Clinically used selective estrogen receptor modulators affect different steps of macrophage-specific reverse cholesterol transport
Por:
Fernandez-Suarez, ME, Escola-Gil, JC, Pastor, O, Davalos, A, Blanco-Vaca, F, Lasuncion, MA, Martinez-Botas, J, Gomez-Coronado, D
Publicada:
7 sep 2016
Resumen:
Selective estrogen receptor modulators (SERMs) are widely prescribed drugs that alter cellular and whole-body cholesterol homeostasis. Here we evaluate the effect of SERMs on the macrophage-specific 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 efflux to apolipoprotein A-I and HDL, and lowered ABCA1 and ABCG1 expression. These effects were not altered by the antiestrogen ICI 182,780 nor were they reproduced by 17 beta-estradiol. The treatment of mice with tamoxifen or raloxifene accelerated HDL-cholesteryl ester catabolism, thereby reducing HDL-cholesterol concentrations in serum. When [H-3] cholesterol-loaded macrophages were injected into mice intraperitoneally, tamoxifen, but not raloxifene, decreased the [3H] 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 efflux to a greater extent than raloxifene. We conclude that SERMs interfere with intracellular cholesterol trafficking and efflux from macrophages. Tamoxifen, but not raloxifene, impair M-RCT in vivo. This effect is primarily attributable to the tamoxifen-mediated reduction of the capacity of HDL to promote cholesterol mobilization from macrophages.
Filiaciones:
Fernandez-Suarez, ME:
Hosp Univ Ramon Y Cajal, IRYCIS, Serv Bioquim Invest, Madrid, Spain
CIBER Fisiopatol Obesidad & Nutr CIBERobn, Madrid, Spain
Escola-Gil, JC:
Inst Invest Biomed, Barcelona, Spain
Univ Autonoma Barcelona, Dept Bioquim & Biol Mol, Bellaterra, Spain
CIBER Diabet & Enfermedades Metab Asociadas CIBER, Barcelona, Spain
Pastor, O:
CIBER Fisiopatol Obesidad & Nutr CIBERobn, Madrid, Spain
Hosp Univ Ramon y Cajal, Serv Bioquim Clin, IRYCIS, Madrid, Spain
Davalos, A:
Inst Madrileno Estudios Avanzados IMDEA Alimentac, Madrid, Spain
Blanco-Vaca, F:
Inst Invest Biomed, Barcelona, Spain
Univ Autonoma Barcelona, Dept Bioquim & Biol Mol, Bellaterra, Spain
CIBER Diabet & Enfermedades Metab Asociadas CIBER, Barcelona, Spain
Lasuncion, MA:
Hosp Univ Ramon Y Cajal, IRYCIS, Serv Bioquim Invest, Madrid, Spain
CIBER Fisiopatol Obesidad & Nutr CIBERobn, Madrid, Spain
Martinez-Botas, J:
Hosp Univ Ramon Y Cajal, IRYCIS, Serv Bioquim Invest, Madrid, Spain
CIBER Fisiopatol Obesidad & Nutr CIBERobn, Madrid, Spain
Gomez-Coronado, D:
Hosp Univ Ramon Y Cajal, IRYCIS, Serv Bioquim Invest, Madrid, Spain
CIBER Fisiopatol Obesidad & Nutr CIBERobn, Madrid, Spain
Gold, Green Published
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