Département des Sciences Biologiques, Centre de recherche BioMed, Université du Québec, C.P. 8888, Succursale Centre-ville, Montréal, Canada, H3C 3P8.
J Cell Commun Signal. 2007 Sep;1(2):113-25. doi: 10.1007/s12079-007-0011-1. Epub 2007 Oct 6.
The stearoyl-CoA desaturase 1 (SCD1) catalyzes the synthesis of monounsaturated fatty acids. This enzyme is a critical control point regulating hepatic lipogenesis and lipid oxidation. Therefore SCD1 may be a potential therapeutic target in the treatment of obesity and metabolic syndrome. Regulation of SCD1 expression occurs primarily at the level of transcription. In the present study, we characterized the insulin response elements (IREs) and the insulin signaling pathway mediating the regulation of SCD1 gene transcription in liver. In chicken embryo hepatocytes (CEH) and HepG2 cells, insulin stimulates SCD1 promoter activity by 2.5 folds. This activation is mediated by two different IREs on the chicken promoter, one localized between -1,975 and -1,610 bp and one between -372 and -297 bp. The latter binds both NF-Y and SREBP-1 transcription factors in response to insulin. We also demonstrated that insulin induction of SCD1 gene expression and promoter activity is abolished by pre-incubation of cells with specific inhibitors of both PI3-kinase (LY294002) and mTor (Rapamycin) or by over-expression of a dominant negative mutant of PI3-kinase. The PI3-kinase and mTor pathway mediates the insulin response on both IREs. In summary, insulin activates SCD1 gene expression in liver via a signaling pathway that involves PI3-kinase and mTor and the downstream transcription factors NF-Y and SREBP-1. Sentence summary: Insulin regulates SCD1 gene expression via two different IREs. The most 3' IRE is localized between -372 and -297 bp and binds the NF-Y and SREBP-1 transcription factors in response to insulin. PI3-kinase and mTor mediate the action of insulin on both IREs.
硬脂酰辅酶 A 去饱和酶 1（SCD1）催化单不饱和脂肪酸的合成。该酶是调节肝内脂肪生成和脂质氧化的关键控制点。因此，SCD1 可能是肥胖和代谢综合征治疗的潜在治疗靶点。SCD1 表达的调节主要发生在转录水平。本研究中，我们描述了胰岛素反应元件（IREs）和胰岛素信号通路，这些通路介导了肝脏中 SCD1 基因转录的调节。在鸡胚肝细胞（CEH）和 HepG2 细胞中，胰岛素将 SCD1 启动子活性刺激 2.5 倍。这种激活是由鸡启动子上的两个不同的 IRE 介导的，一个位于-1975 至-1610 bp 之间，另一个位于-372 至-297 bp 之间。后者在胰岛素的作用下结合 NF-Y 和 SREBP-1 转录因子。我们还证明，细胞用 PI3-激酶（LY294002）和 mTor（雷帕霉素）的特异性抑制剂预先孵育，或过表达 PI3-激酶的显性负突变体，可消除胰岛素诱导的 SCD1 基因表达和启动子活性。PI3-激酶和 mTor 途径介导了两个 IRE 上的胰岛素反应。总之，胰岛素通过涉及 PI3-激酶和 mTor 以及下游转录因子 NF-Y 和 SREBP-1 的信号通路激活肝脏中的 SCD1 基因表达。句子总结：胰岛素通过两个不同的 IRE 调节 SCD1 基因表达。最 3' 的 IRE 位于-372 至-297 bp 之间，在胰岛素的作用下结合 NF-Y 和 SREBP-1 转录因子。PI3-激酶和 mTor 介导了胰岛素对两个 IRE 的作用。
