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
N1 - Funding Information:
A.U. was supported by a Global Grant Scholarship from The Rotary Foundation; K.T. was supported by Postdoctoral Fellowship for Research Abroad, Research Fellowship for Young Scientists from the Japan Society for the Promotion of Science, and the Uehara Memorial Foundation Fellowship; J.H.L. was supported by The Elison Medical Foundation (NS-0932-12); S.S was supported by the German Research Foundation (DFG, SH721/1-1); H.N. was supported by Daiichi Sankyo Foundation for Life Science and Astellas Foundation for Research on Metabolic Disorders. M.K. is an American Cancer Society Research Professor and the Ben and Wanda Hildyard Chair for Mitochondrial and Metabolic Diseases. Research was supported by grants from the NCI, the Superfund Basic Research Program (P42ES010337 to M.K. and E.S.), The Elison Medical Foundation, and the American Association for Study of Liver Diseases/American Liver Foundation.
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 -
