Liver X receptors (LXRs) alpha (a) and beta are nuclear receptors that act as metabolic sensors for cellular cholesterol. LXR agonists increase HDL cholesterol levels, have anti-inflammatory properties and improve insulin sensitivity. Therefore LXRs are now considered promising drug development targets for the management of human metabolic diseases. The search for LXR ligands void of their deleterious hyper-triglyceridemic actions has been traditionally based on their effects on receptor binding. We propose, as an alternative strategy, that regulation of post-translational modifications of LXR could be employed. My previous studies reveal that modulation of post-translational modifications of the receptor, such as phosphorylation, regulate LXRa actions in a gene-specific manner. Our preliminary studies indicate that, in addition to phosphorylation, LXRa is subject to acetylation and that treatment with trichostatin A (TSA), an inhibitor of histone deacetylases, affects LXRa protein concentration. Thus we hypothesize that acetylation of the receptor could also affect the activity of LXRa in macrophages in a gene-selective fashion. In this proposal our main goals will be to: 1) Investigate the influence of LXRa acetylation on LXRa transcriptional activity and determine the mechanisms involved, 2) Elucidate the impact of phosphorylation and acetylation on LXRa protein stability, 3) Determine the crosstalk between phophorylation and acetylation of LXRa and 4) Identify and functionally characterize LXRa phosphorylation– and acetylation-modulated protein complexes employing a proteomic approach. In light of the pivotal role LXRa plays in cholesterol metabolism, identifying the role of acetylation in LXRa activity and the TSA-sensitive signaling pathways that acetylate LXRa is critical to our understanding of the different modes of action of these receptors. This could be exploited for the development of therapies against different metabolic diseases.