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

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

Author information

1
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
2
Department of Medicine, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
3
Department of Molecular and Integrative Physiology, University of Michigan Geriatrics Center, 109 Zina Pitcher Place, 3019 BSRB, Ann Arbor, MI 48109-2200, USA.
4
Department of Pathology, Moores Cancer Center, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
5
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
6
Biozentrum, University of Basel, Klingelbergstrasse 70, 4056 Basel, Switzerland.
7
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. Electronic address: karinoffice@ucsd.edu.

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.

PMID:
24910242
PMCID:
PMC4079758
DOI:
10.1016/j.cmet.2014.05.001
[Indexed for MEDLINE]
Free PMC Article

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