Pathological characterization and morphometric analysis of hepatic lesions in SHRSP5/Dmcr, an experimental non-alcoholic steatohepatitis model, induced by high-fat and high-cholesterol diet
Pathological characterization and morphometric analysis of hepatic lesions in SHRSP5/Dmcr, an experimental non-alcoholic steatohepatitis model, induced by high-fat and high-cholesterol diet
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DOI：
10.1111/iep.12169
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发表时间：
2016-02-01
影响因子：
3
通讯作者：
Fukunari, Atsushi
中科院分区：
文献类型：
--
作者：
Horai, Yasushi;Utsumi, Hiroyuki;Fukunari, Atsushi
SHRSP5/Dmcr是卒中易感型自发性高血压大鼠(SHRSP)的一个新亚系。最近，高脂高胆固醇(HFC)饲料喂养的SHRSP5/Dmcr被报道为一种类似于人类非酒精性脂肪性肝炎(NASH)的新的大鼠肝脏病变模型。本研究旨在用分子生物学方法和形态计量学方法研究HFC饮食诱导的SHRSP5/Dmcr大鼠的详细病理状态。6周龄SHRSP5/Dmcr大鼠分别饲喂HFC饲料和易卒中(SP)饲料2、4、6、8、16周，观察肝脏组织病理学、血液化学及肝组织中mRNA表达水平的变化。SHRSP5/Dmcr大鼠肝脏组织病理学检查显示，肝脂肪变性和小叶炎性改变，从饲喂HFC后2周开始逐渐加重。6周时可见部分肝纤维化，16周时可见较严重的桥接形成，遍及整个肝脏区域。形态计量学分析脂肪变性(脂滴大小分布)、炎症和纤维化等Nash样肝脏病变的程度。肝细胞中的嗜酸性包涵体与COX-4和双膜壁呈免疫反应，被鉴定为巨型线粒体。血清丙氨酸氨基转移酶、胆红素及肝纤维化相关基因表达水平与肝组织病理改变密切相关。饲喂HFC饲料的SHRSP5/Dmcr大鼠出现明显的NASH样肝损伤的进展，这进一步证实了该株可能是一种有用的NASH和炎性纤维性肝病模型。
SHRSP5/Dmcr is a newly established substrain of stroke-prone spontaneously hypertensive rat (SHRSP). Recently, high-fat and high-cholesterol (HFC) diet-fed SHRSP5/Dmcr has been reported as a novel rat model of developing hepatic lesions similar to human non-alcoholic steatohepatitis (NASH). The aim of this study was to investigate the detailed pathological conditions induced by HFC diet in SHRSP5/Dmcr rats using molecular biological methods and morphometric analysis. SHRSP5/Dmcr rats at 6weeks of age were fed on either HFC diet or stroke-prone (SP) diet for 2, 4, 6, 8 and 16weeks and histopathological changes in the liver, blood chemistry and mRNA expression levels in the liver were investigated. As evidenced by the histopathological examination of the liver of the SHRSP5/Dmcr rats, hepatic steatosis and lobular inflammation were present, with gradual increasing severity from 2weeks after the introduction of the HFC diet. Partial hepatic fibrosis was detected at 6weeks and spread over the entire region of the liver with more severe bridging formation by 16weeks. The degrees of NASH-like hepatic lesions such as steatosis (the size distribution of lipid droplets), inflammation and fibrosis were quantified by morphometric analysis. Eosinophilic inclusion bodies encountered in the hepatocytes had immunoreactivity with Cox-4 and double-membrane walls, identified as mega-mitochondria. Serum ALT and bilirubins, and the mRNA expression levels related to fibrosis were closely correlated with hepatic histopathological changes. The clear feeding time-dependent progression of NASH-like hepatic lesion in HFC diet-fed SHRSP5/Dmcr rats reinforced the conclusion that this strain might be a useful model of NASH and of inflammatory fibrotic liver disease.