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Inhibition of Macrophage CD36 Expression by Tamoxifen—A PPARgamma Dependent Mechanism
Author(s) -
Yu Miao,
Jiang Meixiu,
Chen Yuanli,
Duan Yajun,
Han Jihong
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1134.2
Subject(s) - cd36 , tamoxifen , foam cell , scavenger receptor , chemistry , peroxisome proliferator activated receptor , cancer research , receptor , biology , macrophage , endocrinology , medicine , biochemistry , cholesterol , cancer , breast cancer , in vitro , lipoprotein
CD36, a transmembrane glycoprotein, belongs to type B scavenger receptor family. It facilitates macrophage/foam cell formation and development of atherosclerosis. CD36 expression is transcriptionally regulated by peroxisome proliferator‐activated receptor gamma (PPARgamma), a ligand activated nuclear factor. Tamoxifen is a medicine used for treatment of patients with breast cancer for a few decades. Both clinical and basic studies have also demonstrated the cardioprotective effects of tamoxifen. In this study, we determined if tamoxifen can inhibit foam cell formation by inhibiting CD36 expression and the involved mechanisms. We initially observed that tamoxifen inhibited CD36 protein expression in both THP‐1 monocytes and THP‐1/PMA macrophages, and human blood monocyte derived macrophages. Associated with decreased CD36, tamoxifen dramatically reduced accumulated lipid droplets in the cytoplasm of cells and foam cell formation. FACS assay further showed that tamoxifen reduced cell surface CD36 levels. In vivo , administration of tamoxifen reduced CD36 protein expression in peritoneal macrophages and brown/white adipose tissues. Mechanistically, we initially determined that tamoxifen inhibited CD36 expression at the transcriptional level since it reduced CD36 mRNA levels and promoter activity. We further determined that tamoxifen inhibited CD36 expression by inactivating PPARgamma. It blocked PPARgamma‐induced THP‐1/PMA macrophage CD36 expression. In addition, tamoxifen activated ERK1/2 to phosphorylate PPARgamma. The EMSA assay demonstrated that tamoxifen inhibited the binding PPARgamma with the PPAR‐responsive element (PPRE) in CD36 promoter. Finally, we determined that tamoxifen was not able to inhibit CD36 expression in the macrophages lacking PPARgamma expression. Taken together, our study suggests that tamoxifen inhibited CD36 expression through inactivation of PPARgamma pathway and the inhibition of macrophage CD36 expression can be attributed to the anti‐atherogenic properties of tamoxifen.