Novel Function of Native Low-Density Lipoprotein in Inflammation

天然低密度脂蛋白在炎症中的新功能

• 批准号: 10670376
• 负责人: Hasan Zaki
• 金额: $ 54.59万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-21 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10670376
• 关键词: Anabolism; Animal Model; Arterial Fatty Streak; Atherosclerosis; Biochemical; Biological; Biological Assay; Biological Process; Blood; CD36 gene; Cardiovascular Diseases; Cell surface; Chemical Injury; Cholesterol; Chronic; Clinical Markers; Colitis; Critical Pathways; Data; Deposition; Diabetes Mellitus; Disease; Disease susceptibility; Drug usage; Dyslipidemias; Endocytosis; Endosomes; Etiology; Event; Functional disorder; Genetic Models; Goals; High Density Lipoproteins; High Fat Diet; Immune signaling; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Intake; Intestines; Knowledge; LDL Cholesterol Lipoproteins; Link; Lipids; Lipoproteins; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; MAP Kinase Gene; Macrophage; Measures; Mediating; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Modeling; Modification; Molecular Biology Techniques; Molecular Structure; Mus; Myeloid Cells; NF-kappa B; Names; Obesity; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Peripheral; Physiological; Physiology; Play; Predisposition; RIPK1 gene; Research; Risk Factors; Role; Signal Pathway; Signal Transduction; Testing; Time; Tissues; cell type; dextran sulfate sodium induced colitis; gut inflammation; gut microbiota; human disease; in vivo; innate immune pathways; innovation; murine colitis; new therapeutic target; novel; novel therapeutics; oxidized low density lipoprotein; receptor; receptor mediated endocytosis; stem; western diet

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.

总结 富含脂质和胆固醇的西方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道疾病（IBD）。一个共同 与这些炎症和代谢性疾病的发病机制相关的脂质衍生物是低密度的 低密度脂蛋白（LDL），其被几乎所有组织中表达的其受体（LDLR）清除。尽管已知的功能 尽管LDL在动脉粥样硬化中的作用，但其在其他疾病中的作用却知之甚少。炎症是一种常见的触发因素， 动脉粥样硬化和其他非传染性疾病。然而，是否天然低密度脂蛋白，这是最丰富的 LDL的生理形式，参与炎症反应是未知的。 这项研究的目的是确定天然LDL在炎症反应中的作用，因此LDL与许多炎症反应的关系是确定的。 人类疾病是可以解释的。这一至关重要的目标源于我们的初步研究， 我们观察到具有高血液LDL的小鼠对实验性结肠炎高度敏感。有趣的是，老鼠 LDLR缺陷型（Ldlr-/-）对结肠炎具有相对保护作用。Ldlr-/-小鼠结肠炎易感性降低， 与抑制炎症和减少炎症信号通路的激活有关，如NF-κ B， kB和MAPK，指出LDL/LDLR在炎症中的未表征功能。我们观察到， LDL在体外刺激巨噬细胞产生炎症分子。考虑到还没有研究证明 天然LDL在先天免疫信号传导和炎症反应中的作用，我们的观察强调了一种新的 与高血LDL相关的炎症性疾病的发病机制。因此我们假设 LDL通过LDLR的内吞作用诱导骨髓细胞中的炎症反应，引起炎症， 这种炎性途径在炎性疾病如结肠炎中起主要作用。这一假设将 通过两个具体目标进行测试：目标1。为了剖析LDL介导的诱导 炎症反应;目的2.目的探讨天然低密度脂蛋白及其受体在肠道炎症中的作用。使用 生物化学和分子生物学技术，我们将探讨信号事件和机制参与 LDL/LDL R介导的NF-κ B B和MAPK通路的活化。我们将使用Ldlr-/-小鼠和结肠炎小鼠模型 研究LDL/LDLR在炎症性疾病中的体内相关性。 总之，这项研究将探索天然LDL的一种新的生物学功能，这将有助于阐明LDL的致病性。 与高血LDL相关的疾病的机制。此外，这项研究将破译一个未知的作用， 血LDL在结肠炎发病机制中的作用。这项研究的结果将为治疗IBD和其他非炎症性疾病提供机会。 通过靶向LDL合成或LDLR下游信号通路来治疗传染性疾病。