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Title: Liver damage, inflammation, and enhanced tumorigenesis after persistent mTORC1 inhibition.

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

Published In Cell Metab, (2014 Jul 01)

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.

PubMed ID: 24910242 Exiting the NIEHS site

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 Neoplasms/metabolism; Liver Neoplasms/pathology; Liver/drug effects*; Liver/injuries; 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*

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