Liver damage, inflammation, and enhanced tumorigenesis after persistent mTORC1 inhibition

Atsushi Umemura, Eek Joong Park, Koji Taniguchi, Jun Hee Lee, Shabnam Shalapour, Mark A. Valasek, Mariam Aghajan, Hayato Nakagawa, Ekihiro Seki, Michael N. Hall, Michael Karin

Research output: Contribution to journalArticlepeer-review

145 Citations (Scopus)


Obesity can result in insulin resistance, hepatosteatosis, and nonalcoholic steatohepatitis (NASH) and increases liver cancer risk. Obesity-induced insulin resistance depends, in part, on chronic activation of mammalian target of rapamycin complex 1 (mTORC1), which also occurs in human and mouse hepatocellular carcinoma (HCC), a frequently fatal liver cancer. Correspondingly, mTORC1 inhibitors have been considered as potential NASH and HCC treatments. Using a mouse model in which high-fat diet enhances HCC induction by the hepatic carcinogen DEN, we examined whether mTORC1 inhibition attenuates liver inflammation and tumorigenesis. Notably, rapamycin treatment or hepatocyte-specific ablation of the specific mTORC1 subunit Raptor resulted in elevated interleukin-6 (IL-6) production, activation of signal transducer and activator of transcription 3 (STAT3), and enhanced HCC development, despite a transient reduction in hepatosteatosis. These results suggest that long-term rapamycin treatment, which also increases IL-6 production in humans, is unsuitable for prevention or treatment of obesity-promoted liver cancer.

Original languageEnglish
Pages (from-to)133-144
Number of pages12
JournalCell Metabolism
Issue number1
Publication statusPublished - 2014 Jul 1
Externally publishedYes

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology


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