ABCA1/G1 and LXRs in Atherogenesis

 描述(由申请人提供)：血浆高密度脂蛋白水平与冠心病呈负相关，但最近高密度脂蛋白升高疗法的失败试验，以及人类基因组范围的关联研究，都对这种关系的因果性质提出了质疑。这凸显了对高密度脂蛋白和动脉粥样硬化之间的关系有更深层次的机械理解的必要性。高密度脂蛋白和ABC转运体介导的胆固醇外流途径可抑制炎症和动脉粥样硬化。我们最近的工作明确了ABCA1和Abcg1在抑制动脉粥样硬化斑块中的造血干细胞增殖、骨髓生成、单核细胞生成、巨噬细胞聚集和炎症基因表达中的作用。我们最近发现，ABCA1/G1在巨噬细胞中发挥作用，抑制高胆固醇血症和氧化低密度脂蛋白诱导的炎症体激活。此外，ABCA1/G1缺陷的巨噬细胞会发生焦性细胞死亡，这是一种由炎症体启动子激活的caspase-1和炎症体的细胞因子产物(IL-1)诱导的坏死性细胞死亡。目的1通过将巨噬细胞和巨噬细胞特异性ABCA1/G1基因敲除的小鼠与缺乏基本炎性小体成分的菌株杂交，评估炎性小体和炎性下垂对动脉粥样硬化的影响。此外，由于我们发现丹吉尔病患者血浆炎性小体产物IL-1和IL-18水平升高，我们将确定这些受试者的单核细胞是否有炎性小体激活和下垂的证据，从而评估人类的相关性。LXR/RXR转录因子诱导ABCA1/G1，缺乏这些转运蛋白的巨噬细胞在LXR激活剂作用下不能增加胆固醇外流。我们发现，巨噬细胞中ABCA1/G1缺陷的小鼠在使用LXR激活剂治疗时仍显示出动脉粥样硬化的减轻，这表明LXR激活剂在巨噬细胞中的一种新的作用不依赖于胆固醇外流，或者是一种血管效应。在目标2中，我们将寻求在巨噬细胞中鉴定新的LXR抗动脉粥样硬化靶点，例如诱导长链不饱和脂肪酸合成的基因，导致合成可能促进动脉粥样硬化消退的小分子前脂介质(SPM)。另一种解释是，LXRs上调内皮细胞中的ABCA1/G1，具有抗动脉粥样硬化的作用，这将在这些转运蛋白的内皮特异性缺陷的小鼠身上进行测试。总体而言，这些发现可能有助于理解目前正在进行的冠心病人类临床试验中涉及高密度脂蛋白输注和LXR激活剂的治疗干预措施，以及确定潜在的新治疗靶点。

 DESCRIPTION (provided by applicant): Plasma HDL levels have an inverse relationship with coronary heart disease, but recent failed trials of HDL raising therapies, as well as human genome wide association studies have called into the question the causal nature of this relationship. This highlights the need for a deeper mechanistic understanding of the relationship between HDL and atherosclerosis. Cholesterol efflux pathways mediated by HDL and ABC transporters act to suppress inflammation and atherosclerosis. Our recent work has defined the role of ABCA1 and ABCG1 which mediate cholesterol efflux from cells to ApoA-1 and HDL in suppressing hematopoietic stem cell proliferation, myelopoiesis, monocytosis, macrophage accumulation and inflammatory gene expression in atherosclerotic plaques. We recently discovered that ABCA1/G1 act in macrophages to suppress inflammasome activation induced by hypercholesterolemia and oxidized LDL. Moreover, macrophages deficient in ABCA1/G1 undergo pyroptotic cell death, a form of necrotic cell death that is induced by inflammasome-initiator activated caspase-1 and cytokine products of the inflammasome (IL-1). Aim 1 will assess the effects of the inflammasome and pyroptosis on atherosclerosis in macrophages and mice with macrophage-specific knockout of ABCA1/G1, by crossing these mice with strains deficient in essential inflammasome components. Also, since we discovered elevated plasma level of inflammasome products IL-1 and IL-18 in patients with Tangier Disease, we will determine if monocytes from these subjects show evidence of inflammasome activation and pyroptosis, thus evaluating human relevance. LXR/RXR transcription factors induce ABCA1/G1 and macrophages deficient in these transporters fail to increase cholesterol efflux when treated with LXR activators. We discovered that mice with deficiency of ABCA1/G1 in macrophages nonetheless show reduced atherosclerosis when treated with LXR activators, suggesting a novel effect of LXR activators in macrophages independent of cholesterol efflux, or a vascular effect. In Aim 2 we will seek to identify novel LXR anti-atherogenic targets in macrophages, such as genes that induce synthesis of long chain unsaturated fatty acids leading to synthesis of small proresolving lipid mediators (SPMs) that may promote resolution of atherosclerosis. An alternative explanation would be that LXRs upregulate ABCA1/G1 in endothelial cells with anti-atherogenic consequences and this will be tested in mice with endothelial-specific deficiency of these transporters. Overall, the findings are likely to contribute to the understanding of therapeutic interventions involving HDL infusions and LXR activators that are currently in human clinical trials for coronary heart disease, as well as to identify potential new therapeutic target.