肝细胞中活化转录因子ATF6抑制SREBP1的转录活性  

Activating Transcription Factor 6 Inhibits Transcriptional Activity of SREBP1 in Hepatocytes

作　　者：李红玲 [1] ZENG Lingfang  王保国 [2] 庞炜 [2] 朱毅 [1] 

机构地区：[1]北京天坛医院麻醉科,北京,100040 [2]北京大学医学部生理学与病理生理学系,北京大学糖尿病中心,北京,100083

出　　处：《中国生物化学与分子生物学报》2005年第4期546-553,共8页Chinese Journal of Biochemistry and Molecular Biology

基　　金：国家自然科学基金资助项目(No30440003)~~

摘　　要：内质网膜定位的活化转录因子ATF6和SREBP1均是经过蛋白酶切水解激活,激活后的ATF6(N)和SREBP1(N)进入细胞核内,分别指导内质网膜未折叠蛋白聚集反应相关基因和脂肪酸合成相关基因的表达.研究发现,肝细胞内葡萄糖饥饿激活ATF6并抑制SREBP1的转录活性及其靶基因的表达.过表达ATF6(N)能够抑制SREBP1介导的转录及其下游基因的表达.免疫共沉淀实验显示,ATF6(N)在细胞核内结合SREBP1(N),这种结合在无糖状况下增强.不同功能区缺失分析表明,ATF6和SREBP1通过亮氨酸拉链(leucinezipper)功能区相互作用.在葡萄糖饥饿状况下,ATF6对SREBP1转录活性的抑制保证了细胞基本生命活动所需要的能量.The endoplasmic reticulum （ER） membrane bound transcription factors, activating transcription factor 6 （ATF6） and sterol regulatory element-binding proteins （SREBPs）, are activated by proteolytic cleavage. The activated N-termini [i. e. ATF6（N） and SREBP（N）] translocate into nuclear and activate the perspective target genes involved in unfolded protein response and lipogenesis, respectively. Both ATF6 and SREBPs have a similar activation mechanism since they all bind on ER membrane and their leucine-zipper domains interact with the same co-activators for transactivation. ER stress affect lipid heomostasis, but the underlying molecular mechanism is unclear. Glucose deprivation increased the expressions of ATF6-target genes at mRNA level in hepatocytes. The expressions of SREBPl-target genes were suppressed under same conditions. Transient transfection assay demonstrated that glucose deprivation and thapsigargin, an ER stress inducer, activated the transcription activity of ATF6 but suppressed that of SREBP1. Furthermore, overexpression of ATF6 （N） inhibited SREBPl-mediated transcription and its target genes. The coimmunoprecipitation assay revealed that ATF6 physically interacted with SREBP1 in the nuclear, and this interaction was enhanced by glucose deprivation. Deletion analysis of different function domain demonstrated that ATF6 and SREBP1 interacted with each other through their leucine-zipper domains. The inhibitory effect of ATF6 on SREBP1 provides essential energy supply for the basic cellular activity under glucose deprivation. The results provide a novel mechanism for the regulation of the homeostasis between glucose and lipid metabolism.

关 键 词：活化转录因子6 葡萄糖 脂质调节元件结合蛋白1 脂代谢 肝细胞 

分 类 号：Q51[生物学—生物化学]