👤 Cédric Rébé

Liver X Receptors (LXRs) α and β are oxysterol-activated nuclear receptors involved in the control of lipid metabolism and inflammation. Pharmacological activation of LXR is promising in the treatment of atherosclerosis since it can promote cholesterol efflux from macrophages and prevent foam cell formation. However, the development of LXR agonists has been limited by undesirable side-effects such as hepatic steatosis mediated by LXRα activation. Therefore, it has been proposed that targeting LXRα activators to extrahepatic tissues or using LXRβ-specific activators could be used as alternative strategies. It is not clear whether these molecules will retain the full atheroprotective potential of non-selective agonists. Our aim was therefore to determine the contribution of LXRα and LXRβ to the control of cholesterol efflux in human macrophages. LXRα and/or LXRβ expression was suppressed by small interfering RNAs in human primary macrophages treated or not with synthetic LXRα/β dual agonists T0901317 and GW3965. We observed that LXRβ silencing had no detectable impact on the expression of LXR-target genes such as ABCA1 and ABCG1. Moreover it did not affect cholesterol efflux. In contrast, LXRα silencing reduced the response of these LXR-target genes to LXR agonist and inhibited cholesterol efflux to ApoA-I, HDL2 or to endogenous ApoE. Importantly, no differences were observed between LXRα and LXRα/β knockdown conditions. Altogether, our data demonstrate that LXRβ activation is unable to maintain maximal cholesterol efflux capacities in human primary macrophages when LXRα expression is impaired. In contrast to earlier mouse studies, LXRα levels appear as a limiting factor for macrophage cholesterol efflux in humans. Show less

Liver X receptor (LXR) α and LXR β (NR1H3 and NR1H2) are oxysterol-activated nuclear receptors involved in the control of major metabolic pathways such as cholesterol homeostasis, lipogenesis, inflammation and innate immunity. Synthetic LXR agonists are currently under development and could find applications in various fields such as cardiovascular diseases, cancer, diabetes and neurodegenerative diseases. The clinical development of LXR agonists requires the identification of biological markers for pharmacodynamic studies. In this context, monocytes represent an attractive target to monitor LXR activation. They are easily accessible cells present in peripheral blood; they express LXR α and β and respond to LXR agonist stimulation in vitro. The aim of our study was to identify cell surface markers of LXR agonists on monocytes. For this, we focused on clusters of differentiation (CD) markers because they are well characterized and accessible cell surface molecules allowing easy immuno-phenotyping. By using microarray analysis of monocytes treated or not with an LXR agonist in vitro, we selected three CD, i.e. CD82, CD226, CD244 for further analysis by real time PCR and flow cytometry. The three CD were up-regulated by LXR agonist treatment in vitro in a time- and dose- dependent manner and this induction was LXR specific as assessed by a SiRNA or LXR antagonist strategy. By using flow cytometry, we could demonstrate that the expression of these molecules at the cell surface of monocytes was significantly increased after LXR agonist treatment. We have identified three new cell surface markers that could be useful to monitor LXR activation. Future studies will be required to confirm the biological and diagnostic significance of the markers. Show less