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

Abstract

Summary Endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of viral hepatitis, insulin resistance, hepatosteatosis and non-alcoholic 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, 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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Next Generation of Preclinical Liver Cancer Models

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