脂肪酸代谢异常是二甲基亚硝胺诱导的大鼠肝纤维化发病机制之一  

Fatty Acid Metabolic Disorder is One of Mechanisms of Dimethylnitrosamine Induced Hepatic Fibrosis Rats

作　　者：边艳琴[1,2,3] 曹红燕[1,2] 李建缘 武超[1,2] 孙润菲 冯辉 何小鹃[4] 姜淼[4] 孙明瑜[1,2] 

机构地区：[1]上海中医药大学附属曙光医院上海中医药大学肝肾疾病病证教育部重点实验室上海中医药大学肝病研究所,上海201203 [2]上海市中医药研究院,上海201203 [3]上海光华中西医结合医院,上海200052 [4]中国中医科学院中医临床基础医学研究所,北京100700

出　　处：《世界科学技术-中医药现代化》2016年第2期241-249,共9页Modernization of Traditional Chinese Medicine and Materia Medica-World Science and Technology

基　　金：国家自然科学基金委面上项目(81273729):茵陈蒿汤调控Notch信号通路影响库普弗细胞活化的效应机制研究;负责人:孙明瑜;国家自然科学基金委青年科学基金项目(30701070):茵陈蒿汤治疗肝硬化的方证病理基础研究;负责人:孙明瑜;上海中医药大学首届杏林学者;上海市科委专项(15DZ1900104):胃复春治疗胃癌前病变及八宝丹防治肝性脑病的临床和作用机制研究;负责人:孙明瑜

摘　　要：目的:二甲基亚硝胺(DMN)诱导的大鼠肝纤维化模型是经典的动物模型,其病理变化与人类肝纤维化发生相类似。普遍观点认为,DMN化学刺激导致肝细胞的损伤,是诱导肝纤维化发生的直接原因,然而其具体的发病机制并不清楚。糖脂代谢异常是脂肪性肝病发生的主要原因之一。糖脂代谢紊乱是否也在DMN诱导肝纤维化模型中占有重要地位,至今尚不清楚。本研究采用全基因芯片技术与生物信息技术相结合方式,研究糖脂代谢异常与DMN诱导肝纤维化之间关系。方法:雄性Wistar大鼠每周前3天连续腹腔注射10 mg·kg^(-1)DMN,持续4周,正常组大鼠给予等量生理盐水。造模2周末,正常组和模型组各5只大鼠做动态观察;造模4周末,剩余大鼠被全部处死,收集肝脏标本。进行肝组织全基因芯片分析,将结果导入生物信息分析软件IPA进行分析。结果:2周模型组与正常组之间、4周模型组与正常组之间共有55个共同差异基因(logRatio>2)。共同差异基因构成的分子网络,主要参与了9条信号通路,它们与炎症、免疫、肝纤维化、脂代谢和血管新生有密切关系。在造模2周(肝纤维化形成期)时,以脂肪酸代谢异常为主要表现;在造模4周(肝硬化形成期)时,以细胞增殖为主要表现。结论:脂肪酸代谢紊乱可能是DMN诱导肝纤维大鼠发病机制之一。Dimethylnitrosamine（DMN）-induced hepatic fibrosis rat model is a classical model in hepatic fibrosis research over decades.It is recognized as the same pathological changes of hepatic fibrosis in chemical injury as in human.DMN chemical stimulation which induced hepatocyte injury is the direct cause of hepatic fibrosis.However,its pathogenetic mechanism is not clear.Besides,glucolipid metabolism disorder is one of the main causes of fatty liver disease.Whether glucolipid metabolic disorder plays an important role in DMN induced hepatic fibrosis also remains to be understood.So the purpose of this study was to know the relationship between glucolipid metabolic disorder and DMN induced hepatic fibrosis.Male Wistar rats were divided into the control group and DMN group randomly.DMN（10 mg·kg-1） was administered by intraperitoneal injection for consecutive three days each week for four weeks.Equal amount of normal saline was given to rats in the normal group.At the end of the second week,five rats that selected from control group and DMN group respectively were sacrificed to observe fibrosis stage.At the end of the fourth week,all the animals were sacrificed and liver samples were collected and prepared for detection in Affymetrix Gene Chip.Then significant differential genes were analyzed by bioinformatics software IPA.The results showed that there were 55 significant differential genes shared between two-week DMN group and the normal group,four-week DMN and the normal group（logRatio2）.Nine pathways were involved in molecular network that was established by the 55 significant differential genes,which highly correlated with inflammation,immune,hepatic fibrosis,lipid metabolism and angiogenesis process.It was found that fatty acid metabolism disorder was the main performance in the progression of DMN induced hepatic fibrosis（two-week DMN）,while cell proliferation was the main behavior in the period of DMN induced hepatic cirrhosis in rats（four-week DMN）.In conclusion,fatty acid metabolism disorder

关 键 词：肝纤维化 大鼠 脂肪酸代谢 基因分析 发病机制 

分 类 号：R575[医药卫生—消化系统]