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.
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