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

Cell Metab. 2014 Jul 1;20(1):133-44. doi: 10.1016/j.cmet.2014.05.001. Epub 2014 Jun 5.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / deficiency
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Cell Proliferation
  • Cell Transformation, Neoplastic
  • Cells, Cultured
  • DNA Damage / drug effects
  • Diet, High-Fat
  • Diethylnitrosamine / toxicity
  • Fatty Liver / metabolism
  • Fatty Liver / pathology
  • Glucose Tolerance Test
  • Hepatocytes / cytology
  • Hepatocytes / metabolism
  • Humans
  • Inflammation* / pathology
  • Interleukin-6 / metabolism
  • Liver / drug effects*
  • Liver / injuries
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Obese
  • Mitosis
  • Multiprotein Complexes / antagonists & inhibitors
  • Multiprotein Complexes / metabolism*
  • Reactive Oxygen Species / metabolism
  • Regulatory-Associated Protein of mTOR
  • STAT3 Transcription Factor / metabolism
  • Sirolimus / toxicity*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Interleukin-6
  • Multiprotein Complexes
  • Reactive Oxygen Species
  • Regulatory-Associated Protein of mTOR
  • Rptor protein, mouse
  • STAT3 Transcription Factor
  • Diethylnitrosamine
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Sirolimus