Abstract
NAFLD is the most common liver disease worldwide but it is the potential evolution to NASH and eventually to hepatocellular carcinoma (HCC), even in the absence of cirrhosis, that makes NAFLD of such clinical importance. Aim: we aimed to create a mouse model reproducing the pathological spectrum of NAFLD and to investigate the role of possible co-factors in promoting HCC. Methods: mice were treated with a choline-deficient L-amino-acid-defined-diet (CDAA) or its control (CSAA diet) and subjected to a low-dose i.p. injection of CCl4 or vehicle. Insulin resistance was measured by the euglycemic-hyperinsulinemic clamp method. Steatosis, fibrosis and HCC were evaluated by histological and molecular analysis. Results: CDAA-treated mice showed peripheral insulin resistance at 1 month. At 1–3 months, extensive steatosis and fibrosis were observed in CDAA and CDAA+CCl4 groups. At 6 months, equal increase in steatosis and fibrosis was observed between the two groups, together with the appearance of tumor. At 9 months of treatment, the 100% of CDAA+CCl4 treated mice revealed tumor versus 40% of CDAA mice. Insulin-like Growth Factor-2 (IGF-2) and Osteopontin (SPP-1) were increased in CDAA mice versus CSAA. Furthermore, Immunostaining for p-AKT, p-c-Myc and Glypican-3 revealed increased positivity in the tumors. Conclusions: the CDAA model promotes the development of HCC from NAFLD-NASH in the presence of insulin resistance but in the absence of cirrhosis. Since this condition is increasingly recognized in humans, our study provides a model that may help understanding mechanisms of carcinogenesis in NAFLD.
Highlights
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide. [1,2]
Non-Alcoholic Fatty Liver Disease (NAFLD) is a major health problem that integrates several liver conditions ranging from simple fatty liver to Non-Alcoholic Steatohepatitis (NASH), which is associated with fibrosis that may evolve into cirrhosis and results into HCC [5]
Treatment with choline-deficient L-amino-acid-defined-diet (CDAA) Induces Insulin Resistance We evaluated the effects of CSAA and CDAA diets with the association of CCl4 on peripheral insulin resistance by the euglycemic-hyperinsulinemic clamp method
Summary
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide. [1,2]. Several studies have shown that 5% to 30% of patients with HCC lack a readily identifiable risk factor for their cancer [1]. Most of these ‘‘cryptogenic’’ HCC might be attributed to Non-Alcoholic Fatty Liver Disease (NAFLD) and the concomitant metabolic syndrome [2,3], it is not yet clear what predisposes to the progression of the disease [4]. Some hypotheses suggest that obesity, insulin resistance, release of inflammatory cytokines and autophagy can contribute to the carcinogenic potential in NASH liver, where HCC can occur in
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