Zhao Jingmin, Zhou Guangde, Li Meirong, Li Wenshu, Lü Jiyun, Xiong Lu, Liang Li, Zhao Yulai, Xu Dongping, Yu Jun
Department of Pathology and Hepatology, Beijing 302 Hospital, Beijing, China.
Scand J Gastroenterol. 2010 Nov;45(11):1360-71. doi: 10.3109/00365521.2010.497938. Epub 2010 Jun 21.
There is no animal model that displays the features of non-alcoholic steatohepatitis (NASH) characterized by insulin resistance (IR) and fibrosing steatohepatitis. This study aimed to develop a novel IR-associated rat model of NASH.
Male Sprague-Dawley rats were fed with the high-fat diet (HFD) supplemented with 0.25% propylthiouracil for 2, 4, 6, 8 and 12 weeks. The IR-associated metabolic parameters, histological assessment and the expression of key insulin signaling molecules were determined. The circulating and tissue pro-inflammatory factors and adipocytokines were examined.
In the HFD-fed rats, the systemic and multiple-organ IR was developed after 4 weeks, whereas the histological changes characterized by steatohepatitis, inflammatory response in the visceral adipose tissue and proliferative pancreatic islet β-cells appeared after 6 weeks, concomitant with altered expression of key insulin signaling molecules. In addition, the elevated levels of serum tumor necrosis factor α (TNF-α), soluble TNF receptor2, interleukin (IL)-6, CC-chemokine ligand (CCL)2 and resistin were parallel with the severity of hepatic inflammation, while the levels of serum adiponectin, leptin and TNF-α, but not resistin, were correlated with IR.
We have developed a systemic IR-associated NASH model of rats, with impaired insulin signaling, systemic inflammation and appropriate pathology characterized by human NASH, and provided a realistic experimental model for elucidating the association between IR and the pathogenesis of NASH.
目前尚无动物模型能够展现出以胰岛素抵抗（IR）和纤维化脂肪性肝炎为特征的非酒精性脂肪性肝炎（NASH）的特点。本研究旨在建立一种新型的与IR相关的NASH大鼠模型。
雄性Sprague-Dawley大鼠喂食补充有0.25%丙基硫氧嘧啶的高脂饮食（HFD），持续2、4、6、8和12周。测定与IR相关的代谢参数、组织学评估以及关键胰岛素信号分子的表达。检测循环和组织中的促炎因子及脂肪细胞因子。
在喂食HFD的大鼠中，4周后出现全身和多器官IR，而6周后出现以脂肪性肝炎、内脏脂肪组织炎症反应和胰岛β细胞增殖为特征的组织学变化，同时关键胰岛素信号分子的表达发生改变。此外，血清肿瘤坏死因子α（TNF-α）、可溶性TNF受体2、白细胞介素（IL）-6、CC趋化因子配体（CCL）2和抵抗素水平的升高与肝脏炎症的严重程度平行，而血清脂联素、瘦素和TNF-α水平（而非抵抗素）与IR相关。
我们建立了一种与全身IR相关的大鼠NASH模型，其胰岛素信号受损、存在全身炎症且具有以人类NASH为特征的适当病理学表现，为阐明IR与NASH发病机制之间的关联提供了一个现实的实验模型。
