Mells Jamie E, Fu Ping P, Kumar Pradeep, Smith Tekla, Karpen Saul J, Anania Frank A
Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, 30322, USA.
Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA.
J Nutr Biochem. 2015 Mar;26(3):285-92. doi: 10.1016/j.jnutbio.2014.11.002. Epub 2014 Dec 6.
Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome (MetS). Up to a third of NAFLD subjects are at risk for developing nonalcoholic steatohepatitis (NASH). Many rodent models fail to replicate both MetS and NASH. The purpose of this study was to develop a reliable mouse model of NASH and MetS using a diet containing cholesterol, saturated fat and carbohydrate that is reflective of Western diets of North Americans.
We used adult male C57BL/6 J 4- to 5-week-old mice and administered a solid diet containing 0.2% cholesterol, 45% of its calories from fat, with 30% of the fat in the form of partially hydrogenated vegetable oil. We also provided carbohydrate largely as high-fructose corn syrup equivalent in water. In a separate cohort, we gave the identical diet in the absence of cholesterol. Glucose and insulin tolerance testing was conducted throughout the feeding period. The feeding was conducted for 16 weeks, and the mice were sacrificed for histological analysis, markers of MetS, liver inflammation, circulating lipids, as well as liver staining for fibrosis and alpha smooth muscle actin (α-SMA).
We found that cholesterol significantly increased serum leptin, interleukin-6, liver weight and liver weight/body weight ratio, fibrosis and liver α-SMA.
Mice administered a diet accurately reflecting patterns associated with humans afflicted with MetS can reliably replicate features of MetS, NASH and significant liver fibrosis. The model we describe significantly reduces the time by several months for development of stage 3 hepatic fibrosis.
非酒精性脂肪性肝病（NAFLD）是代谢综合征（MetS）的肝脏表现。高达三分之一的NAFLD患者有发展为非酒精性脂肪性肝炎（NASH）的风险。许多啮齿动物模型无法同时复制MetS和NASH。本研究的目的是使用一种含有胆固醇、饱和脂肪和碳水化合物的饮食来建立一种可靠的NASH和MetS小鼠模型，这种饮食反映了北美人的西方饮食。
我们使用4至5周龄的成年雄性C57BL/6 J小鼠，并给予一种固体饮食，其中含有0.2%的胆固醇，45%的热量来自脂肪，其中30%的脂肪以部分氢化植物油的形式存在。我们还主要以等量的高果糖玉米糖浆形式在水中提供碳水化合物。在另一个队列中，我们在不含胆固醇的情况下给予相同的饮食。在整个喂养期间进行葡萄糖和胰岛素耐受性测试。喂养持续16周，然后处死小鼠进行组织学分析、MetS标志物、肝脏炎症、循环脂质分析，以及肝脏纤维化和α平滑肌肌动蛋白（α-SMA）染色。
我们发现胆固醇显著增加了血清瘦素、白细胞介素-6、肝脏重量和肝脏重量/体重比、纤维化和肝脏α-SMA。
给予准确反映与患有MetS的人类相关模式的饮食的小鼠能够可靠地复制MetS、NASH和显著肝脏纤维化的特征。我们描述的模型显著缩短了3期肝纤维化发展所需的时间，缩短了几个月。
