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.
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.
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