Feedback modulation of cholesterol metabolism by the lipid-responsive non-coding RNA LeXis.

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 the study performed the majority of mouse experiments and data analysis. participated in mouse experiments and data analysis. performed RNA-seq experiments and validated LeXis as an LXR target. and processed and analyzed next-generation sequencing data. MCJ performed and analyzed the RACE experiments. JW performed the Mass Spectrometry Analysis. MK and RL provided and independently validated ASOs targeting LeXis. TS and PT the manuscript. TS, MCJ and PT edited the manuscript with input from all authors. All discussed the results and approved the final version of the manuscript. non-coding LeXis additional mediator of the complex effects of LXR signaling on hepatic lipid metabolism. LeXis the ability of LXRs inhibit cholesterol synthesis. involvement additional pathways in this crosstalk resulting tested For expression analysis, using PCR Applied Biosystems Applied Biosystems Quant Studio 6 Flex. Results are normalized to cyclophilin. Immunohistochemical staining of paraffin-embedded livers were done by Translational Pathology Core Laboratory.