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

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