👤 Amalia Trousson

Liver X receptors (LXRs) α (NR1H3) and β (NR1H2) are nuclear receptors that have been involved in the regulation of many physiological processes, principally in the control of cholesterol homeostasis, as well as in the control of the cell death and proliferation balance. These receptors are thus promising therapeutic targets in various pathologies such as dyslipidemia, atherosclerosis, diabetes and/or cancers. These receptors are known to be activated by specific oxysterol compounds. The screening for LXR-specific ligands is a challenging process: indeed, these molecules should present a specificity towards each LXR-isoform. Because some natural products have significant effects in the regulation of the LXR-regulated homeostasis and are enriched in flavonoids, we have decided to test in cell culture the effects of 4 selected flavonoids (galangin, quercetin, apigenin and naringenin) on the modulation of LXR activity using double-hybrid experiments. In silico, molecular docking suggests specific binding pattern between agonistic and antagonistic molecules. Altogether, these results allow a better understanding of the ligand binding pocket of LXRα/β. They also improve our knowledge about flavonoid mechanism of action, allowing the selection and development of better LXR selective ligands. Show less

Prostate cancer (PCa) incidence has been dramatically increasing these last years in westernized countries. Though localized PCa is usually treated by radical prostatectomy, androgen deprivation therapy is preferred in locally advanced disease in combination with chemotherapy. Unfortunately, PCa goes into a castration-resistant state in the vast majority of the cases, leading to questions about the molecular mechanisms involving the steroids and their respective nuclear receptors in this relapse. Interestingly, liver X receptors (LXRα/NR1H3 and LXRβ/NR1H2) have emerged as new actors in prostate physiology, beyond their historical roles of cholesterol sensors. More importantly LXRs have been proposed to be good pharmacological targets in PCa. This rational has been based on numerous experiments performed in PCa cell lines and genetic animal models pointing out that using selective liver X receptor modulators (SLiMs) could actually be a good complementary therapy in patients with a castration resistant PCa. Hence, this review is focused on the interaction among the androgen receptors (AR/NR3C4), estrogen receptors (ERα/NR3A1 and ERβ/NR3A2), and LXRs in prostate homeostasis and their putative pharmacological modulations in parallel to the patients' support. Show less

Screening of bona fide ligands for nuclear receptors is a real tour de force as the identified molecules are supposed to be able to activate the targeted proteins in cell culture as well as in vivo. Indeed orphan nuclear receptors are putative pharmacologically targets for various diseases. It is thus necessary to have quick and reproductive systems that help in identifying new ligands, agonist or antagonist, before using them in vivo in animal models to check for secondary effects. Here, we describe the transient transfections (homologous and heterologous) used for the screening of ligands for liver X receptor α (LXRα, NR1H3) in HeLa cells. Show less

Liver X receptors (LXRs) are key regulators of lipid homeostasis and are involved in multiple testicular functions. The Lxrα(-/-);Lxrβ(-/-) mice have illuminated the roles of both isoforms in maintenance of the epithelium in the seminiferous tubules, spermatogenesis, and T production. The requirement for LXRβ in Sertoli cells have been emphasized by early abnormal cholesteryl ester accumulation in the Lxrβ(-/-) and Lxrα(-/-);Lxrβ(-/-) mice. Other phenotypes, such as germ cell loss and hypogonadism, occur later in life in the Lxrα(-/-);Lxrβ(-/-) mice. Thus, LXRβ expression in Sertoli cells seems to be essential for normal testicular physiology. To decipher the roles of LXRβ within the Sertoli cells, we generated Lxrα(-/-);Lxrβ(-/-):AMH-Lxrβ transgenic mice, which reexpress Lxrβ in Sertoli cells in the context of Lxrα(-/-);Lxrβ(-/-) mice. In addition to lipid homeostasis, LXRβ is necessary for maintaining the blood-testis barrier and the integrity of the germ cell epithelium. LXRβ is also implicated in the paracrine action of Sertoli cells on Leydig cells to modulate T synthesis. The Lxrα(-/-);Lxrβ(-/-) and Lxrα(-/-);Lxrβ(-/-):AMH-Lxrβ mice exhibit lipid accumulation in germ cells after the Abcg8 down-regulation, suggesting an intricate LXRβ-dependent cooperation between the Sertoli cells and germ cells to ensure spermiogenesis. Further analysis revealed also peritubular smooth muscle defects (abnormal lipid accumulation and disorganized smooth muscle actin) and spermatozoa stagnation in the seminiferous tubules. Together the present work elucidates specific roles of LXRβ in Sertoli cell physiology in vivo beyond lipid homeostasis. Show less

The identification of new pathways governing myelination provides innovative avenues for remyelination. Liver X receptors (LXRs) α and β are nuclear receptors activated by oxysterols that originated from the oxidation of cholesterol. They are crucial for cholesterol homeostasis, a major lipid constituent of myelin sheaths that are formed by oligodendrocytes. However, the role of LXRs in myelin generation and maintenance is poorly understood. Here, we show that LXRs are involved in myelination and remyelination processes. LXRs and their ligands are present in oligodendrocytes. We found that mice invalidated for LXRs exhibit altered motor coordination and spatial learning, thinner myelin sheaths, and reduced myelin gene expression. Conversely, activation of LXRs by either 25-hydroxycholesterol or synthetic TO901317 stimulates myelin gene expression at the promoter, mRNA, and protein levels, directly implicating LXRα/β in the transcriptional control of myelin gene expression. Interestingly, activation of LXRs also promotes oligodendroglial cell maturation and remyelination after lysolecithin-induced demyelination of organotypic cerebellar slice cultures. Together, our findings represent a conceptual advance in the transcriptional control of myelin gene expression and strongly support a new role of LXRs as positive modulators in central (re)myelination processes. Show less