ABCA1-Super Enhancer RNA Promotes Cholesterol Efflux, Reduces Macrophage-Mediated Inflammation and Atherosclerosis

We describe a previously uncharacterized ATP-binding cassette A1 super enhancer RNA (ABCA1-seRNA)-mediated cholesterol efflux. In addition, it promoted macrophage inflammatory cytokine release, and was causally correlated with coronary artery disease severity. Mechanistically, ABCA1-seRNA upregulated cholesterol efflux by interacting with mediator complex subunit 23 and recruiting retinoid X receptor-alpha and liver X receptor-alpha to promote ABCA1 transcription in a cis manner. Meanwhile, ABCA1-seRNA induced P65 ubiquitination degradation, and thereby repressed the macrophage inflammatory response. Consistently, overexpression of ABCA1-seRNA in ApoE^-/- mice decreased plasma lipids, cytokines, and atherosclerotic plaques. These findings indicate ABCA1-seRNA is a critical epigenetic regulator that maintains cholesterol homeostasis and modulates inflammation, thus promising a therapeutic target for atherosclerotic cardiovascular diseases.