Selective estrogen receptor modulators (SERMs) affect cholesterol homeostasis through the master regulators SREBP and LXR

被引:21
作者
Fernandez-Suarez, Maria E. [1 ,2 ,6 ]
Daimiel, Lidia [1 ,2 ,7 ]
Villa-Turegano, Gemma [1 ]
Vazquez Pavon, Maria [1 ,8 ]
Busto, Rebeca [1 ,2 ]
Escola-Gil, Joan C. [3 ,4 ,5 ]
Platt, Frances M. [6 ]
Lasuncion, Miguel A. [1 ,2 ]
Martinez-Botas, Javier [1 ,2 ]
Gomez-Coronado, Diego [1 ,2 ]
机构
[1] IRYCIS, Hosp Univ Ramon y Cajal, Serv Bioquim Invest, Ctra Colmenar,Km 9, Madrid 28034, Spain
[2] Inst Salud Carlos III, CIBER Fisiopatol Obesidad & Nutr CIBEROBN, Madrid, Spain
[3] Inst Invest Biomed IIB St Pau, Inst Recerca, Hosp Santa Creu & St Pau, Barcelona, Spain
[4] Inst Salud Carlos III, CIBER Diabet & Enfermedades Metab Asociadas CIBER, Madrid, Spain
[5] Univ Autonoma Barcelona, Dept Bioquim & Biol Mol, Barcelona, Spain
[6] Univ Oxford, Dept Pharmacol, Mansfield Rd, Oxford OX1 3QT, England
[7] IMDEA Food, Ctra Cantoblanco 8, Madrid 28049, Spain
[8] Natl Univ Singapore, Dept Physiol, Singapore 117597, Singapore
关键词
Tamoxifen; Raloxifene; Toremifene; SREBP; LXR; Cholesterol; LIVER X RECEPTOR; DRUGS ACTIVATE SREBP; BREAST-CANCER; ANTIPSYCHOTIC-DRUGS; SERUM-CHOLESTEROL; INTRACELLULAR-TRANSPORT; ANTIDEPRESSANT-DRUGS; GENE-EXPRESSION; TAMOXIFEN; STEROL;
D O I
10.1016/j.biopha.2021.111871
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Selective estrogen receptor modulators (SERMs) are nonsteroidal drugs that display an estrogen-agonist or estrogen-antagonist effect depending on the tissue targeted. SERMs have attracted great clinical interest for the treatment of several pathologies, most notably breast cancer and osteoporosis. There is strong evidence that SERMs secondarily affect cholesterol metabolism, although the mechanism has not been fully elucidated. In this study, we analysed the effect of the SERMs tamoxifen, raloxifene, and toremifene on the expression of lipid metabolism genes by microarrays and quantitative PCR in different cell types, and ascertained the main mechanisms involved. The three SERMs increased the expression of sterol regulatory element-binding protein (SREBP) target genes, especially those targeted by SREBP-2. In consonance, SERMs increased SREBP-2 processing. These effects were associated to the interference with intracellular LDL-derived cholesterol trafficking. When the cells were exposed to LDL, but not to cholesterol/methyl-cyclodextrin complexes, the SERM-induced increases in gene expression were synergistic with those induced by lovastatin. Furthermore, the SERMs reduced the stimulation of the transcriptional activity of the liver X receptor (LXR) by exogenous cholesterol. However, their impact on the expression of the LXR canonical target ABCA1 in the presence of LDL was cell-type dependent. These actions of SERMs were independent of estrogen receptors. We conclude that, by inhibiting the intracellular trafficking of LDL-derived cholesterol, SERMs promote the activation of SREBP-2 and prevent the activation of LXR, two master regulators of cellular cholesterol metabolism. This study highlights the impact of SERMs on lipid homeostasis regulation beyond their actions as estrogen receptor modulators.
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页数:13
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