Letter | Published:

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

Nature volume 534, pages 124128 (02 June 2016) | Download Citation

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 RNA LeXis as a mediator of this effect. Hepatic LeXis expression is robustly induced in response to a Western diet (high in fat and cholesterol) or to pharmacological LXR activation. Raising or lowering LeXis levels in the liver affects the expression of genes involved in cholesterol biosynthesis and alters the cholesterol levels in the liver and plasma. LeXis interacts 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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Accessions

Primary accessions

Gene Expression Omnibus

Data deposits

Sequencing and microarray data have been deposited in the Gene Expression Omnibus (GEO) under accessions GSE77793, GSE77786, GSE77802 and GSE77805.

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Acknowledgements

We thank members of the Tontonoz, Nagy, Smale and Black laboratories and the UCLA Atherosclerosis Research Unit for technical assistance and useful discussions. This work was support by NIH grants HL030568, HL066088, DK063491, HL128822, DK102559 and HL69766; American Heart Association grant 13POST17080115; American College of Cardiology Presidential CDA; and the UCLA Cardiovascular Discovery Fund (Lauren B. Leichtman and Arthur E. Levine Investigator Award).

Author information

Author notes

    • Tamer Sallam
    •  & Marius C. Jones

    These authors contribute equally to this work.

Affiliations

  1. Department of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, University of California, Los Angeles, California 90095, USA

    • Tamer Sallam
    • , Marius C. Jones
    • , Thomas Gilliland
    • , Li Zhang
    • , Xiaohui Wu
    • , Jaspreet Sandhu
    • , David Casero
    • , Cynthia Hong
    •  & Peter Tontonoz
  2. Department of Medicine, Division of Cardiology, University of California, Los Angeles, California 90095, USA

    • Tamer Sallam
    • , Xiaohui Wu
    •  & Thomas Q. de Aguiar Vallim
  3. Departement of Human Genetics, University of California, Los Angeles, California 90095, USA

    • Ascia Eskin
  4. Ionis Pharmaceuticals, Carlsbad, California 92008, USA

    • Melanie Katz
    •  & Richard Lee
  5. Pasarow Mass Spectrometry Laboratory, NPI-Semel Institute, University of California, Los Angeles, California 90095, USA

    • Julian Whitelegge

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Contributions

T.S. and P.T. conceived and designed the study, guided the interpretation of the results and the preparation of the manuscript. P.T. supervised the study and provided critical suggestions. T.S. and X.W. performed most mouse experiments and data analysis. M.C.J., T.G., L.Z., J.S., C.H., T.d.A.V. participated in mouse experiments and data analysis. T.S. performed RNA-seq experiments and validated LeXis as an LXR target. A.E. and D.C. processed and analysed next-generation sequencing data. M.C.J. performed and analysed the RACE experiments. J.W. performed the mass spectrometry analysis. M.K. and R.L. provided and independently validated ASOs targeting LeXis. T.S. and P.T. drafted the manuscript. T.S., M.C.J. and P.T. edited the manuscript with input from all authors. All authors discussed the results and approved the final version of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Peter Tontonoz.

Extended data

Supplementary information

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  1. 1.

    Supplementary Information

    This file contains the uncropped scans with size marker indications and primer sequences.

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DOI

https://doi.org/10.1038/nature17674

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