Role of PPARdelta in Lipid Metabolism /Atherosclerosis

我们的长期目标是了解在生理和疾病中脂质调节基因表达的机制。修饰的脂类影响动脉壁细胞功能的主要机制是通过激活核受体超家族成员。PPAR8是一种由天然和氧化多不饱和脂肪酸激活的核受体，其在哺乳动物生理中的作用尚不清楚。初步数据表明，PPARdelta在内皮细胞和平滑肌细胞中表达，并在单核细胞向巨噬细胞分化过程中受到强烈诱导。最近的研究也表明，PPARdelta的合成配体诱导了假定的胆固醇/磷脂转运体ABCA1的表达，并提高了灵长类动物的HDL水平。这些研究表明，PPARdelta是胆固醇逆向转运途径的重要调节剂。本提案的重点是确定核受体PPARdelta在脂质代谢和动脉粥样硬化中的作用。第一个目的是确定PPARdelta在巨噬细胞和其他外周细胞中调控基因表达的作用。由于PPARdelta广泛表达，它有可能调节许多不同细胞类型的基因表达，包括那些也表达pparα或pparγ的细胞。巨噬细胞和脂肪组织均表达PPARgamma和PPARdelta8，但这些受体之间是否存在功能重叠尚不清楚。虽然在巨噬细胞中已知许多pparγ靶基因，但尚不清楚这些基因是否

Our long-term goal is to understand the mechanisms by which lipids regulate gene expression in physiology and disease. A principal mechanism whereby modified iipids influence the function of cells of the artery wall is through activation of members of the nuclear receptor superfamily. PPAR8 is a nuclear receptor activated by native and oxidized polyunsaturated fatty acids whose role in mammalian physiology remains obscure. Preliminary data indicate that PPARdelta is expressed in endothelial cells and smooth muscle cells and is strongly induced during the differentiation of monocytes to macrophages. Recent work has also shown that synthetic ligands for PPARdelta induce expression of the putative cholesterol/phospholipid transporter ABCA1 and raise HDL levels in primates. These studies suggest that PPARdelta is an important modulator of the reverse cholesterol transport pathway. This proposal is focused on defining the role of the nuclear receptor PPARdelta in lipid metabolism and atherosclerosis. The first aim is to define the role of PPARdelta in regulating gene expression in macrophages and other peripheral cells. Since PPARdelta is widely expressed, it has the potential to regulate gene expression in many different cell types, including those that also express PPARalpha or PPARgamma. Macrophages and adipose tissue express both PPARgamma and PPARdelta8 however, it is not yet clear whether there is functional overlap between these receptors. While many PPARgamma target genes are known in macrophages, it is not known whether these are also targets of PPARdelta or whether there are PPARdelta selective targets. Preliminary data presented below indicates that ABCA1 is a PPARdelta selective target in human macrophages. The second aim is to characterize gene expression and lipid metabolism in genetically defined macrophages that lack PPARdelta. The importance of PPARdelta in regulating gene expression, lipid uptake, cholesterol efflux and cytokine production will be tested. We will also endeavor to determine whether there is functional overlap between the PPARdelta and PPARgamma pathways. The third aim is to analyze the role of PPARdelta in macrophage function and atherogenesis in vivo. First, PPARdelta null mice will be crossed to the LDLR-/- and apoE-/- mice to determine the impact of ubiquitous PPARdelta expression on reverse cholesterol transport and atherogenesis. Second, transgenic mice will be created that express multiple copies of the PPARdelta locus.