Role of PPARdelta in Lipid Metabolism /Atherosclerosis

我们的长期目标是了解脂质在生理和疾病中调节基因表达的机制。修饰后的脂肪影响动脉壁细胞功能的一个主要机制是通过激活核受体超家族成员。PPAR8是一种核受体，由天然和氧化的多不饱和脂肪酸激活，其在哺乳动物生理中的作用尚不清楚。初步研究表明，PPARDelta在血管内皮细胞和平滑肌细胞中均有表达，并在单核细胞向巨噬细胞分化过程中强烈诱导表达。最近的工作还表明，PPARDelta的合成配体可以诱导可能的胆固醇/磷脂转运蛋白ABCA1的表达，并提高灵长类动物的高密度脂蛋白水平。这些研究表明，PPARDelta是胆固醇反向运输途径的重要调节器。这项建议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。第一个目标是确定PPARDelta在巨噬细胞和其他外周细胞中调节基因表达的作用。由于PPARDelta被广泛表达，它有可能在许多不同类型的细胞中调节基因表达，包括那些也表达PPARpha或PPARGamma的细胞。巨噬细胞和脂肪组织都表达PPARGamma和PPARdelta8，然而，目前还不清楚这些受体之间是否存在功能重叠。虽然在巨噬细胞中已知许多PPARGamma靶基因，但尚不清楚这些基因是否 也是PPARDelta的目标，或者是否有PPARDelta选择性目标。以下提供的初步数据表明，ABCA1是人巨噬细胞中的PPARDelta选择性靶点。第二个目标是研究缺乏PPAR Delta的基因定义的巨噬细胞的基因表达和脂质代谢。PPARDelta在调节基因表达、脂质摄取、胆固醇流出和细胞因子产生方面的重要性将得到测试。我们还将努力确定PPARDelta和PPARGamma通路之间是否存在功能重叠。第三个目的是分析PPARDelta在巨噬细胞功能和 体内动脉粥样硬化的发生。首先，PPARDelta缺失的小鼠将与LDLR-/-和apoE-/-小鼠杂交，以确定普遍存在的PPARDelta表达对胆固醇反向运输和动脉粥样硬化形成的影响。其次，将创造出表达PPARDelta基因多个拷贝的转基因小鼠。

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.