Selective estrogen receptor modulators (SERMs) affect cholesterol homeostasis through the master regulators SREBP and LXR
Fernández-Suárez, M.E. (Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición)
Daimiel, Lidia (Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición)
Villa-Turégano, G. (Instituto Ramón y Cajal de Investigación Sanitaria (Madrid))
Pavón, M.V. (Instituto Ramón y Cajal de Investigación Sanitaria (Madrid))
Busto, R. (Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición)
Escolà-Gil, Joan Carles (Institut d'Investigació Biomèdica Sant Pau)
Platt, F.M. (Department of Pharmacology. University of Oxford)
Lasunción, M.A. (Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición)
Martínez-Botas, J. (Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición)
Gómez-Coronado, D. (Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición)
Universitat Autònoma de Barcelona

Date:	2021
Abstract:	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.
Grants:	Ministerio de Ciencia, Innovación y Universidades RTI2018-098113-B-I00
Note:	Altres ajuts: Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020; Fondo Europeo de Desarrollo Regional (FEDER); European Cooperation in Science and Technology (BM0904); Comunidad de Madrid (Programme ALIBIRD S2013/ABI-2728).
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Tamoxifen ; Raloxifene ; Toremifene ; SREBP ; LXR ; Cholesterol
Published in:	Biomedicine & pharmacotherapy, Vol. 141 (september 2021) , p. 111871, ISSN 1950-6007

DOI: 10.1016/j.biopha.2021.111871
PMID: 34225017

13 p, 4.0 MB

The record appears in these collections:
Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Recerca Sant Pau
Articles > Research articles
Articles > Published articles