Overexpression of miR-155 in the liver of transgenic mice alters the expression profiling of hepatic genes associated with lipid metabolism.
Overexpression of miR-155 in the liver of transgenic mice alters the expression profiling of hepatic genes associated with lipid metabolism.
复制标题
转基因小鼠肝脏中 miR-155 的过度表达改变了与脂质代谢相关的肝脏基因的表达谱
DOI：
10.1371/journal.pone.0118417
复制
发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Xiao D
中科院分区：
文献类型：
--
作者：
Lin X;Jia J;Du T;Li W;Wang X;Wei J;Lin X;Zeng H;Yao L;Chen X;Zhuang J;Weng J;Liu Y;Lin J;Wu Q;Wang W;Yao K;Xu K;Xiao D
肝脏表达谱显示肝脏疾病中miRNA的变化，而小鼠非酒精性脂肪性肝病中肝脏miR-155的表达增加，提示miR-155可能调节脂质代谢的生物学过程。为了说明转基因小鼠肝脏中miR-155功能获得对脂质代谢的影响，将转基因小鼠（即，本研究在国际上首次建立了Cre/lox P系统介导的小鼠miR-155转基因条件性过表达的实验动物模型（Rm 155 LG小鼠）。将Rm 155 LG小鼠与Alb-Cre小鼠进一步杂交，以实现Rm 155 LG/Alb-Cre双转基因小鼠中miR-155转基因的肝脏特异性过表达，所述Rm 155 LG/Alb-Cre双转基因小鼠显示出体重、肝脏重量、附睾脂肪垫重量以及肝脏的大体形态和外观不变。肝脏特异性过表达miR-155转基因可显著降低Rm 155 LG/Alb-Cre转基因小鼠血清总胆固醇、甘油三酯（TG）和高密度脂蛋白（HDL）水平，以及肝脏脂质、TG、HDL和游离脂肪酸含量。更重要的是，微阵列数据揭示了肝脏基因表达谱的总体下降趋势，这些基因的功能通常与脂肪酸、胆固醇和甘油三酯代谢相关，这可能至少部分地导致在Rm 155 LG/Alb-Cre小鼠中观察到的血清胆固醇和甘油三酯降低。在这项研究中，我们证明了miR-155的肝脏过表达减轻了高脂饮食诱导的非酒精性脂肪肝。此外，羧酸酯酶3/三酰甘油水解酶（Ces 3/TGH）被鉴定为直接的miR-155靶基因，可能导致在Rm 155 LG/Alb-Cre小鼠中观察到的部分肝脏表型。综上所述，来自miR-155功能获得研究的这些数据表明，我们认为这是第一次，改变了脂质代谢，并为Rm 155 LG/Alb-Cre小鼠的肝脏代谢状态提供了新的见解。
Hepatic expression profiling has revealed miRNA changes in liver diseases, while hepatic miR-155 expression was increased in murine non-alcoholic fatty liver disease, suggesting that miR-155 might regulate the biological process of lipid metabolism. To illustrate the effects of miR-155 gain of function in transgenic mouse liver on lipid metabolism, transgenic mice (i.e., Rm155LG mice) for the conditional overexpression of mouse miR-155 transgene mediated by Cre/lox P system were firstly generated around the world in this study. Rm155LG mice were further crossed to Alb-Cre mice to realize the liver-specific overexpression of miR-155 transgene in Rm155LG/Alb-Cre double transgenic mice which showed the unaltered body weight, liver weight, epididymal fat pad weight and gross morphology and appearance of liver. Furthermore, liver-specific overexpression of miR-155 transgene resulted in significantly reduced levels of serum total cholesterol, triglycerides (TG) and high-density lipoprotein (HDL), as well as remarkably decreased contents of hepatic lipid, TG, HDL and free fatty acid in Rm155LG/Alb-Cre transgenic mice. More importantly, microarray data revealed a general downward trend in the expression profile of hepatic genes with functions typically associated with fatty acid, cholesterol and triglyceride metabolism, which is likely at least partially responsible for serum cholesterol and triglyceride lowering observed in Rm155LG/Alb-Cre mice. In this study, we demonstrated that hepatic overexpression of miR-155 alleviated nonalcoholic fatty liver induced by a high-fat diet. Additionally, carboxylesterase 3/triacylglycerol hydrolase (Ces3/TGH) was identified as a direct miR-155 target gene that is potentially responsible for the partial liver phenotypes observed in Rm155LG/Alb-Cre mice. Taken together, these data from miR-155 gain of function study suggest, for what we believe is the first time, the altered lipid metabolism and provide new insights into the metabolic state of the liver in Rm155LG/Alb-Cre mice.
登录
查看更多内容
DOI：
10.1038/labinvest.2010.113
发表时间：
2010-10
期刊：
Laboratory investigation; a journal of technical methods and pathology
影响因子：
--
作者：
通讯作者：
--
影响因子：
3.7
作者：
Miller AM;Gilchrist DS;Nijjar J;Araldi E;Ramirez CM;Lavery CA;Fernández-Hernando C;McInnes IB;Kurowska-Stolarska M
通讯作者：
Kurowska-Stolarska M
影响因子：
4.6
作者：
Dawson, Paul Anthony;Gardiner, Brooke;Markovich, Daniel
通讯作者：
Markovich, Daniel
影响因子：
8.8
作者：
Chen, H-C;Chen, G-H;Chen, Y-H;Liao, W-L;Liu, C-Y;Chang, K-P;Chang, Y-S;Chen, S-J
通讯作者：
Chen, S-J
影响因子：
64.8
作者：
Kornfeld, Jan-Wilhelm;Baitzel, Catherina;Bruening, Jens C.
通讯作者：
Bruening, Jens C.