Increased hepatic apoptosis in high-fat diet-induced NASH in rats may be associated with downregulation of hepatic stimulator substance
Increased hepatic apoptosis in high-fat diet-induced NASH in rats may be associated with downregulation of hepatic stimulator substance
复制标题
高脂饮食诱导的大鼠 NASH 中肝细胞凋亡增加可能与肝刺激物质的下调有关
DOI：
10.1007/s00109-011-0790-y
复制
发表时间：
2011-12-01
影响因子：
4.7
通讯作者：
An, Wei
中科院分区：
文献类型：
--
作者：
Jiang, Ying;Zhao, Miaoyun;An, Wei
从脂肪肝发展到脂肪性肝炎和肝硬化的机制尚未完全阐明。肝细胞凋亡可能是非酒精性脂肪性肝炎（NASH）发病的关键因素之一。肝刺激物质（HSS）保护肝细胞免受各种毒素的侵害。我们以前报道过，HSS是至关重要的肝细胞的生存，由于其线粒体协会。本研究旨在通过高脂饮食诱导的NASH体内模型和棕榈酸诱导的肝细胞损伤体外模型研究HSS与肝细胞凋亡的关系。Sprague-Dawley大鼠喂食高脂饮食8周、12周和16周。检测肝组织病理学改变、肝功能和细胞凋亡。HSS的表达，与caspase-3和细胞色素渗漏，这两个指标的细胞凋亡，进行了测量。结果显示，高脂饮食以类似NASH的方式改变了肝功能和组织学。肝HSS蛋白和mRNA表达随NASH进展而降低。同时，细胞凋亡增加，caspase-3激活，细胞色素释放增加，提示HSS可能参与NASH的发病过程。此外，在棕榈酸诱导的肝细胞损伤中，HSS的过度表达减少了细胞凋亡。相比之下，通过SiRNA抑制HSS表达会增加细胞凋亡。总之，这些数据意味着细胞凋亡有助于NASH的发病机制，在此期间HSS表达下调。肝细胞中HSS表达的增加可能会阻止脂肪酸损伤导致的细胞凋亡。
The mechanisms of progression from fatty liver to steatohepatitis and cirrhosis are not well elucidated. Hepatocellular apoptosis could be one of the key factors in the pathogenesis of non-alcoholic steatohepatitis (NASH). Hepatic stimulator substance (HSS) protects liver cells from various toxins. We previously reported that HSS is critically important for the survival of hepatocytes due to its mitochondrial association. This study aims to investigate the relationship between HSS and hepatocellular apoptosis in vivo models of high-fat diet-induced NASH and in vitro models of palmitic acid-induced hepatocyte injury. Sprague–Dawley rats were fed a high-fat diet for 8, 12 and 16 weeks. Hepatic histological lesions, liver function and apoptosis were examined. HSS expression, in association with caspase-3 and cytochromecleakage, which are both indicators of cell apoptosis, was measured. Results showed that a high-fat diet altered liver function and histology in a manner resembling NASH. Hepatic protein and mRNA HSS expression was decreased as NASH progressed. Meanwhile, cell apoptosis increased as result of caspase-3 activation and cytochromecrelease, indicating that HSS might be involved in NASH pathogenesis. Furthermore, in palmitic acid-induced hepatic cell damage, over-expression of HSS decreased cells apoptosis. In contrast, repression of HSS expression by siRNA increased cell apoptosis. In conclusion, these data imply that cell apoptosis contributes to the pathogenesis of NASH, during which HSS expression is downregulated. Increasing HSS expression in hepatocytes may forestall cell apoptosis as result of fatty acid insult.