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

• Published in: Biomedicine & pharmacotherapy 2021-09, Vol.141, p.111871-111871, Article 111871
• Main Authors: Fernández-Suárez, María E., Daimiel, Lidia, Villa-Turégano, Gemma, Pavón, María Vázquez, Busto, Rebeca, Escolà-Gil, Joan C., Platt, Frances M., Lasunción, Miguel A., Martínez-Botas, Javier, Gómez-Coronado, Diego
• Format: Article
• Language: English
• Subjects: Cholesterol; Cholesterol - metabolism; Cholesterol, LDL - metabolism; Hep G2 Cells; Homeostasis - drug effects; Homeostasis - physiology; Humans; Liver X Receptors - antagonists & inhibitors; Liver X Receptors - metabolism; LXR; MCF-7 Cells; Raloxifene; Selective Estrogen Receptor Modulators - pharmacology; SREBP; Sterol Regulatory Element Binding Protein 2 - metabolism; Tamoxifen; Toremifene
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2021.111871

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. [Display omitted] •SERMs disrupt intracellular trafficking of LDL-derived colesterol.•SERMs stimulate SREBP processing and the expression of SREBP target genes.•SERMs have a synergistic effect with that of lovastatin in an LDL-dependent manner.•SERMs impair the transcriptional response of LXR to exogenous colesterol.•The actions of SERMs on SREBP and LXR pathways are independent of estrogen receptors.