RNA sequencing of db/db mice liver identifies lncRNA H19 as a key regulator of gluconeogenesis and hepatic glucose output.
RNA sequencing of db/db mice liver identifies lncRNA H19 as a key regulator of gluconeogenesis and hepatic glucose output.
复制标题
DOI：
10.1038/s41598-017-08281-7
复制
发表时间：
2017-08-16
影响因子：
4.6
通讯作者：
Datta M
中科院分区：
文献类型：
--
作者：
Goyal N;Sivadas A;Shamsudheen KV;Jayarajan R;Verma A;Sivasubbu S;Scaria V;Datta M
肝脏在维持葡萄糖稳态中起关键作用，肝脏葡萄糖代谢受损与2型糖尿病相关。在本研究中，我们使用RNA测序来分析糖尿病db/db小鼠与正常db/+小鼠相比的肝脏转录组，并确定了218个差异表达基因。其中，有3个lncRNA显著下调，H19是db/db小鼠肝脏中变化最大的lncRNA。H19的表达与糖酵解和代谢途径的基因表达显著相关，这表明改变的肝脏H19水平可以直接或间接地调节它们的表达。在HepG 2细胞和原代小鼠肝细胞中使用特异性siRNA抑制H19显著增加了致瘤基因的水平。这随后伴随着肝葡萄糖输出增加。此外，HepG 2细胞中的H19缺失损害了胰岛素信号传导，并增加了FoxO 1的核定位，FoxO 1是致瘤基因表达的重要转录调节因子。我们的研究结果揭示了H19水平下降和受损的通过调节FoxO 1核水平的胚胎发育之间的新联系。这些结果对H19在糖尿病期间改变肝脏生理学的调节作用提出了有趣的观察结果。
Liver plays a key role in maintaining glucose homeostasis and impaired hepatic glucose metabolism is associated with type 2 diabetes. In the present study, we used RNA sequencing to profile the transcriptome of the livers of diabetic db/db mice as compared to the normal db/+ mice and identified 218 differentially expressed genes. Amongst these, there were 3 lncRNAs that were significantly downregulated and H19 was the most altered lncRNA in the livers of db/db mice. H19 expression significantly correlated with the expression of genes of the glycolysis and gluconeogenesis pathways, which suggest that altered hepatic H19 levels can directly or indirectly modulate their expression. Inhibition of H19 using specific siRNA in HepG2 cells and primary mouse hepatocytes significantly increased the levels of gluconeogenic genes. This was subsequently accompanied by increased hepatic glucose output. Further,H19 depletion in HepG2 cells impaired insulin signaling and increased nuclear localization of FoxO1, an important transcriptional regulator of gluconeogenic gene expression. Our results reveal a novel link between decreased H19 levels and impaired gluconeogenesis via regulation of FoxO1 nuclear levels. These put forth interesting observations on the regulatory role of H19 in altering hepatic physiology during diabetes.
登录
查看更多内容
影响因子：
56.9
作者：
Carninci, P;Kasukawa, T;Hayashizaki, Y
通讯作者：
Hayashizaki, Y
影响因子：
2.9
作者：
Leonardini A;Laviola L;Perrini S;Natalicchio A;Giorgino F
通讯作者：
Giorgino F
DOI：
10.1152/ajpendo.00549.2003
发表时间：
2004-07-01
影响因子：
5.1
作者：
Basu, R;Schwenk, WF;Rizza, RA
通讯作者：
Rizza, RA
影响因子：
10.5
作者：
Cabili, Moran N.;Trapnell, Cole;Rinn, John L.
通讯作者：
Rinn, John L.
DOI：
10.1093/bioinformatics/btp101
发表时间：
2009-04-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Bindea G;Mlecnik B;Hackl H;Charoentong P;Tosolini M;Kirilovsky A;Fridman WH;Pagès F;Trajanoski Z;Galon J
通讯作者：
Galon J