Melanocortin 4 Receptor-Deficient Mice as a Novel Mouse Model of Nonalcoholic Steatohepatitis
Melanocortin 4 Receptor-Deficient Mice as a Novel Mouse Model of Nonalcoholic Steatohepatitis
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DOI：
10.1016/j.ajpath.2011.07.014
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发表时间：
2011-11-01
影响因子：
6
通讯作者：
Ogawa, Yoshihiro
中科院分区：
文献类型：
--
作者：
Itoh, Michiko;Suganami, Takayoshi;Ogawa, Yoshihiro
肥胖可以被视为参与代谢综合征发展的慢性低度炎症状态。非酒精性脂肪性肝炎（NASH）被认为是代谢综合征的一种肝脏表型，并且是进展为肝硬化和肝细胞癌的高风险。尽管“两次打击”假说表明涉及肝脏脂质过度积聚和慢性炎症，但NASH发展的分子机制仍不清楚，部分原因是缺乏适当的动物模型。在此，我们报告了黑皮质素4受体缺陷小鼠（MC 4 R-KO）在喂食高脂饮食时发生脂肪性肝炎，这与肥胖、胰岛素抵抗和血脂异常有关。组织学分析揭示了MC 4 R-KO小鼠肝脏中的炎性细胞浸润、肝细胞气球样变和细胞周纤维化。值得注意的是，所有检查的MC 4 R-KO小鼠在喂食高脂肪饮食1年后都发生了分化良好的肝细胞癌。他们还证明了脂肪组织炎症增强，即巨噬细胞浸润和纤维化变化增加，这可能导致肝脏中脂质过度积聚和纤维化增强。因此，MC 4 R-KO小鼠提供了一种新的NASH小鼠模型，用于研究构成饮食诱导的肝脂肪变性、肝纤维化和肝细胞癌的事件序列，并有助于理解NASH的发病机制，寻求特异性生物标志物，并评估潜在的治疗策略。(Am J Pathol 2011，179：2454-2463; DOI：10.1016/j.ajpath.2011.07.014）
Obesity may be viewed as a state of chronic low-grade inflammation that participates in the development of the metabolic syndrome. Nonalcoholic steatohepatitis (NASH) is considered a hepatic phenotype of the metabolic syndrome and a high risk for progression to cirrhosis and hepatocellular carcinoma. Although the "two hit" hypothesis suggests involvement of excessive hepatic lipid accumulation and chronic inflammation, the molecular mechanisms underlying the development of NASH remain unclear, in part because of lack of appropriate animal models. Herein we report that melanocortin 4 receptor deficient mice (MC4R-KO) develop steatohepatitis when fed a high-fat diet, which is associated with obesity, insulin resistance, and dyslipidemia. Histologic analysis reveals inflammatory cell infiltration, hepatocyte ballooning, and pericellular fibrosis in the liver in MC4R-KO mice. Of note, all of the MC4R-KO mice examined developed well-differentiated hepatocellular carcinoma after being fed a high-fat diet for 1 year. They also demonstrated enhanced adipose tissue inflammation, ie, increased macrophage infiltration and fibrotic changes, which may contribute to excessive lipid accumulation and enhanced fibrosis in the liver. Thus, MC4R-KO mice provide a novel mouse model of NASH with which to investigate the sequence of events that make up diet-induced hepatic steatosis, liver fibrosis, and hepatocellular carcinoma and to aid in understanding the pathogenesis of NASH, pursuing specific biomarkers, and evaluating potential therapeutic strategies. (Am J Pathol 2011, 179:2454-2463; DOI: 10.1016/j.ajpath.2011.07.014)