TY - JOUR
T1 - Liver damage, inflammation, and enhanced tumorigenesis after persistent mTORC1 inhibition
AU - Umemura, Atsushi
AU - Park, Eek Joong
AU - Taniguchi, Koji
AU - Lee, Jun Hee
AU - Shalapour, Shabnam
AU - Valasek, Mark A.
AU - Aghajan, Mariam
AU - Nakagawa, Hayato
AU - Seki, Ekihiro
AU - Hall, Michael N.
AU - Karin, Michael
PY - 2014/7/1
Y1 - 2014/7/1
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cmet.2014.05.001
DO - 10.1016/j.cmet.2014.05.001
M3 - Article
C2 - 24910242
AN - SCOPUS:84903958633
VL - 20
SP - 133
EP - 144
JO - Cell Metabolism
JF - Cell Metabolism
SN - 1550-4131
IS - 1
ER -