In vivo promoter analysis on refeeding response of hepatic sterol regulatory element-binding protein-1c expression
In vivo promoter analysis on refeeding response of hepatic sterol regulatory element-binding protein-1c expression
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DOI：
10.1016/j.bbrc.2007.08.165
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发表时间：
2007-11-16
影响因子：
3.1
通讯作者：
Shimano, Hitoshi
中科院分区：
文献类型：
--
作者：
Takeuchi, Yoshinori;Yahagi, Naoya;Shimano, Hitoshi
甾醇调节元件结合蛋白（SREBP）-1c 是肝脏中脂肪生成基因表达的主要调节因子。当动物在饥饿后重新进食时，SREBP-1c 的 mRNA 丰度会显着诱导，但其调节机制目前尚不清楚。为了研究体内 SREBP-1c 基因表达的再进食反应机制，我们构建了一个转基因小鼠模型，该模型携带与荧光素酶报告基因融合的 2.2 kb 启动子区域。这些转基因小鼠在肝脏和脂肪组织中表现出报告基因的再进食反应，其程度与内源性 SREBP-1c mRNA 的反应程度基本相同。使用腺病毒介导的SREBP-1c启动子-荧光素酶融合基因转导至肝脏的实验获得了相同的结果。这些数据表明SREBP-1c基因表达的调节是在转录水平，并且2.2 kb 5'侧翼区域足以进行这种调节。此外，当这些转基因或腺病毒感染的小鼠通过链脲佐菌素处理而处于胰岛素耗尽状态时，报告基因的表达与对照小鼠一样强烈上调，表明这种调节不受血清胰岛素水平的支配。这些小鼠是第一个提供 SREBP1c 基因体内转录调控机制的模型。 (C) 2007 Elsevier Inc. 保留所有权利。
Sterol regulatory element-binding protein (SREBP)-1c is the master regulator of lipogenic gene expression in liver. The mRNA abundance of SREBP- 1c is markedly induced when animals are refed after starvation, although the regulatory mechanism is so far unknown. To investigate the mechanism of refeeding response of SREBP-1c gene expression in vivo, we generated a transgenic mouse model that carries 2.2 kb promoter region fused to the luciferase reporter gene. These transgenic mice exhibited refeeding responses of the reporter in liver and adipose tissues with extents essentially identical to those of endogenous SREBP-1c mRNA. The same results were obtained from experiments using adenovirus-mediated SREBP-1c-promoter-luciferase fusion gene transduction to liver. These data demonstrate that the regulation of SREBP-1c gene expression is at the transcription level, and that the 2.2 kb 5'-flanking region is sufficient for this regulation. Moreover, when these transgenic or adenovirus-infected mice were placed on insulin-depleted state by streptozotocin treatment, the reporter expression was upregulated as strongly as in control mice, demonstrating that this regulation is not dominated by serum insulin level. These mice are the first models to provide the mechanistic insight into the transcriptional regulation of SREBP1c gene in vivo. (C) 2007 Elsevier Inc. All rights reserved.