IDO1 regulation of SR-BI and cholesterol homeostasis in macrophages

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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