Model of nonalcoholic steatohepatitis.
Model of nonalcoholic steatohepatitis.
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DOI：
10.1093/ajcn/79.3.502
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发表时间：
2004-03
期刊：
影响因子：
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通讯作者：
C. Lieber;M. A. Leo;K. Mak;Youqing Xu;Q. Cao;C. Ren;A. Ponomarenko;L. Decarli
中科院分区：
文献类型：
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作者：
C. Lieber;M. A. Leo;K. Mak;Youqing Xu;Q. Cao;C. Ren;A. Ponomarenko;L. Decarli
背景肥胖和糖尿病通常与非酒精性脂肪性肝炎（NASH）相关，但由于缺乏合适的实验模型，研究受到阻碍。目的建立NASH大鼠模型。设计Sprague-Dawley大鼠喂食高脂流质饮食（71%的能量来自脂肪，11%来自碳水化合物，18%来自蛋白质）或标准Lieber-DeCarli饮食（35%的能量来自脂肪，47%来自碳水化合物，18%来自蛋白质）。自由采食或以自由采食量的三分之二饲喂饲料。结果高脂饲料喂养大鼠3 wk后出现全小叶性脂肪变性，而标准饲料喂养大鼠脂肪滴较少。相应地，高脂饮食和标准饮食的总脂质浓度分别为129.9 +/- 9.1（+/- SEM）和66.7 +/- 4.6 mg/g肝脏（P < 0.001）。高脂饮食导致线粒体和单核细胞炎症异常，并伴有肝肿瘤坏死因子α（TNF-α; P < 0.001）、TNF-α信使RNA（mRNA）（P < 0.001）、1型胶原和α 1（I）前胶原mRNA（P < 0.001）增加。此外，这些大鼠具有细胞色素P4502 E1（CYP 2 E1）mRNA的增加（P < 0.001），这伴随着CYP 2 E1诱导（P < 0.001）和氧化应激与增加的4-羟基壬烯醛（P < 0.001）。血浆胰岛素升高，反映胰岛素抵抗，NASH的致病因素。喂食限制性高脂饮食的大鼠仅出现轻度脂肪变性，生化变化减弱，而喂食限制性标准饮食的大鼠肝脏正常。结论该大鼠模型再现了NASH的主要特征，为阐明NASH的治疗提供了一个现实的实验模型。
BACKGROUND Obesity and diabetes are frequently associated with nonalcoholic steatohepatitis (NASH), but studies have been hampered by the absence of a suitable experimental model. OBJECTIVE Our objective was to create a rat model of NASH. DESIGN Sprague-Dawley rats were fed a high-fat, liquid diet (71% of energy from fat, 11% from carbohydrates, 18% from protein) or the standard Lieber-DeCarli diet (35% of energy from fat, 47% from carbohydrates, 18% from protein). The diets were given ad libitum or as two-thirds of the amount consumed ad libitum. RESULTS Rats fed the high-fat diet ad libitum for 3 wk developed panlobular steatosis, whereas those fed the standard diet had few fat droplets. Accordingly, total lipid concentrations with the high-fat and standard diets were 129.9 +/- 9.1 ( +/- SEM) and 66.7 +/- 4.6 mg/g liver, respectively (P < 0.001). The high-fat diet caused abnormal mitochondria and mononuclear inflammation, which were accompanied by increased hepatic tumor necrosis factor alpha (TNF-alpha; P < 0.001), TNF-alpha messenger RNA (mRNA) (P < 0.001), collagen type 1, and alpha1(I) procollagen mRNA (P < 0.001). In addition, these rats had increased cytochrome P4502E1 (CYP2E1) mRNA (P < 0.001), which was accompanied by CYP2E1 induction (P < 0.001) and oxidative stress with increased 4-hydroxynonenal (P < 0.001). Plasma insulin was elevated, which reflected insulin resistance, a NASH pathogenic factor. Rats fed a restricted high-fat diet developed only mild steatosis with attenuated biochemical changes, whereas those given a restricted standard diet had normal livers. CONCLUSION This rat model reproduces the key features of human NASH and provides a realistic experimental model for elucidating its treatment.