1 Scientific RepoRts | 6:32105 | DOI: 10.1038/srep32105 www.nature.com/scientificreports Clinically used selective estrogen receptor modulators afect diferent steps of macrophage- specifc reverse cholesterol transport María e. Fernández-Suárez 1,2 , Joan C. Escolà-Gil 3,4,5 , oscar pastor 2,6 , Alberto Dávalos 7 , Francisco Blanco-Vaca 3,4,5 , Miguel A. Lasunción 1,2 , Javier Martínez-Botas 1,2 & Diego Gómez-Coronado 1,2 Selective estrogen receptor modulators (SERMs) are widely prescribed drugs that alter cellular and whole-body cholesterol homeostasis. Here we evaluate the efect of SERMs on the macrophage- specifc reverse cholesterol transport (M-RCT) pathway, which is mediated by HDL. Treatment of human and mouse macrophages with tamoxifen, raloxifene or toremifene induced the accumulation of cytoplasmic vesicles of acetyl-LDL-derived free cholesterol. The SERMs impaired cholesterol efux to apolipoprotein A-I and HDL, and lowered ABCA1 and ABCG1 expression. These efects were not altered by the antiestrogen ICI 182,780 nor were they reproduced by 17β-estradiol. The treatment of mice with tamoxifen or raloxifene accelerated HDL-cholesteryl ester catabolism, thereby reducing HDL- cholesterol concentrations in serum. When [ 3 H]cholesterol-loaded macrophages were injected into mice intraperitoneally, tamoxifen, but not raloxifene, decreased the [ 3 H]cholesterol levels in serum, liver and feces. Both SERMs downregulated liver ABCG5 and ABCG8 protein expression, but tamoxifen reduced the capacity of HDL and plasma to promote macrophage cholesterol efux to a greater extent than raloxifene. We conclude that SERMs interfere with intracellular cholesterol trafcking and efux from macrophages. Tamoxifen, but not raloxifene, impair M-RCT in vivo. This efect is primarily attributable to the tamoxifen-mediated reduction of the capacity of HDL to promote cholesterol mobilization from macrophages. Reverse cholesterol transport (RCT) is the process by which high-density lipoproteins (HDL) convey cholesterol from peripheral cells to the liver for excretion into bile and feces 1 . Promotion of RCT from cholesterol-laden macrophages (M-RCT) present in the arterial wall is considered a major anti-atherogenic function of HDL 2,3 . Te removal of excessive cholesterol from cells by HDL or lipid-poor apolipoprotein (apo) A-I constitutes the frst step in RCT 1 . Cholesterol efux is mainly mediated by ATP-binding cassette transporter (ABC) A1 and ABCG1, with lipid-poor apoA-I and mature HDL particles, respectively, serving as acceptors. Additionally, scavenger receptor class B type I (SR-BI) can also promote cholesterol export to mature HDL. In the liver, SR-BI mediates the selec- tive uptake of HDL cholesterol. Subsequently, cholesterol can be converted to bile acids or be directly excreted to the bile through the heterodimeric transporter formed by ABCG5 and ABCG8 (ABCG5/G8). Tese four ABC proteins are transcriptionally upregulated by the liver X receptor (LXR), which is activated by oxysterols 1 Servicio de Bioquímica-investigación, Hospital Universitario Ramón y cajal, iRYciS, Madrid, Spain. 2 ciBeR de fisiopatología de la Obesidad y nutrición (ciBeROBn), Madrid, Spain. 3 institut d’investigacions Biomèdiques (iiB) Sant Pau, Barcelona , Spain. 4 Departament de Bioquímica i Biología Molecular, Universitat Autònoma de Barcelona, Bellaterra, Spain. 5 ciBeR de Diabetes y enfermedades Metabólicas Asociadas (ciBeRDeM), Spain. 6 Servicio de Bioquímica clínica, Hospital Universitario Ramón y cajal, iRYciS, Madrid, Spain. 7 instituto Madrileño de estudios Avanzados (iMDeA)-Alimentación, Madrid, Spain. correspondence and requests for materials should be addressed to D.G.-c. (email: diego.gomez@hrc.es.) Received: 24 February 2016 Accepted: 29 July 2016 Published: 07 September 2016 opeN