LXR-activated Genes and Lipid Homeostasis

该子项目将测试在当前资助期内产生的假设，这些假设与LXR和LXR靶基因在控制脂质稳态、巨噬细胞功能和动脉粥样硬化发展中的作用有关。在目前的资助期内，我们确定了巨噬细胞暴露于LXR配体时诱导的一些基因；这些基因包括ABCG1、ABCA1、ADRP （adipophilin）、PLTP、syndecan-1和Spa，共约70个基因。人类ABCG1基因是非典型的；它利用5个启动子和选择性剪接产生b>8转录本和5种蛋白质同工型。我们现在建议通过基因靶向和人ABCG1转基因小鼠来确定ABCG1的功能。这些研究将通过机制研究和旨在确定ABCG1功能伴侣的研究来补充。这些方法将使我们能够测试ABCG1亚型的新假设

This subproject will test hypotheses, generated in the current grant period, that relate to the role of LXR and LXR target genes in the control of lipid homeostasis, macrophage function and the development of atherosclerosis. In the current grant period, we identified a number of genes that are induced when macrophages are exposed to LXR ligands; these genes (>70 total genes) include ABCG1, ABCA1, ADRP (adipophilin), PLTP, syndecan-1 and Spa. The human ABCG1 gene was shown to be atypical; it utilizes five promoters and alternative splicing to produce >8 transcripts and 5 protein isoforms. We now propose to determine the function of ABCG1 by utilizing both gene targeting and human ABCG1 transgenic mice. These studies will be complemented by mechanistic studies and studies that aim to identify the functional partner of ABCG1. These approaches will allow us to test the novel hypothesis that ABCG1 isoforms heterodimerize to form functional transmembrane transporters and that these heterodimers affect lipid efflux from cells. In addition, we will determine the importance of other LXR target genes (some of which are listed below) that are thought to be involved in a number of critical events related to atherosclerosis. These genes are thought to be involved in intracellular lipid droplet formation (ADRP), lipoprotein binding/uptake to cells (syndecan-1), apoptosis (Spa), phospholipid transfer/lipoprotein metabolism (PLTP) etc. We will investigate the mechanisms of regulation of these, and other genes, and use various strategies (activation in vivo, generation of knock out and transgenic mice, bone marrow transplants etc) to elucidate the function of these genes in controlling lipid homeostasis and atherosclerosis.