Macrophages possess a number of mechanisms to regulate the balance between cholesterol uptake/synthesis and export. Of major importance are transport mechanisms that promote the efflux of excess cholesterol to extracellular acceptors. The removal of excess cholesterol is critical in the vessel wall, where macrophage uptake of lipoprotein-derived lipid can lead to a pathological cholesterol load in the absence of sufficient removal systems. Two members of the ATP binding cassette (ABC) superfamily of transmembrane transporters, ABCA1 and ABCG1, play critical roles in preventing cholesterol lipid accumulation in macrophages. Extensive studies have shown that ABCA1 promotes efflux of both cholesterol and phospholipids to lipid-poor apolipoproteins, in particular, apoA-l. In contrast, ABCG1 appears to promote efflux by redistributing intracellular cholesterol to plasma membrane domains accessible for removal by HDL, but not lipid-poor apoA-l. Thus, factors that affect the lipidated state of apoA-l may modulate the activity of these two transporters. During inflammation, HDL undergoes extensive remodeling that leads to the generation of particles that are significantly altered in size, charge, and apolipoprotein and lipid content. These alterations are primarily brought about by the acute phase reactants serum amyloid A (SAA) and Group IIA secretory phospholipase A2. Accumulating evidence from multiple laboratories, including ours, has established that SAA, either delivered as acute phase HDL or in a lipid-free form, can enhance macrophage cholesterol efflux. In Preliminary Data, we provide evidence that in the presence of cholesterol ester transfer protein, phospholipid depletion of HDL particles by Group IIA sPLA2 can lead to the generation of small, lipid-depleted HDL particles.
We aim to show that a major consequence of the acute phase response is an increase in the mobilization of cholesterol from the periphery, and an accelerated rate of macrophage reverse cholesterol transport. We hypothesize that SAA and sPLA2 promote macrophage lipid efflux by modifying HDL acceptors and through direct interactions with macrophage cells. To test this hypothesis, we propose the following Specific Aims: 1) To demonstrate that inflammation-induced remodeling of HDL generates substrates that enhance ABCA1 and ABCG1-dependent efflux;2) To investigate the mechanism(s) by which SAA and sPLA2 promote macrophage cholesterol efflux;and 3) To test the hypothesis that SAA protects against atherosclerotic lipid accumulation through an ABCA1 and/or ABCG1 -dependent mechanism.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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University of Kentucky
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Kim, Myung-Hee; de Beer, Maria C; Wroblewski, Joanne M et al. (2016) Impact of individual acute phase serum amyloid A isoforms on HDL metabolism in mice. J Lipid Res 57:969-79
Webb, Nancy R; De Beer, Maria C; Wroblewski, Joanne M et al. (2015) Deficiency of Endogenous Acute-Phase Serum Amyloid A Protects apoE-/- Mice From Angiotensin II-Induced Abdominal Aortic Aneurysm Formation. Arterioscler Thromb Vasc Biol 35:1156-65
Meyer, Jason M; Ji, Ailing; Cai, Lei et al. (2014) Minimally oxidized LDL inhibits macrophage selective cholesteryl ester uptake and native LDL-induced foam cell formation. J Lipid Res 55:1648-56
Ji, Ailing; Wroblewski, Joanne M; Webb, Nancy R et al. (2014) Impact of phospholipid transfer protein on nascent high-density lipoprotein formation and remodeling. Arterioscler Thromb Vasc Biol 34:1910-6
De Beer, Maria C; Wroblewski, Joanne M; Noffsinger, Victoria P et al. (2014) Deficiency of endogenous acute phase serum amyloid A does not affect atherosclerotic lesions in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 34:255-61
Tang, Tao; Thompson, Joel C; Wilson, Patricia G et al. (2013) Decreased body fat, elevated plasma transforming growth factor-? levels, and impaired BMP4-like signaling in biglycan-deficient mice. Connect Tissue Res 54:5-13
Meyer, Jason M; Graf, Gregory A; van der Westhuyzen, Deneys R (2013) New developments in selective cholesteryl ester uptake. Curr Opin Lipidol 24:386-92
de Beer, Maria C; Wroblewski, Joanne M; Noffsinger, Victoria P et al. (2013) The Impairment of Macrophage-to-Feces Reverse Cholesterol Transport during Inflammation Does Not Depend on Serum Amyloid A. J Lipids 2013:283486
Kim, Myung-Hee; de Beer, Maria C; Wroblewski, Joanne M et al. (2013) SAA does not induce cytokine production in physiological conditions. Cytokine 61:506-12
Cai, Lei; Wang, Zhen; Meyer, Jason M et al. (2012) Macrophage SR-BI regulates LPS-induced pro-inflammatory signaling in mice and isolated macrophages. J Lipid Res 53:1472-81

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