Sterol Regulatory Element Binding Proteins in Regulation of Lipid Metabolism

描述（由申请人提供）：甾醇调节元件结合蛋白（SREBPs）已被研究为脂质代谢的关键调节剂，但新出现的数据表明它们还参与其他细胞途径和过程。在哺乳动物中，有三个主要的SREBP亚型由两个非连锁基因编码。SREBP-1基因有两个异构体，它们只在氨基末端区域不同。SREBP-1a氨基末端结构域较长，作为强激活结构域，与非dna结合转录共激活因子相互作用良好。相比之下，较短的SREBP-1c氨基末端是一个相对较差的激活域，与SREBP-1a相同的共激活子相互作用较弱。不同SREBP-1 mrna的相对比例和绝对水平在不同组织中差异很大，它们在肝脏中被研究最多，其中SREBP-1c受胰岛素和LXR调节，其表达水平比SREBP-1a高10倍。关于srebp在肝脏外的作用知之甚少，本研究主要关注SREBP-1在巨噬细胞中的功能，我们的初步研究表明，SREBP-1a的表达水平比SREBP-1c高10倍，其表达受细菌脂多糖（LPS）调节。我们已经建立了一种靶向SREBP-1a缺陷的新小鼠模型，我们的初步数据表明，这种异构体在巨噬细胞功能中起着关键作用。本研究的重点是利用这一新模型，结合最新的分子方法和新技术来研究SREBP-1在巨噬细胞营养和代谢中的作用。

DESCRIPTION (provided by applicant): The sterol regulatory element binding proteins (SREBPs) have been studied as key modulators of lipid metabolism but emerging data indicate they are involved in additional cellular pathways and processes. In mammals, there are three major SREBP isoforms encoded by two unlinked genes. The SREBP-1 gene has two isomers that only differ at their amino-terminal regions. The SREBP-1a amino terminal domain is longer, functions as a strong activation domain and interacts well with non-DNA binding transcriptional co-activators. In contrast, the shorter SREBP-1c amino-terminus is a relatively poor activation domain that interacts weakly with the same co-activators as SREBP-1a. The relative ratios and absolute levels of the mRNAs for the different SREBP-1's vary considerably across different tissues and they have been most studied in the liver where SREBP-1c is regulated by insulin and LXR and is expressed at 10 fold higher levels than SREBP-1a. Little is known about the role of SREBPs outside of the liver and this proposal is focused on the function of SREBP-1 in macrophages where our preliminary studies show SREBP-1a is expressed at 10 fold higher levels than SREBP-1c levels and its expression is regulated by bacterial lipopolysaccharide (LPS). We have generated a new mouse model that has a targeted deficiency of SREBP-1a and our preliminary data indicates that this isoform plays a key role in macrophage function. The focus of this renewal application is to use this new model along with state-of-the art molecular approaches and novel technology to investigate the roles of SREBP-1 in nutrition and metabolism in the macrophage. PUBLIC HEALTH RELEVANCE: The overall goal of this proposal is to investigate the basic mechanism of macrophage lipid metabolism and to decipher the communication between different signaling pathways that must work together to keep cellular metabolism in balance. These studies use a new animal model of disease and state of the art methods and techniques that will uncover previously unappreciated ways that connect nutritional regulation of lipid metabolism to the Immune system with significant relevance to the development and progression of cardiovascular disease.