Dihydromyricetin ameliorates foam cell formation via LXRα-ABCA1/ABCG1-dependent cholesterol efflux in macrophages

Biomed Pharmacother. 2018 May;101:543-552. doi: 10.1016/j.biopha.2018.02.124. Epub 2018 Mar 22.

Abstract

As the most abundant flavonoid in Ampelopsis grossedentata, the protective effects of dihydromyricetin on atherosclerosis have been well established, yet the detailed mechanisms are not fully understood. The aim of the present study was to examine the effect of dihydromyricetin on lipid accumulation and the underlying molecular mechanisms in macrophages and ApoE-/- mice. Incubation with dihydromyricetin significantly attenuated oxidized low-density lipoprotein (ox-LDL)-mediated cholesterol and lipid accumulation in THP-1-derived macrophages, which was due to increased cholesterol efflux. In addition, dihydromyricetin increased mRNA and protein expressions of ATP-binding cassette transporter A1 (ABCA1) and ABCG1 but had no effect on the mRNA and protein expressions of SR-A, CD36, or SR-BI involved in cholesterol homeostasis. Furthermore, the upregulation of ABCA1 and ABCG1 by dihydromyricetin depended on liver X receptor α (LXRα), as evidenced by an increase in the nuclear level of LXRα and its prevention of the expression of ABCA1 and ABCG1 after inhibition of LXRα activity by knockdown of LXRα expression with small interfering RNA (siRNA). Accordingly, dihydromyricetin-mediated suppression of cholesterol and lipid accumulation in macrophages was also abrogated by LXRα siRNA. Moreover, the lesion size of atherosclerosis was smaller in dihydromyricetin-treated ApoE-/- mice compared with the vehicle-treated mice, and the protein expression of CD36, SR-A, ABCA1, ABCG1 and LXRα in aortas was modulated similar to that observed in THP-1-derived macrophages. These data suggest that promotion of LXRα-ABCA1/ABCG1-dependent cholesterol efflux is crucial event in suppression of lipid accumulation by dihydromyricetin in the transformation of macrophage foam cells.

Keywords: ATP-binding cassette transporter; Dihydromyricetin; Liver X receptor α; Macrophages.

MeSH terms

  • ATP Binding Cassette Transporter 1 / biosynthesis*
  • ATP Binding Cassette Transporter, Subfamily G, Member 1 / biosynthesis*
  • Animals
  • Atherosclerosis / drug therapy
  • Atherosclerosis / metabolism
  • Cholesterol / metabolism*
  • Dose-Response Relationship, Drug
  • Flavonols / pharmacology*
  • Flavonols / therapeutic use
  • Foam Cells / drug effects
  • Foam Cells / metabolism*
  • Humans
  • Liver X Receptors / biosynthesis*
  • Macrophages / drug effects
  • Macrophages / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • THP-1 Cells

Substances

  • ABCA1 protein, human
  • ABCG1 protein, human
  • ATP Binding Cassette Transporter 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 1
  • Flavonols
  • Liver X Receptors
  • NR1H3 protein, human
  • Cholesterol
  • dihydromyricetin