Regulation of Macrophage Reverse Cholesterol Transport by BRCA1

描述（由申请人提供）：动脉粥样硬化发展的一个关键事件是巨噬细胞向血管壁下层上皮的募集和氧化胆固醇的不受控制的摄取。巨噬细胞氧化胆固醇的持续积累和相关的炎症反应导致泡沫细胞的形成和动脉粥样硬化的开始。逆转巨噬细胞胆固醇积累的过程已被认为是心血管疾病的一种潜在的新治疗方法，然而，除了可注射形式的载脂蛋白A1；目前还没有增强巨噬细胞逆转胆固醇转运（RCT）的药物在临床上被证实可用于人类。肝脏X受体LXR和LXR已被确定为胆固醇稳态的重要调节因子。合成LXR激动剂治疗至少部分通过刺激巨噬细胞RCT减少心血管疾病动物模型中的动脉粥样硬化。LXR激动剂增强巨噬细胞RCT的能力激发了人们对这些药物治疗潜力的极大兴趣。然而，LXR激动剂诱导肝脏脂肪生成的倾向减缓了这些化合物进入临床的进程。我们推断，鉴定控制LXR活性的蛋白可能为巨噬细胞RCT和心血管疾病的调节提供新的途径。在寻找这些因素的过程中，我们发现乳腺癌和卵巢癌易感性1基因产物（BRCA1）是一种选择性控制LXR活性的蛋白质。先前的研究表明，BRCA1及其异二聚体伙伴BRCA1环相关结构域1 （BARD1）作为E3泛素连接酶，控制几种核受体的半衰期。我们的初步数据表明，BARD1/BRCA1的缺失增加了LXR的半衰期，降低了LXR的转录活性

DESCRIPTION (provided by applicant): A critical event in the development of atherosclerosis is the recruitment of macrophages to the underlying epithelial layer of blood vessel walls and the uncontrolled uptake of oxidized cholesterol. Continued accumulation of oxidized cholesterol by macrophages and an associated inflammatory response leads to foam cell formation and the initiation of atherosclerosis. Reversing the process of macrophage cholesterol accumulation has been held out as a potential novel treatment for cardiovascular disease, however other than injectable forms of apolipoprotein A1; no drugs that enhance macrophage reverse cholesterol transport (RCT) have been validated in the clinic for use in humans. The liver X receptors LXR and LXR have been identified as important regulators of cholesterol homeostasis. Treatment with synthetic LXR agonists reduces atherosclerosis in animal models of cardiovascular disease at least in part by stimulating macrophage RCT. The ability of LXR agonists to enhance macrophage RCT has stimulated great interest in the therapeutic potential of these agents. Nevertheless, the propensity of LXR agonists to induce hepatic lipogenesis has slowed the progression of these compounds to the clinic. We reasoned that identifying proteins that control LXR activity may reveal new approaches for the regulation of macrophage RCT and cardiovascular disease. In a search for such factors we have identified the Breast and Ovarian Cancer Susceptibility 1 gene product (BRCA1) as a protein that selectively controls LXR activity. Previous studies have demonstrated that BRCA1 and its heterodimeric partner BRCA1 ring associated domain 1 (BARD1) function as an E3 ubiquitin ligase that controls the half-life of several nuclear receptors. Our preliminary data indicates that depletion of BARD1/BRCA1 increases the half-life of LXR and decreases its transcriptional activity while having little or no effect on LXR. Importantly, it is the LXR subtype which plays the dominant role in regulating macrophage RCT. The contributions of BARD1/BRCA1 to DNA repair, genome stability and oncogenesis have been well studied. Our preliminary studies, however, suggest a new and unexpected role for BARD1/BRCA1 in the pathogenesis of cardiovascular disease and macrophage biology. We will use genetic approaches to deplete BARD1/BRCA1 in macrophages along with genome wide profiling to determine the contribution of BARD1/BRCA1 to the control of macrophage RCT and to define the genetic networks controlled by BRCA1 in macrophages. We believe that these studies will facilitate a paradigm shift in our understanding of BARD1/BRCA1 function by identifying potential new roles for BARD1/BRCA1 in the control of macrophage function that may facilitate the therapeutic targeting of the RCT pathway.