The AMPK/mTOR pathway is involved in D-dopachrome tautomerase gene transcription in adipocytes differentiated from SGBS cells, a human preadipocyte cell line
The AMPK/mTOR pathway is involved in D-dopachrome tautomerase gene transcription in adipocytes differentiated from SGBS cells, a human preadipocyte cell line
复制标题
DOI：
10.1016/j.cyto.2017.04.017
复制
发表时间：
2017-08-01
期刊：
影响因子：
3.8
通讯作者：
Yoshimoto, Katsuhiko
中科院分区：
文献类型：
--
作者：
Iwata, Takeo;Kuribayashi, Kyoko;Yoshimoto, Katsuhiko
在脂肪组织中，D-多巴色素互变异构酶（DDT）是一种与巨噬细胞移动抑制因子结构相似的细胞因子，主要表达于脂肪细胞而非前脂肪细胞，以自分泌方式发挥抗肥胖脂肪因子的作用。然而，其转录调节在很大程度上尚不清楚。为了探索影响DDT转录的分子，使用稳定表达DDT启动子-报告基因构建体的HEK 293细胞进行化学文库筛选。5-氨基咪唑-4-甲酰胺-1-β-（D）-呋喃核糖苷（AICAR）是一种AMP激活蛋白激酶（AMPK）激活剂，其几种衍生物被鉴定为DDT基因的转录激活剂。此外，DDT mRNA水平降低SGBS脂肪细胞处理与化合物C，AMPK抑制剂，表明参与DDT的转录AMPK。FOXO 1组成型活性形式的过表达降低了SGBS细胞中DDT基因的转录活性，但增加了HEK 293细胞中DDT基因的转录活性。在用FOXO 1抑制剂AS 1842856处理的细胞的DDT基因表达中也观察到细胞类型特异性效应。最后，研究了哺乳动物雷帕霉素靶蛋白（mTOR）信号转导在SGBS脂肪细胞中DDT转录中的参与。雷帕霉素，mTOR的抑制剂，增加DDT mRNA水平，减弱化合物C对SGBS脂肪细胞中DDT mRNA水平的抑制作用。总之，DDT的转录可能以细胞依赖的方式受到调节，并且AMPK通过抑制mTOR信号而增强SGBS脂肪细胞中DDT的转录。
In adipose tissue, D-dopachrome tautomerase (DDT), a cytokine with structural similarity to macrophage migration inhibitory factor, is mainly expressed in adipocytes rather than preadipocytes and acts as an anti obesity adipokine in an autocrine manner. However, its transcriptional regulation is largely unknown. In order to explore molecules affecting DDT transcription, a chemical library screening using HEK293 cells stably expressing a DDT promoter-reporter construct was performed. Several derivatives of 5-aminoimidazole-4-carboxamide-1-beta-(D)-ribofuranoside (AICAR), an AMP-activated protein kinase (AMPK) activator, were identified as transcriptional activators of the DDT gene. Furthermore, DDT mRNA levels were reduced in SGBS adipocytes treated with compound C, an AMPK inhibitor, suggesting involvement of AMPK in DDT transcription. Overexpression of the FOXO1 constitutive active form reduced transcriptional activity of the DDT gene in SGBS cells, but increased it in HEK293 cells. Cell-type specific effects were also observed in the DDT gene expression of cells treated with AS1842856, a FOXO1 inhibitor. Finally, involvement of the mammalian target of rapamycin (mTOR) signaling in DDT transcription in SGBS adipocytes was investigated. Rapamycin, an inhibitor of mTOR, increased DDT mRNA levels and attenuated the inhibitory effects of compound C on DDT mRNA levels in SGBS adipocytes. In conclusion, DDT transcription may be regulated in a cell-dependent manner, and were enhanced by AMPK activation in SGBS adipocytes through inhibiting the mTOR signaling.