Control of Macrophage Cholesterol Efflux and Atherogenesis by the Noncoding RNA MeXis

The ligand-dependent nuclear receptor LXR regulates the expression of genes involved in responses to excess cholesterol including Abca1. Macrophage-specific cholesterol efflux driven by Abca1 has been causally linked to the prevention and reversal of heart disease, but therapeutic strategies for targeting efflux pathways in macrophages have been elusive. Here, we define a novel regulatory axis controlling macrophage responses to cholesterol overload. We identify the lncRNA MeXis as an amplifier of LXR-dependent Abca1 gene transcription in macrophages. MeXis interacts with and guides the promoter binding of nuclear receptor transcriptional coactivators. Loss of MeXis in murine immune cells has a marked impact on chromosome architecture at the Abca1 locus, impairs cellular responses to cholesterol overload, and accelerates the development of atherosclerosis. Our findings identify MeXis as a transcriptional gatekeeper that modifies the actions of LXR in lipid-dependent control of macrophage gene expression. It is conceivable that therapeutic approaches that enhance MeXis activity might augment reverse cholesterol transport and reduce foam cell formation.