Abstract
Non-alcoholic steatohepatitis (NASH), characterized by chronic inflammation and fibrosis, is predicted to be the leading cause of cirrhosis and hepatocellular carcinoma (HCC) in the next decade. Although recent evidence suggests the importance of fibrosis as the strongest determinant of HCC development, the molecular mechanisms underlying NASH-induced carcinogenesis still remain unclear. Here we performed RNA sequencing analysis to compare gene expression profiles of activated fibroblasts prepared from two distinct liver fibrosis models: carbon tetrachloride–induced fibrosis as a model without obesity and HCC and genetically obese melanocortin 4 receptor–deficient (MC4R-KO) mice fed Western diet, which develop steatosis, NASH, and eventually HCC. Our data showed that activated fibroblasts exhibited distinct gene expression patterns in each etiology, and that the ‘pathways in cancer’ were selectively upregulated in the activated fibroblasts from MC4R-KO mice. The most upregulated gene in these pathways was fibroblast growth factor 9 (FGF9), which was induced by metabolic stress such as palmitate. FGF9 exerted anti-apoptotic and pro-migratory effects in fibroblasts and hepatoma cells in vitro and accelerated tumor growth in a subcutaneous xenograft model. This study reveals upregulation of cancer-associated gene expression in activated fibroblasts in NASH, which would contribute to the progression from NASH to HCC.
Highlights
Non-alcoholic steatohepatitis (NASH), characterized by chronic inflammation and fibrosis, is predicted to be the leading cause of cirrhosis and hepatocellular carcinoma (HCC) in the decade
RNA sequencing analysis revealed that activated fibroblasts exhibited distinct gene expression patterns in each etiology, and we focused on fibroblast growth factor 9 (FGF9), which belongs to the ‘pathways in cancer’ selectively upregulated in the activated fibroblasts from MC4R-KO mice
We demonstrate for the first time that activated fibroblasts in a murine model of NASH show unique gene expression profiles, which would be involved in tumorigenesis during the progression from NASH to HCC
Summary
Non-alcoholic steatohepatitis (NASH), characterized by chronic inflammation and fibrosis, is predicted to be the leading cause of cirrhosis and hepatocellular carcinoma (HCC) in the decade. Various animal models of NASH have been proposed using hepatotoxic agents, genetic engineering, and dietary challenges[15], whereas few of them exhibit both obesity phenotypes and HCC development In this regard, we previously reported melanocortin 4 receptor–deficient (MC4R-KO) mice as a novel murine model of NASH and HCC15,16. The histological features and gene expression patterns of livers from MC4R-KO mice were closely similar to those of human NASH and HCC with metabolic risk factors[16,18]. Using this model, we demonstrated that CD11c+ resident macrophages would be a novel macrophage subset that accelerates obesity-induced liver fibrosis[19,20]. Little is known about activated fibroblasts in the model
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