ER Stress Cooperates with Hypernutrition to Trigger TNF-Dependent Spontaneous HCC Development

• Published in: Cancer cell Vol. 26; no. 3; pp. 331 - 343
• Main Authors: Nakagawa, Hayato, Umemura, Atsushi, Taniguchi, Koji, Font-Burgada, Joan, Dhar, Debanjan, Ogata, Hisanobu, Zhong, Zhenyu, Valasek, Mark A., Seki, Ekihiro, Hidalgo, Juan, Koike, Kazuhiko, Kaufman, Randal J., Karin, Michael
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08-09-2014
• Subjects: Animals; Carcinoma, Hepatocellular - etiology; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cells, Cultured; Diet, High-Fat - adverse effects; Endoplasmic Reticulum Stress; Fatty Liver - etiology; Fatty Liver - metabolism; Heat-Shock Proteins - metabolism; Lipogenesis; Liver Neoplasms, Experimental - etiology; Liver Neoplasms, Experimental - metabolism; Liver Neoplasms, Experimental - pathology; Male; Mice; Mice, Transgenic; Overnutrition - complications; Receptors, Tumor Necrosis Factor, Type I - metabolism; Signal Transduction; Tumor Burden; Tumor Necrosis Factor-alpha - physiology; Urokinase-Type Plasminogen Activator - genetics; Urokinase-Type Plasminogen Activator - metabolism
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccr.2014.07.001

Endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of viral hepatitis, insulin resistance, hepatosteatosis, and nonalcoholic steatohepatitis (NASH), disorders that increase risk of hepatocellular carcinoma (HCC). To determine whether and how ER stress contributes to obesity-driven hepatic tumorigenesis we fed wild-type (WT) and MUP-uPA mice, in which hepatocyte ER stress is induced by plasminogen activator expression, with high-fat diet. Although both strains were equally insulin resistant, the MUP-uPA mice exhibited more liver damage, more immune infiltration, and increased lipogenesis and, as a result, displayed classical NASH signs and developed typical steatohepatitic HCC. Both NASH and HCC development were dependent on TNF produced by inflammatory macrophages that accumulate in the MUP-uPA liver in response to hepatocyte ER stress.
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•A mouse model is created for high-fat-diet (HFD)-induced NASH and HCC•ER stress increases NASH and HCC risk in response to HFD•NASH and HFD-driven HCC depend on TNF and IKKβ signaling•ER stress increases NASH and HCC risk independently of insulin resistance
Nakagawa et al. examine the role of ER stress in obesity-driven hepatic tumorigenesis. They find that ER stress increases the risk of high-fat diet-induced nonalcoholic steatohepatitis and hepatocellular carcinoma and concurrently develop a mouse model of the disease based on these findings.