Feedback modulation of cholesterol metabolism by LeXis, a lipid-responsive non-coding RNA

The liver X receptors (LXRs) are transcriptional regulators of cellular and systemic cholesterol homeostasis. In the setting of cholesterol excess, LXR activation induces the expression of a battery of genes involved in cholesterol efflux (1), facilities cholesterol esterification by promoting fatty acid synthesis (2), and inhibits cholesterol uptake by the low-density lipoprotein receptor (LDLR)(3). The fact that sterol content is maintained in a narrow range in most cell types and in the organism as a whole suggests that extensive crosstalk between regulatory pathways must exist. However, the molecular mechanisms that integrate LXRs with other lipid metabolic pathways, are incompletely understood. Here we show that ligand activation of LXRs in liver not only promotes cholesterol efflux, but also simultaneously inhibits cholesterol biosynthesis. We further identify the long non-coding RNA LeXis as one mediator of this effect. Hepatic LeXis expression is robustly induced in response to western diet feeding or pharmacologic LXR activation. Raising or lowering the levels of LeXis in liver affects the expression of cholesterol biosynthetic genes, and the levels of cholesterol in the liver and plasma. LeXis interacts with and affects the DNA interactions of Raly, a heterogeneous ribonucleoprotein that is required for the maximal expression of cholesterologenic genes in mouse liver. These studies outline a regulatory role for a non-coding RNA in lipid metabolism and advance our understanding of the mechanisms orchestrating sterol homeostasis.