期刊
CELL METABOLISM
卷 20, 期 1, 页码 133-144出版社
CELL PRESS
DOI: 10.1016/j.cmet.2014.05.001
关键词
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资金
- Rotary Foundation
- Japan Society for the Promotion of Science
- Uehara Memorial Foundation Fellowship
- Elison Medical Foundation [NS-0932-12]
- German Research Foundation (DFG) [SH721/1-1]
- Daiichi Sankyo Foundation for Life Science
- Astellas Foundation for Research on Metabolic Disorders
- NCI
- Superfund Basic Research Program [P42ES010337]
- Elison Medical Foundation
- American Association for Study of Liver Diseases/American Liver Foundation
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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