Feedback modulation of cholesterol metabolism by the lipid-responsive non-coding RNALeXis

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Abstract

Liver X receptors (LXRs) are transcriptional regulators of cellular and systemic cholesterol homeostasis. Under conditions of excess cholesterol, LXR activation induces the expression of several genes involved in cholesterol efflux1, facilitates cholesterol esterification by promoting fatty acid synthesis2, and inhibits cholesterol uptake by the low-density lipoprotein receptor3. 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 mouse liver not only promotes cholesterol efflux, but also simultaneously inhibits cholesterol biosynthesis. We further identify the long non-coding RNALeXisas a mediator of this effect. HepaticLeXisexpression is robustly induced in response to a Western diet (high in fat and cholesterol) or to pharmacological LXR activation. Raising or loweringLeXislevels in the liver affects the expression of genes involved in cholesterol biosynthesis and alters the cholesterol levels in the liver and plasma.LeXisinteracts with and affects the DNA interactions of RALY, a heterogeneous ribonucleoprotein that acts as a transcriptional cofactor for cholesterol biosynthetic genes in the mouse liver. These findings outline a regulatory role for a non-coding RNA in lipid metabolism and advance our understanding of the mechanisms that coordinate sterol homeostasis.

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