|Whitman, Stewart - UNIV OF OTTAWA|
|Kurowska, Elzbieta - KGK SUNERGIZE, INC.|
|Daugherty, Alan - UNIV OF KENTUCKY|
Submitted to: Atherosclerosis
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: December 1, 2004
Publication Date: January 1, 2005
Citation: Whitman, S.C., Kurowska, E.M., Manthey, J.A., Daugherty, A. 2005. Nobiletin, a citrus flavonoid isolated from tangerines, selectively inhibits class a scavenger receptor-mediated metabolism of acetylated ldl by mouse macrophages. Atherosclerosis. 178:25-32. Interpretive Summary: Chemicals in citrus peel have strong cholesterol-lowering actions in animals. The biological mechanisms of these chemicals have been investigated, and have been shown to block the production of lipids (fats) and cholesterol by liver cells. An additional mechanism has been found to occur for one of these compounds, nobiletin. This study shows that nobiletin prevents atherosclerosis at the level of the vascular wall by inhibiting macrophage foam cell formation.
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.