Abstract 13674: Feedback Regulation of Cholesterol Metabolism by Lexis, a Lipid-responsive Non-coding RNA

The LXR and SREBP transcription factors are key regulators of cellular and systemic cholesterol homeostasis in animals. The molecular mechanisms that integrate these pathways are incompletely understood. Here we show that ligand activation of LXR in liver not only promotes cholesterol efflux, but also simultaneously inhibits the cholesterol biosynthesis pathway. We further identify the long non-coding RNA LeXis as an unexpected mediator of this effect. LeXis is the most robustly induced transcript in mouse liver in response to western diet feeding or pharmacologic LXR activation. Tissue-specific overexpression of LeXis inhibits liver cholesterol biosynthesis and lowers plasma cholesterol levels. Reciprocally, knockdown of LeXis increases hepatic cholesterol content and raises plasma cholesterol levels. These studies outline a regulatory role for a non-coding RNA in lipid metabolism and advance our understanding of the mechanisms by which LXRs orchestrate systemic sterol homeostasis.