Technical Abstract: Our current studies examined whether citrus flavonoids possess antiatherogenic effects by modulating macrophage metabolism of the specific class A scavenger receptor (SR-A) ligand, acetylated LDL (acLDL). In this study, both acLDL-metabolism and AR-A expression by cultured murine J774A.1 macrophages was examined following 24 h pretreatment (100'M) with the flavonoids: naringenin (from grapefruit), hesperetin (from oranges), and tengeretin and nobiletin (from tangerines). Of these flavonoids, only nobiletin inhibited (50-72%) acLDL metabolism as measured by both cellular cholesterol ester mass and [3H]oleate incorporation into cholesterol esters. This nobiletin-mediated effect was specific for SR-A and not a global effect on lipoprotein metabolism by the macrophage, as all four citrus flavonoids significantly reduce the metabolism of beta-VLDL, which is primarily taken up by macrophages via the LDL receptor. Nevertheless, nobiletin did not affect SR-A protein expression, as measured by Western blot analysis, nor was cell surface expression of SR-A affected as measured by 4°C binding studies using [125I]acLDL. In conclusion, our findings suggest that in addition to reducing plasma cholesterol concentrations, nobiletin may prevent atherosclerosis at the level of the vascular wall by inhibiting macrophage foam-cell formation.