[PDF][PDF] Liver damage, inflammation, and enhanced tumorigenesis after persistent mTORC1 inhibition

A Umemura, EJ Park, K Taniguchi, JH Lee… - Cell metabolism, 2014 - cell.com
A Umemura, EJ Park, K Taniguchi, JH Lee, S Shalapour, MA Valasek, M Aghajan…
Cell metabolism, 2014cell.com
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 …
Summary
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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