Novel Function of Native Low-Density Lipoprotein in Inflammation

摘要 富含脂肪和胆固醇的西式饮食是许多非传染性疾病的主要风险因素，包括 心血管疾病、肥胖、糖尿病、代谢综合征和炎症性肠病(IBD)。一种常见的 与这些炎症性和代谢性疾病的发病机制相关的脂衍生物是低密度的 脂蛋白(LDL)被其受体(LDLR)清除，几乎在所有组织中都有表达。尽管已知的功能 关于低密度脂蛋白在动脉粥样硬化中的作用，人们对其在其他疾病中的作用知之甚少。炎症是常见的诱因 动脉粥样硬化和其他非传染性疾病。然而，无论是天然的低密度脂蛋白，这是最丰富的 生理形态的低密度脂蛋白，是否参与炎症反应尚不清楚。 这项研究的目的是确定天然低密度脂蛋白在炎症反应中的作用，因此低密度脂蛋白与许多 人类的疾病是可以解释的。这一极其重要的目标源于我们在#年的初步研究。 我们观察到，血液中低密度脂蛋白水平高的小鼠极易患实验性结肠炎。有趣的是，老鼠 LDLR缺陷(Ldlr-/-)对结肠炎有相对的保护作用。降低LDLR-/-小鼠对结肠炎的易感性 与抑制炎症和降低炎症信号通路的激活有关，如核因子-2 KB和MAPK，指出了低密度脂蛋白/低密度脂蛋白受体在炎症中的未知功能。事实上，我们观察到当地人 低密度脂蛋白在体外刺激巨噬细胞产生炎症分子。鉴于目前还没有研究证明这一角色 天然低密度脂蛋白在先天免疫信号和炎症反应中的作用，我们的观察强调了一个新的 高低密度脂蛋白相关炎症性疾病的发病机制。因此，我们假设 低密度脂蛋白通过低密度脂蛋白受体的内吞作用在髓系细胞中诱导炎症反应，从而引起炎症 这种炎症途径在结肠炎等炎症性疾病中起着重要作用。这一假说将 通过两个特定的目的进行测试：目的1.剖析参与低密度脂蛋白介导的 炎症反应；目的2.明确天然低密度脂蛋白及其受体在肠道炎症中的作用。vbl.使用 生物化学和分子生物学技术，我们将探索涉及的信号事件和机制 低密度脂蛋白/低密度脂蛋白受体介导的NF-B和MAPK通路的激活。我们将使用Ldlr-/-小鼠和结肠炎小鼠模型 探讨低密度脂蛋白/低密度脂蛋白受体在炎症性疾病中的体内相关性。 总之，这项研究将探索天然低密度脂蛋白的一种新的生物学功能，这将有助于阐明 高血低密度脂蛋白相关疾病的发病机制。此外，这项研究将破译一个尚不清楚的角色 血低密度脂蛋白在结肠炎发病机制中的作用这项研究的发现将开启治疗IBD和其他非传染性疾病的机会 以低密度脂蛋白合成或低密度脂蛋白受体下游信号通路为靶点的传染性疾病。

SUMMARY Lipid and cholesterol-rich Western diet is a major risk factor for many non-communicable diseases, including cardiovascular disease, obesity, diabetes, metabolic syndrome, and inflammatory bowel disease (IBD). A common lipid derivative associated with the pathogenesis of these inflammatory and metabolic diseases is low-density lipoprotein (LDL) which is scavenged by its receptor (LDLR) expressed in almost all tissue. Despite the known function of LDL in atherosclerosis, its role in other diseases is poorly understood. Inflammation is a common trigger for atherosclerosis and other non-communicable diseases. However, whether native LDL, which is the most abundant physiological form of LDL, is involved in the inflammatory response is unknown. The goal of this study is to define a role of native LDL in inflammatory response, so the association of LDL with many human diseases can be explained. This critically important objective was stemmed from our preliminary studies in which we observed that mice having high blood LDL are highly susceptible to experimental colitis. Interestingly, mice defective in LDLR (Ldlr-/-) were relatively protective against colitis. Reduced colitis susceptibility of Ldlr-/- mice was associated with suppressed inflammation and decreased activation of inflammatory signaling pathways such as NF- kB and MAPK, pointing to an uncharacterized function of LDL/LDLR in inflammation. Indeed, we observed that native LDL stimulates macrophages in vitro to produce inflammatory molecules. Given that no study yet documented a role of native LDL in innate immune signaling and inflammatory responses, our observation underscored a novel mechanism of pathogenesis of inflammatory disorders associated with high blood LDL. We, therefore, hypothesize that endocytosis of LDL through LDLR induces inflammatory responses in myeloid cells causing inflammation, and such an inflammatory pathway imparts a major contribution in inflammatory disorders like colitis. This hypothesis will be tested through two specific aims: Aim 1. To dissect the pathway involved in LDL-mediated induction of inflammatory responses; Aim 2. To define the role of native LDL and its receptor in intestinal inflammation. Using biochemical and molecular biology techniques, we will explore signaling events and mechanisms involved in LDL/LDLR-mediated activation of NF-B and MAPK pathways. We will use Ldlr-/- mice and mouse models of colitis to investigate the in vivo relevance of LDL/LDLR in inflammatory disorders. Overall, this study will explore a novel biological function of native LDL which will help elucidate the pathogenic mechanism of diseases associated with high blood LDL. Furthermore, this study will decipher a yet unknown role of blood LDL in colitis pathogenesis. The findings of this study will open the opportunity to treat IBD and other non- communicable diseases by targeting LDL synthesis or LDLR downstream signaling pathways.