Sterol Regulatory Element Binding Proteins in Regulation of Lipid Metabolism

描述（由申请人提供）：已将固醇调节元件结合蛋白（SREBP）作为脂质代谢的关键调节剂进行了研究，但新出现的数据表明它们参与了其他细胞途径和过程。在哺乳动物中，有三种主要的SREBP亚型由两个不连锁的基因编码。SREBP-1基因有两种异构体，仅在其氨基末端区域不同。SREBP-1a氨基末端结构域较长，作为强激活结构域发挥作用，并与非DNA结合转录共激活因子良好相互作用。相比之下，较短的SREBP-1c氨基末端是相对较差的活化结构域，其与SREBP-1a相同的共活化剂弱相互作用。不同SREBP-1的mRNA的相对比例和绝对水平在不同组织中变化很大，并且它们在肝脏中研究得最多，其中SREBP-1c受胰岛素和LXR调节，并且以比SREBP-1a高10倍的水平表达。关于SREBP在肝脏外的作用知之甚少，该提议集中在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。我们已经产生了一种新的小鼠模型，该模型具有SREBP-1a的靶向缺陷，我们的初步数据表明这种亚型在巨噬细胞功能中起着关键作用。本更新申请的重点是使用这种新模型，沿着最先进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。 公共卫生相关性：该提案的总体目标是研究巨噬细胞脂质代谢的基本机制，并破译必须共同努力以保持细胞代谢平衡的不同信号通路之间的通信。这些研究使用了一种新的疾病动物模型和最先进的方法和技术，这些方法和技术将揭示以前未被认识到的将脂质代谢的营养调节与免疫系统联系起来的方式，这些方式与心血管疾病的发展和进展具有显著相关性。

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.