Yu-Zhou Gui1,2, Hong Yan1,2, Fei Gao1,2, Cong Xi1,2, Hui-Hui Li1,2, Yi-Ping Wang1,2. 1. University of Chinese Academy of Sciences, Beijing 100049, China. 2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Abstract
AIM: Betulin is a pentacyclic triterpenoid isolated from the bark of yellow and white birch trees with anti-cancer and anti-malaria activities. In this study we examined the effects of betulin on atherosclerosis in apoE-/- mice and the underlying mechanisms. METHODS: Murine macrophage RAW264.7 cells and human monocyte-derived THP-1 cells were tested. Foam cell formation was detected with Oil Red O staining. Cholesterol efflux was assessed using [3H]-cholesterol efflux assay. The expression of ATP-binding cassette transporter A1 and G1 (ABCA1 and ABCG1) was examined using RT-PCR and Western-blotting. The ABCA1 promoter activity was evaluated using luciferase activity assay. Male apoE-/- mice fed on a high-fat-diet (HFD), and received betulin (20 and 40 mg·kg-1·d-1, ig) for 12 weeks. The macrophage content and ABCA1 expression in the aortic sinuses were evaluated with immunofluorescence staining. The hepatic, intestinal and fecal cholesterol were also analyzed in the mice. RESULTS: In RAW264.7 cells, betulin (0.1-2.5 μg/mL) dose-dependently ameliorated oxLDL-induced cholesterol accumulation and enhanced cholesterol efflux. In both RAW264.7 and THP-1 cells, betulin increased the expression of ABCA1 and ABCG1 via suppressing the transcriptional repressors sterol-responsive element-binding proteins (SREBPs) that bound to E-box motifs in ABCA1 promoter, whereas E-box binding site mutation markedly attenuated betulin-induced ABCA1 promoter activity. In HFD-fed apoE-/- mice, betulin administration significantly reduced lesions in en face aortas and aortic sinuses. Furthermore, betulin administration significantly increased ABCA1 expression and suppressed macrophage positive areas in the aortic sinuses. Moreover, betulin administration improved plasma lipid profiles and enhanced fecal cholesterol excretion in the mice. CONCLUSION: Betulin attenuates atherosclerosis in apoE-/- mice by promoting cholesterol efflux in macrophages.
AIM: Betulin is a pentacyclic triterpenoid isolated from the bark of yellow and white birch trees with anti-cancer and anti-malaria activities. In this study we examined the effects of betulin on atherosclerosis in apoE-/- mice and the underlying mechanisms. METHODS:Murine macrophage RAW264.7 cells and human monocyte-derived THP-1 cells were tested. Foam cell formation was detected with Oil Red O staining. Cholesterol efflux was assessed using [3H]-cholesterol efflux assay. The expression of ATP-binding cassette transporter A1 and G1 (ABCA1 and ABCG1) was examined using RT-PCR and Western-blotting. The ABCA1 promoter activity was evaluated using luciferase activity assay. Male apoE-/- mice fed on a high-fat-diet (HFD), and received betulin (20 and 40 mg·kg-1·d-1, ig) for 12 weeks. The macrophage content and ABCA1 expression in the aortic sinuses were evaluated with immunofluorescence staining. The hepatic, intestinal and fecal cholesterol were also analyzed in the mice. RESULTS: In RAW264.7 cells, betulin (0.1-2.5 μg/mL) dose-dependently ameliorated oxLDL-induced cholesterol accumulation and enhanced cholesterol efflux. In both RAW264.7 and THP-1 cells, betulin increased the expression of ABCA1 and ABCG1 via suppressing the transcriptional repressors sterol-responsive element-binding proteins (SREBPs) that bound to E-box motifs in ABCA1 promoter, whereas E-box binding site mutation markedly attenuated betulin-induced ABCA1 promoter activity. In HFD-fed apoE-/- mice, betulin administration significantly reduced lesions in en face aortas and aortic sinuses. Furthermore, betulin administration significantly increased ABCA1 expression and suppressed macrophage positive areas in the aortic sinuses. Moreover, betulin administration improved plasma lipid profiles and enhanced fecal cholesterol excretion in the mice. CONCLUSION:Betulin attenuates atherosclerosis in apoE-/- mice by promoting cholesterol efflux in macrophages.
Authors: Xiao-Ping Yang; Lita A Freeman; Catherine L Knapper; Marcelo J A Amar; Alan Remaley; H Bryan Brewer; Silvia Santamarina-Fojo Journal: J Lipid Res Date: 2002-02 Impact factor: 5.922
Authors: J J Repa; S D Turley; J A Lobaccaro; J Medina; L Li; K Lustig; B Shan; R A Heyman; J M Dietschy; D J Mangelsdorf Journal: Science Date: 2000-09-01 Impact factor: 47.728
Authors: A S Plump; J D Smith; T Hayek; K Aalto-Setälä; A Walsh; J G Verstuyft; E M Rubin; J L Breslow Journal: Cell Date: 1992-10-16 Impact factor: 41.582
Authors: Manuela Sauter; Reinhard J Sauter; Henry Nording; Chaolan Lin; Marcus Olbrich; Stella Autenrieth; Christian Gleissner; Martin Thunemann; Nadia Otero; Esther Lutgens; Zouhair Aherrahrou; Dennis Wolf; Lars Zender; Sven Meuth; Robert Feil; Harald F Langer Journal: iScience Date: 2021-12-25