Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, MN 55905, USA.
Am J Physiol Gastrointest Liver Physiol. 2011 Nov;301(5):G825-34. doi: 10.1152/ajpgi.00145.2011. Epub 2011 Aug 11.
Although there are small animal platforms that recapitulate some of the histological features of nonalcoholic fatty liver disease, there are no small animal models of nonalcoholic steatohepatitis (NASH) with consistent hepatocellular ballooning and progressive fibrosis that also exhibit fidelity to the human condition physiologically. We examined the metabolic and histological effects of a diet on the basis of the composition of "fast food" (high saturated fats, cholesterol, and fructose). Mice (n = 8 in each group) were assigned to diets as follows: 1) standard chow (SC), i.e., 13% energy as fat [1% saturated fatty acids (SFA)], 2) high fat (HF), i.e., 60% energy as fat (1% SFA), and 3) fast food (FF), i.e., 40% energy as fat (12% SFA, 2% cholesterol). All three diets were supplemented with high fructose. All diets produced obesity. The HF and FF diets produced insulin resistance. Liver histology was normal in animals fed the SC diet. Steatohepatitis with pronounced ballooning and progressive fibrosis (stage 2) was observed in mice fed the FF diet. Although the HF diet produced obesity, insulin resistance, and some steatosis; inflammation was minimal, and there was no increase in fibrosis. The FF diet produced a gene expression signature of increased fibrosis, inflammation, and endoplasmic reticulum stress and lipoapoptosis. A diet based on high cholesterol, high saturated fat, and high fructose recapitulates features of the metabolic syndrome and NASH with progressive fibrosis. This represents a novel small animal model of fibrosing NASH with high fidelity to the human condition. These results highlight the contribution of dietary composition to the development of nonalcoholic fatty liver disease and NASH.
尽管有一些小动物平台可以再现非酒精性脂肪性肝病的一些组织学特征,但没有一种能够一致地再现非酒精性脂肪性肝炎(NASH)的特征,包括肝细胞气球样变和进行性纤维化,并且在生理上与人类疾病状态相吻合。我们研究了一种基于“快餐”(高脂肪、高胆固醇和高果糖)组成的饮食对代谢和组织学的影响。将小鼠(每组 8 只)分配到以下饮食中:1)标准饮食(SC),即 13%的能量来自脂肪[1%饱和脂肪酸(SFA)],2)高脂肪饮食(HF),即 60%的能量来自脂肪(1% SFA),3)快餐饮食(FF),即 40%的能量来自脂肪(12% SFA,2%胆固醇)。所有三种饮食均补充高果糖。所有饮食均导致肥胖。HF 和 FF 饮食导致胰岛素抵抗。SC 饮食喂养的动物肝脏组织学正常。FF 饮食喂养的小鼠发生明显的气球样变和进行性纤维化(2 期)。尽管 HF 饮食导致肥胖、胰岛素抵抗和一些脂肪变性,但炎症很少,纤维化也没有增加。FF 饮食导致纤维化、炎症和内质网应激以及脂肪凋亡增加的基因表达特征。基于高胆固醇、高饱和脂肪和高果糖的饮食再现了代谢综合征和伴有进行性纤维化的 NASH 的特征。这代表了一种新型的纤维化 NASH 小动物模型,与人类疾病状态具有高度的一致性。这些结果强调了饮食成分对非酒精性脂肪性肝病和 NASH 发展的贡献。