C/EBP transcription factors regulate SREBP1c gene expression during adipogenesis.
C/EBP transcription factors regulate SREBP1c gene expression during adipogenesis.
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DOI：
10.1042/bj20091112
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发表时间：
2009-12-14
期刊：
影响因子：
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通讯作者：
Rochford JJ
中科院分区：
文献类型：
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作者：
Payne VA;Au WS;Lowe CE;Rahman SM;Friedman JE;O'Rahilly S;Rochford JJ
转录因子SREBP 1c（固醇调节元件结合蛋白1c）在脂肪组织中高度表达，在脂肪细胞发育的几个方面发挥核心作用，包括过氧化物酶体增殖物激活受体γ（过氧化物酶体增殖物激活受体γ）的诱导、内源性过氧化物酶体增殖物激活受体γ配体的产生和几个对脂质生物合成至关重要的基因的表达。尽管其意义，在脂肪形成过程中的SREBP 1c表达的调节没有得到很好的表征。我们已经注意到，在几种脂肪形成模型中，SREBP 1c的表达与已知的C/EBPβ（CCAAT/增强子结合蛋白β）靶点的表达非常相似。通过表达显性阴性C/EBPβ LIP（肝脏富集抑制蛋白）亚型、共阻遏物ETO（8 - 21/MTG 8）或使用靶向C/EBPβ或C/EBPδ的siRNA（小干扰RNA）抑制脂肪形成期间的C/EBP活性，可显著削弱早期SREBP 1c诱导。此外，ChIP（染色质免疫沉淀）分析鉴定了完整细胞中C/EBPβ和C/EBPδ结合的SREBP 1c启动子中的特定序列，表明这些因子可能直接调节SREBP 1c表达。使用使用shRNA（短发夹RNA）和ChIP检测抑制C/EBPα表达的细胞，我们表明C/EBPα取代C/EBPβ和C/EBPδ作为成熟脂肪细胞中SREBP 1c表达的调节剂。这些结果为脂肪形成过程中SREBP 1c表达的诱导提供了新的见解。此外，本研究的发现确定了一个重要的额外机制，通过该机制，C/EBP转录因子可以控制调节脂肪生成、脂肪生成和胰岛素敏感性的基因表达网络。
The transcription factor SREBP1c (sterol-regulatory-element-binding protein 1c) is highly expressed in adipose tissue and plays a central role in several aspects of adipocyte development including the induction of PPARγ (peroxisome-proliferator-activated receptor γ), the generation of an endogenous PPARγ ligand and the expression of several genes critical for lipid biosynthesis. Despite its significance, the regulation of SREBP1c expression during adipogenesis is not well characterized. We have noted that in several models of adipogenesis, SREBP1c expression closely mimics that of known C/EBPβ (CCAAT/enhancer-binding protein β) targets. Inhibition of C/EBP activity during adipogenesis by expressing either the dominant-negative C/EBPβ LIP (liver-enriched inhibitory protein) isoform, the co-repressor ETO (eight-twenty one/MTG8) or using siRNAs (small interfering RNAs) targeting either C/EBPβ or C/EBPδ significantly impaired early SREBP1c induction. Furthermore, ChIP (chromatin immunoprecipitation) assays identified specific sequences in the SREBP1c promoter to which C/EBPβ and C/EBPδ bind in intact cells, demonstrating that these factors may directly regulate SREBP1c expression. Using cells in which C/EBPα expression is inhibited using shRNA (short hairpin RNA) and ChIP assays we show that C/EBPα replaces C/EBPβ and C/EBPδ as a regulator of SREBP1c expression in maturing adipocytes. These results provide novel insight into the induction of SREBP1c expression during adipogenesis. Moreover, the findings of the present study identify an important additional mechanism via which the C/EBP transcription factors may control a network of gene expression regulating adipogenesis, lipogenesis and insulin sensitivity.