Komatsu Ginga, Nonomura Toru, Sasaki Mai, Ishida Yuki, Arai Satoko, Miyazaki Toru
Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Research Division Pharmacology Group, New Drug Research Center Inc., 452-1 Toiso, Eniwa-shi, Hokkaido 061-1405, Japan.
Exp Anim. 2019 May 8;68(2):147-158. doi: 10.1538/expanim.18-0108. Epub 2018 Nov 28.
Owing to changes in lifestyle, nonalcoholic fatty liver disease (NAFLD) is becoming a common form of chronic liver injury. NAFLD comprises a wide variety of disease stages, from simple steatosis to nonalcoholic steatohepatitis, which is a risk factor for the development of hepatocellular carcinoma (HCC). Because animal models for NAFLD are needed to investigate the precise pathogenesis, we aimed to establish a new mouse model employing mice deficient for apoptosis inhibitor of macrophage (AIM), which exhibit accelerated lipid storage in the liver and high susceptibility to developing HCC in response to a high-fat diet (HFD). AIM mice were fed the D09100301 diet, which contains 40 kcal% fat (trans fat 30 kcal%), high cholesterol (2%), and 40 kcal% carbohydrates (20 kcal% fructose), and then features of obesity and NAFLD including steatosis, inflammation, fibrosis, and HCC development were analyzed. Although a comparable grade of liver steatosis was promoted in AIM mice by the D09100301 diet and the standard HFD (60 kcal% largely lard fat), significantly less lipid storage in visceral fat was observed when the mice were fed the D09100301 diet. Accelerated liver inflammation was promoted by the D09100301 diet compared with the HFD, but interestingly, HCC development was decreased in mice fed the D09100301 diet. Our findings suggest that AIM mice fed the D09100301 diet exhibited a phenotype that resembled nonobese NAFLD patients and thus could be an appropriate tool to study the pathophysiology by which obesity increases the risk of HCC.
由于生活方式的改变，非酒精性脂肪性肝病（NAFLD）正成为慢性肝损伤的一种常见形式。NAFLD包括从单纯性脂肪变性到非酒精性脂肪性肝炎等多种疾病阶段，而非酒精性脂肪性肝炎是肝细胞癌（HCC）发生的一个危险因素。因为需要NAFLD动物模型来研究其确切发病机制，我们旨在建立一种新的小鼠模型，该模型使用缺乏巨噬细胞凋亡抑制因子（AIM）的小鼠，这些小鼠在高脂饮食（HFD）下肝脏脂质储存加速且易发生HCC。给AIM小鼠喂食D09100301饲料，其含有4０千卡%的脂肪（反式脂肪3０千卡%）、高胆固醇（2%）和4０千卡%的碳水化合物（2０千卡%果糖），然后分析肥胖和NAFLD的特征，包括脂肪变性、炎症、纤维化和HCC的发生情况。尽管D09100301饲料和标准HFD（6０千卡%主要是猪油脂肪）在AIM小鼠中促进了相当程度的肝脏脂肪变性，但当给小鼠喂食D09100301饲料时，在内脏脂肪中观察到的脂质储存明显较少。与HFD相比，D09100301饲料促进了肝脏炎症的加速，但有趣的是，喂食D09100301饲料的小鼠中HCC的发生减少。我们的研究结果表明，喂食D09100301饲料的AIM小鼠表现出一种类似于非肥胖NAFLD患者的表型，因此可能是研究肥胖增加HCC风险的病理生理学的合适工具。
