine months of age, all L-Atg5/mTOR DKO and L-Atg5/Raptor DKO had developed liver tumors. Mechanistically, L-Atg5/mTOR DKO and L-Atg5/Raptor DKO mice had deceased levels of hepatic ubiquitinated proteins and persistent Nrf2 activation but had increased Akt activation compared with L-Atg5 KO mice. In conclusion, loss of mTOR signaling attenuates the liver pathogenesis in mice with impaired-hepatic autophagy but paradoxically promotes tumorigenesis in mice at a relatively young age. Therefore, the balance of mTOR is critical in regulating the liver pathogenesis and tumorigenesis in mice with impaired hepatic autophagy. This article is protected by copyright. All rights reserved.
This article was published in the following journal.
Name: Hepatology (Baltimore, Md.)
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