Plasma high density lipoproteins (HDL) are a major protective factor in atherosclerosis. The mechanisms of? the protective effect of HDL are incompletely understood. Mutations in ABCA1 result in low HDL and? impaired efflux of cholesterol from macrophage foam cells to lipid-poor apoA-l. However, while ABCA1 plays? a key role in HDL formation, ABCA1 interacts poorly with HDL particles that form the bulk of plasma HDL.? This observation led to our recent discovery that two LXR-induced half-transporters, ABCG1 and ABCG4,? mediate cholesterol efflux to HDL particles but not to lipid-poor apoA-l. ABCG1 is primarily responsible for? cholesterol efflux to HDL in LXR-activated macrophages. The primary hypothesis of this project is that the? activity of ABCG1 mediates the protective effect of HDL by promoting efflux of cholesterol from macrophages? and possibly other vascular cells to HDL. A secondary hypothesis is that changes in cellular cholesterol? efflux or distribution mediated by ABCG1 inhibit cholesterol-induced cell death, an idea we will explore? collaboratively with Dr.Tabas.
In Aim 1, we will evaluate the cellular mechanisms of cholesterol efflux? mediated by ABCG1 and the role of ABC transporters in preventing cholesterol-induced apoptosis.
In Aim 2 ? the role of ABCG1 in vivo will be evaluated in gene knock-out mice and effects on atherosclerosis will be? determined in atherosclerosis-susceptible backgrounds.
In Aim 3, the function of ABCG1 in macrophages? and hepatocytes will be evaluated by development of conditional knock-outs. The specific roles of ABCG1? and ABCA1 in HDL protection will be evaluated by seeing if the protective effect of increased HDL levels? resulting from apoA-l overexpression is reduced in a setting of macrophage ABCG1 and/or ABCA1? deficiency. The results of these studies will be directly relevant to new treatments aiming to reduce? atherosclerosis by increasing HDL levels.
|Fredman, Gabrielle; Kamaly, Nazila; Spolitu, Stefano et al. (2015) Targeted nanoparticles containing the proresolving peptide Ac2-26 protect against advanced atherosclerosis in hypercholesterolemic mice. Sci Transl Med 7:275ra20|
|Libby, Peter; Tabas, Ira; Fredman, Gabrielle et al. (2014) Inflammation and its resolution as determinants of acute coronary syndromes. Circ Res 114:1867-79|
|Subramanian, Manikandan; Tabas, Ira (2014) Dendritic cells in atherosclerosis. Semin Immunopathol 36:93-102|
|Subramanian, Manikandan; Hayes, Crystal D; Thome, Joseph J et al. (2014) An AXL/LRP-1/RANBP9 complex mediates DC efferocytosis and antigen cross-presentation in vivo. J Clin Invest 124:1296-308|
|Nagareddy, Prabhakara R; Murphy, Andrew J; Stirzaker, Roslynn A et al. (2013) Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis. Cell Metab 17:695-708|
|Subramanian, Manikandan; Thorp, Edward; Hansson, Goran K et al. (2013) Treg-mediated suppression of atherosclerosis requires MYD88 signaling in DCs. J Clin Invest 123:179-88|
|Gautier, Emmanuel L; Westerterp, Marit; Bhagwat, Neha et al. (2013) HDL and Glut1 inhibition reverse a hypermetabolic state in mouse models of myeloproliferative disorders. J Exp Med 210:339-53|
|Rodríguez, José M; Wolfrum, Susanne; Robblee, Megan et al. (2013) Altered expression of Raet1e, a major histocompatibility complex class 1-like molecule, underlies the atherosclerosis modifier locus Ath11 10b. Circ Res 113:1054-64|
|Tabas, Ira; Glass, Christopher K (2013) Anti-inflammatory therapy in chronic disease: challenges and opportunities. Science 339:166-72|
|Rong, James X; Blachford, Courtney; Feig, Jonathan E et al. (2013) ACAT inhibition reduces the progression of preexisting, advanced atherosclerotic mouse lesions without plaque or systemic toxicity. Arterioscler Thromb Vasc Biol 33:4-12|
Showing the most recent 10 out of 124 publications