IDO1 regulation of SR-BI and cholesterol homeostasis in macrophages

IDO1 对巨噬细胞中 SR-BI 和胆固醇稳态的调节

• 批准号: 10731003
• 负责人: Subhrangsu S Mandal
• 金额: $ 45.75万
• 依托单位: UNIVERSITY OF TEXAS ARLINGTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10731003
• 关键词: Address; Animal Model; Animals; Aryl Hydrocarbon Receptor; Atherosclerosis; Biochemical; Biological Process; Blood; Body Weight; Cardiovascular Diseases; Cells; Cholesterol; Cholesterol Homeostasis; Chronic; Complex; Diabetes Mellitus; Dioxygenases; Disease; Down-Regulation; Endotoxins; Environment; Estradiol; Estrogen Receptors; Excision; Foam Cells; Functional disorder; Genes; Genotoxic Stress; Goals; HDL cholesteryl ester; Hallmark Cell; Health; Hemostatic function; High Density Lipoproteins; Homeostasis; Host Defense; Hyperlipidemia; Hypertension; Immune response; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Insulin Resistance; Kupffer Cells; Kynurenine; Link; Lipids; Lipopolysaccharides; Lipoprotein Receptor; Liver; Low Density Lipoprotein Receptor; Macrophage; Macrophage Activation; Mediating; Metabolic Diseases; Metabolic dysfunction; Metabolic syndrome; Metabolism; Minority-Serving Institution; Obesity; Ovarian hormone; Ovariectomy; Pathogenicity; Plasma; Play; Rattus; Receptor Activation; Receptor Signaling; Regulation; Repression; Research; Research Training; Role; Signal Pathway; Signal Transduction; Starvation; Students; Therapeutic; Tissues; Tryptophan; Tryptophan 2,3 Dioxygenase; aryl hydrocarbon receptor ligand; atheroprotective; biological adaptation to stress; cardiovascular disorder risk; career; cytokine; experience; experimental study; high density lipoprotein receptor; human disease; in vivo; lipid metabolism; liver inflammation; novel; potential biomarker; receptor; scavenger receptor; therapeutic target; transcriptome sequencing; transdifferentiation; undergraduate student; uptake

Inflammation is a fundamental biological process that plays key roles in immune response. However, uncontrolled, and chronic inflammation are the root causes of many human diseases including metabolic disorders, obesity, insulin resistance, diabetes, hypertension, and atherosclerosis. Macrophage activation plays a central role in inflammation, regulates the host defense during pathogenic infection, and maintain tissue homeostasis. Recent studies indicate that macrophage functions are influenced by lipid metabolism.10-15 The imbalance in lipid uptake, metabolism, and removal in macrophages cause tissue trans-differentiation contributing to hyperlipidemia and metabolic syndrome. For example, macrophages and derived foams cells are the hallmarks of atherosclerosis. The signaling mechanism associated with lipid homeostasis and metabolism in macrophages is complex and poorly understood. The primary goal of this proposal is to investigate the cholesterol homeostasis mechanism in macrophages under inflammation. In particular, HDLR-SR-BI (SR-BI), a receptor for the cholesterol-rich HDL, facilitates the selective delivery of HDL-cholesteryl ester to the liver. It promotes atheroprotection via HDL metabolism. SR-BI is also expressed in in macrophages and regulates lipid homeostasis. In a preliminary study, we observed that the SR-BI expression is downregulated in macrophages upon LPS stimulation, and this is potentially regulated viaIndoleamine-2,3-dioxygenase 1 (IDO1). We found that IDO1 and its down-stream catabolite, kynurenine (KYN), are also elevated in LPS-stimulated macrophages and inhibition of IDO1 reversed the LPS-induced downregulation of SR-BI, suggesting potential role of IDO1 in SR- BI expression and cholesterol homeostasis, in macrophages. Notably, KYN is a ligand for aryl hydrocarbon receptor (AhR) which regulates genotoxic stress and inflammatory response. Here, we propose biochemical and cell-based experiments to investigate the roles of IDO1 and KYN-AhR signaling in SR-BI expression and cholesterol homeostasis, in macrophages (aim 1). In the aim 2, we propose to investigate the roles of IDO1 in hepatic inflammation, Kupffer cells (resident macrophage in liver) activation, SR-BI expression, and cholesterol homeostasis in vivo using ovariectomized (OVX) rat as animal model. Overall, our studies will lead to the discovery of novel signaling pathways associated with SR-BI expression and cholesterol homeostasis in macrophages under inflammation. In addition to addressing an important scientific problem, this proposal will also serve to enrich student (especially undergraduates) research experiences at UTA, a minority-serving institution. 1

炎症是一个基本的生物过程，在免疫反应中发挥着关键作用。然而， 不受控制的慢性炎症是许多人类疾病（包括代谢性疾病）的根源 疾病、肥胖、胰岛素抵抗、糖尿病、高血压和动脉粥样硬化。巨噬细胞激活作用 在炎症中发挥核心作用，在病原体感染期间调节宿主防御，并维持组织 体内平衡。最近的研究表明，巨噬细胞的功能受到脂质代谢的影响。10-15 巨噬细胞脂质摄取、代谢和清除的不平衡导致组织转分化 导致高脂血症和代谢综合征。例如，巨噬细胞和衍生泡沫细胞是 动脉粥样硬化的特征。脂质稳态和代谢相关的信号机制 巨噬细胞很复杂，人们对它知之甚少。该提案的主要目标是调查 炎症下巨噬细胞的胆固醇稳态机制。特别是 HDLR-SR-BI (SR-BI)， 富含胆固醇的 HDL 受体，促进 HDL-胆固醇酯选择性递送至肝脏。它 通过 HDL 代谢促进动脉粥样硬化保护。 SR-BI 也在巨噬细胞中表达并调节脂质 体内平衡。在初步研究中，我们观察到巨噬细胞中 SR-BI 表达下调 LPS 刺激后，这可能通过吲哚胺-2,3-双加氧酶 1 (IDO1) 进行调节。我们发现 IDO1 及其下游分解代谢物犬尿氨酸 (KYN) 在 LPS 刺激的巨噬细胞中也升高， 抑制 IDO1 可逆转 LPS 诱导的 SR-BI 下调，表明 IDO1 在 SR-BI 中的潜在作用 巨噬细胞中的 BI 表达和胆固醇稳态。值得注意的是，KYN 是芳基烃的配体 受体（AhR）调节基因毒性应激和炎症反应。在这里，我们建议生化和 基于细胞的实验研究 IDO1 和 KYN-AhR 信号在 SR-BI 表达和 巨噬细胞中的胆固醇稳态（目标 1）。在目标 2 中，我们建议研究 IDO1 在 肝脏炎症、库普弗细胞（肝脏中的常驻巨噬细胞）激活、SR-BI 表达和胆固醇 使用卵巢切除（OVX）大鼠作为动物模型进行体内稳态。总的来说，我们的研究将导致 发现与 SR-BI 表达和胆固醇稳态相关的新信号通路 巨噬细胞处于炎症状态。除了解决一个重要的科学问题之外，该提案还将 也有助于丰富 UTA 的学生（尤其是本科生）的研究经验，UTA 是一个少数族裔服务机构 机构。 1