Nobiletin, a citrus flavonoid isolated from tangerines, selectively inhibits class A scavenger receptor-mediated metabolism of acetylated LDL by mouse macrophages

Stewart C. Whitman, Elzbieta M. Kurowska, John A. Manthey, Alan Daugherty

Research output: Contribution to journalArticlepeer-review

153 Scopus citations


Flavonoids are a class of chemically related polyphenols that are nearly ubiquitous in nature. Of the more-than 4000 flavonoids thus identified, citrus fruit-derived flavonoids are suggested to have an inverse association with the occurrence of coronary heart disease via their ability to reduce plasma cholesterol concentrations. Our current studies examined whether citrus flavonoids possess an additional antiatherogenic effect by modulating macrophage metabolism of the specific class A scavenger receptor (SR-A) ligand, acetylated LDL (acLDL). In this study, both acLDL-metabolism and SR-A expression by cultured murine J774A.1 macrophages was examined following 24 h pretreatment (100 μM) with the flavonoids: naringenin (from grapefruit), hesperetin (from oranges), and tangeretin 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.

Original languageEnglish
Pages (from-to)25-32
Number of pages8
Issue number1
StatePublished - Jan 2005

Bibliographical note

Funding Information:
This work was supported by the Heart and Stroke Foundation of Ontario Grant NA-5086 (SCW), Canadian Institutes of Health Research Grants MOP-53344 and GHS-60663 (SCW), an American Heart Association Grant-in-Aid (AD) and a National Institutes of Health Grant RO1 HL55487 (AD). SCW is the recipient of a Great-West Life & London Life New Investigator Award from the Heart and Stroke Foundation of Canada.


  • Acetylated LDL
  • Atherosclerosis
  • Flavonoids
  • Foam cells
  • Macrophages

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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