【摘要】 为了开发与人类非酒精性脂肪性肝炎(Non-alcoholic steatohepatitis,NASH)特征相似的动物疾病模型,本试验利用肝脏特异性Dicer1基因敲除(KO)小鼠,经高脂高糖饮食诱导12周构建了一种新型NASH小鼠模型。试验分为4组包括正常饮食的野生型小鼠组(CW组)、正常饮食的KO小鼠组(CK组)、高脂高糖饮食的野生小鼠组(HW组)、高脂高糖饮食的KO小鼠组(HK组,本试验模型组)。研究结果显示,HK组小鼠体重和肝脏比重升高,谷丙转氨酶(ALT)、谷草转氨酶(AST)水平显著升高;HK和HW组肾周白色脂肪和附睾白色脂肪比重均明显升高;血脂相关指标显示,HK组甘油三酯(TG)、总胆固醇(TC)、低密度脂蛋白(LDLC)水平明显升高;口服糖耐量测试(OGTT)结果显示,HW、HK组糖耐量降低;组织病理学方面,HK组和CK组均可见肝脏脂肪变性、肝小叶炎症及纤维化,且HK组程度更为严重;此外,HK组还可见肝细胞气球样,个别肝细胞胞浆内Mallory-Denk小体,以及单个肝细胞凋亡。而HW组仅存在肝细胞脂肪变性。油红O染色证实肝细胞中的空泡为脂肪滴。天狼星红染色显示,HK和CK组存在肝纤维化。综上所述,本试验构建了一种新型非酒精性脂肪性肝炎小鼠模型,与人类NASH在诸多方面特征相似,包括体重增长快、肝功异常、白色脂肪蓄积、血脂异常、糖耐量降低、以及NASH相关的肝脏病理特征。此外,该模型相对诱导周期短,且饮食结构与引起人类NASH的常见的膳食结构相似。这一新模型的建立将有助于NASH疾病机制以及治疗方面的研究。更多还原

【Abstract】 In order to develop a non-alcoholic steatohepatitis(NASH) animal model similar to human NASH, a new NASH model was established in liver-specific Dicer1 knockout mice(KO) induced by high-fat and high-sugar diet for 12 weeks. There were four groups in this study: wild-type mice fed with normal chow diet(CW group), KO mice fed with normal chow diet(CK group), wild mice fed with high fat and high-sugar diet(HW group), and KO mice fed with high-fat and high-sugar diet(HK group, that is modeling group). The results showed that mice in HK group had increased body weight, liver weight to body weight ratio, and levels of serum ALT and AST.The ratio of perirenal white fat weight or epididymal white fat weight to body weight significantly increased in HK and HW groups. In terms of serum lipid indicators, the concentrations of triglyceride(TG), total cholesterol(TC), and low-density lipoprotein(LDLC) significantly increased in HK group; oral glucose tolerance test(OGTT) showed decreased glucose tolerance in HW and HK groups. Histopathological findings included steatosis of hepatocytes, lobular inflammation, and fibrosis in the liver in both HK and CK groups. The severity of the above findings was more serious in HK group. In addition, hepatocellular ballooning, individual intracytoplasmic Mallory-Denk bodies, and single hepatocyte apoptosis were present in the liver of HK group.Mice in HW group had only steatosis in the liver. Oil red O staining confirmed that the vacuoles in the hepatocytes were fat droplets. Sirius red staining indicated the presence of fibrosis in the liver of HK and CK groups. In conclusion, we have established a diet-induced new NASH animal model in mice with liver-specific Dicer1 gene knockout, which mimics human NASH in many aspects, including increased body weight, abnormal liver function, white fat accumulation, dyslipidemia, glucose tolerance reduction, and NASH-related pathological characteristics of liver. In addition, this model has a relatively short induction period, and the diets used for dietary induction well simulate the dietary structure of human NASH. This new model can facilitate the study of pathogenesis and therapeutic targets of NASH.更多还原