Macrophages possess a number of mechanisms to regulate the balance between cholesteroluptake/synthesis and export. Of major importance are transport mechanisms that promote the efflux ofexcess 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 theabsence of sufficient removal systems. Two members of the ATP binding cassette (ABC) superfamily oftransmembrane transporters, ABCA1 and ABCG1, play critical roles in preventing cholesterol lipidaccumulation in macrophages. Extensive studies have shown that ABCA1 promotes efflux of bothcholesterol and phospholipids to lipid-poor apolipoproteins, in particular, apoA-l. In contrast, ABCG1 appearsto promote efflux by redistributing intracellular cholesterol to plasma membrane domains accessible forremoval by HDL, but not lipid-poor apoA-l. Thus, factors that affect the lipidated state of apoA-l maymodulate the activity of these two transporters. During inflammation, HDL undergoes extensive remodelingthat leads to the generation of particles that are significantly altered in size, charge, and apolipoprotein andlipid 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, canenhance macrophage cholesterol efflux. In Preliminary Data, we provide evidence that in the presence ofcholesterol ester transfer protein, phospholipid depletion of HDL particles by Group IIA sPLA2 can lead to thegeneration of small, lipid-depleted HDL particles.
We aim to show that a major consequence of the acutephase response is an increase in the mobilization of cholesterol from the periphery, and an accelerated rateof macrophage reverse cholesterol transport. We hypothesize that SAA and sPLA2 promote macrophagelipid efflux by modifying HDL acceptors and through direct interactions with macrophage cells. To test thishypothesis, we propose the following Specific Aims: 1) To demonstrate that inflammation-inducedremodeling of HDL generates substrates that enhance ABCA1 and ABCG1-dependent efflux; 2) Toinvestigate the mechanism(s) by which SAA and sPLA2 promote macrophage cholesterol efflux; and 3) Totest the hypothesis that SAA protects against atherosclerotic lipid accumulation through an ABCA1 and/orABCG1 -dependent mechanism.
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