LXR-activated Genes and Lipid Homeostasis

这一子项目将测试在当前赠款期间产生的假说，这些假说与LXR和LXR目标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。在当前的授权期内，我们发现了一些当巨噬细胞暴露于LXR配体时被诱导的基因；这些基因(共70个基因)包括Abcg1、ABCA1、adrp(脂联素)、PLTP、syndecan-1和SpA。人类Abcg1基因被证明是非典型的；它利用5个启动子和选择性剪接产生&gt；8个转录本和5个蛋白质亚型。我们现在建议利用基因打靶和人类Abcg1转基因小鼠来确定Abcg1的功能。这些研究将得到机械学研究和旨在确定Abcg1功能伙伴的研究的补充。这些方法将使我们能够测试Abcg1异构体的新假设 异二聚体形成功能性的跨膜转运体，这些异二聚体影响细胞的脂类外流。此外，我们将确定其他LXR靶基因(其中一些列在下面)的重要性，这些基因被认为与许多与动脉粥样硬化相关的关键事件有关。这些基因被认为与细胞内脂滴形成(Adrp)、脂蛋白与细胞的结合/摄取(syndecan-1)、细胞凋亡(Spa)、磷脂转移/脂蛋白代谢(Pltp)等有关。我们将研究这些基因和其他基因的调控机制，并采用不同的策略(体内激活、基因敲除和转基因小鼠的产生、骨髓移植等)来阐明这些基因的功能。 控制脂代谢平衡和动脉粥样硬化的基因。

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.