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HCC Development Is Associated to Peripheral Insulin Resistance in a Mouse Model of NASH

机译：在NASH小鼠模型中肝癌的发展与周围胰岛素抵抗有关

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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.
机译：NAFLD是全球最常见的肝脏疾病，但即使没有肝硬化，它也是向NASH并最终发展为肝细胞癌（HCC）的潜在进化，使得NAFLD具有如此的临床重要性。目的：我们旨在建立一个小鼠模型，再现NAFLD的病理光谱，并研究可能的辅助因子在促进肝癌中的作用。方法：用胆碱缺乏的L-氨基酸定饮食（CDAA）或其对照（CSAA饮食）治疗小鼠，并低剂量腹腔注射。注入四氯化碳或媒介。胰岛素抵抗通过正常血糖-高胰岛素钳夹法测量。通过组织学和分子分析评估脂肪变性，纤维化和肝癌。结果：CDAA处理的小鼠在1个月时表现出外周胰岛素抵抗。在1-3个月时，在CDAA和CDAA + CCl4组中观察到广泛的脂肪变性和纤维化。在6个月时，两组之间的脂肪变性和纤维化程度均增加，并且出现了肿瘤。在治疗9个月时，用CDAA + CCl4处理的小鼠中有100％显示出肿瘤，而使用CDAA + CCl4处理过的小鼠中有40％显示出肿瘤。与CSAA相比，CDAA小鼠中的胰岛素样生长因子2（IGF-2）和骨桥蛋白（SPP-1）升高。此外，对p-AKT，p-c-Myc和Glypican-3的免疫染色显示了在肿瘤中阳性的增加。结论：在有胰岛素抵抗但无肝硬化的情况下，CDAA模型可促进NAFLD-NASH诱导HCC的发展。由于这种情况已在人类中得到越来越多的认识，因此我们的研究提供了一个模型，可以帮助理解NAFLD的致癌机理。

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