Development of a novel mouse model of hepatocellular carcinoma with nonalcoholic steatohepatitis using a high-fat, choline-deficient diet and intraperitoneal injection of diethylnitrosamine.
Development of a novel mouse model of hepatocellular carcinoma with nonalcoholic steatohepatitis using a high-fat, choline-deficient diet and intraperitoneal injection of diethylnitrosamine.
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DOI：
10.1186/s12876-016-0477-5
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发表时间：
2016-06-13
影响因子：
2.4
通讯作者：
Kitagawa Y
中科院分区：
文献类型：
--
作者：
Kishida N;Matsuda S;Itano O;Shinoda M;Kitago M;Yagi H;Abe Y;Hibi T;Masugi Y;Aiura K;Sakamoto M;Kitagawa Y
肝细胞癌合并非酒精性脂肪性肝炎的发病率呈上升趋势，其临床病理特征已有较好的认识。一些非酒精性脂肪性肝炎的动物模型已经被开发出来，以便于其研究；然而，很少有动物模型完全概括其所有的临床特征，包括胰岛素抵抗、炎症、纤维化和癌变。此外，这些模型需要相对较长的时间才能可靠地产生肝细胞癌。这项研究的目的是建立一种发展迅速并反映所有临床相关特征的非酒精性脂肪性肝炎的小鼠肝细胞癌模型。三周龄的C57BL/6J雄性小鼠分别饲喂标准饲料(MF)和胆碱缺乏的高脂饲料(HFCD)。MF + 二乙基亚硝胺(DEN)组和HFCD + DEN组在各自喂养方案开始时一次性腹腔注射DEN。Hfcd和hfcd + DEN组的小鼠在实验早期出现肥胖，12周后出现胰岛素抵抗。所有四组的甘油三酯水平都在8周时达到峰值，此后下降。丙氨酸氨基转移酶水平每4周升高一次，其中HFCD和HFCD + DEN组表现出显著的高水平；HFCD + DEN组非酒精性脂肪性肝炎的发生率最高。肝纤维化和脂肪变性的程度各不相同，但在HFCD和HFCD + DEN组中，它们倾向于每4周增加一次。计算机断层扫描显示，所有HFCD + DEN小鼠在20周后都出现了肝脏肿瘤，其中一些是谷氨酰胺合成酶阳性的。我们在这里描述的非酒精性脂肪性肝炎-肝细胞癌模型建立简单，导致快速肿瘤形成，并概括了非酒精性脂肪性肝炎的大多数关键特征。因此，它可以促进对这种疾病的发展、致癌潜力、诊断和治疗的进一步研究。本文的在线版本(doi：10.1186/s12876-0160477-5)包含补充材料，授权用户可以使用。
The incidence of hepatocellular carcinoma with nonalcoholic steatohepatitis is increasing, and its clinicopathological features are well established. Several animal models of nonalcoholic steatohepatitis have been developed to facilitate its study; however, few fully recapitulate all its clinical features, which include insulin resistance, inflammation, fibrosis, and carcinogenesis. Moreover, these models require a relatively long time to produce hepatocellular carcinoma reliably. The aim of this study was to develop a mouse model of hepatocellular carcinoma with nonalcoholic steatohepatitis that develops quickly and reflects all clinically relevant features. Three-week-old C57BL/6J male mice were fed either a standard diet (MF) or a choline-deficient, high-fat diet (HFCD). The mice in the MF + diethylnitrosamine (DEN) and HFCD + DEN groups received a one-time intraperitoneal injection of DEN at the start of the respective feeding protocols. The mice in the HFCD and HFCD + DEN groups developed obesity early in the experiment and insulin resistance after 12 weeks. Triglyceride levels peaked at 8 weeks for all four groups and decreased thereafter. Alanine aminotransferase levels increased every 4 weeks, with the HFCD and HFCD + DEN groups showing remarkably high levels; the HFCD + DEN group presented the highest incidence of nonalcoholic steatohepatitis. The levels of fibrosis and steatosis varied, but they tended to increase every 4 weeks in the HFCD and HFCD + DEN groups. Computed tomography scans indicated that all the HFCD + DEN mice developed hepatic tumors from 20 weeks, some of which were glutamine synthetase-positive. The nonalcoholic steatohepatitis-hepatocellular carcinoma model we describe here is simple to establish, results in rapid tumor formation, and recapitulates most of the key features of nonalcoholic steatohepatitis. It could therefore facilitate further studies of the development, oncogenic potential, diagnosis, and treatment of this condition. The online version of this article (doi:10.1186/s12876-016-0477-5) contains supplementary material, which is available to authorized users.