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


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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


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.


  1. 1.

    Transcriptional and posttranscriptional control of cholesterol homeostasis by liver X receptors. Cold Spring Harb. Symp. Quant. Biol. 76, 129–137 (2011)

  2. 2.

    et al. Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRα and LXRβ. Genes Dev. 14, 2819–2830 (2000)

  3. 3.

    , , & LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor. Science 325, 100–104 (2009)

  4. 4.

    & The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 89, 331–340 (1997)

  5. 5.

    et al. Liver LXRα expression is crucial for whole body cholesterol homeostasis and reverse cholesterol transport in mice. J. Clin. Invest. 122, 1688–1699 (2012)

  6. 6.

    et al. Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc. Natl Acad. Sci. USA 107, 21931–21936 (2010)

  7. 7.

    The ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57–74 (2012)

  8. 8.

    & Liver X receptors as integrators of metabolic and inflammatory signaling. J. Clin. Invest. 116, 607–614 (2006)

  9. 9.

    et al. ABCA1 overexpression leads to hyperalphalipoproteinemia and increased biliary cholesterol excretion in transgenic mice. J. Clin. Invest. 108, 303–309 (2001)

  10. 10.

    , & SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J. Clin. Invest. 109, 1125–1131 (2002)

  11. 11.

    et al. SREBP cleavage-activating protein (SCAP) is required for increased lipid synthesis in liver induced by cholesterol deprivation and insulin elevation. Genes Dev. 15, 1206–1216 (2001)

  12. 12.

    et al. The LXR-Idol axis differentially regulates plasma LDL levels in primates and mice. Cell Metab. 20, 910–918 (2014)

  13. 13.

    et al. A long noncoding RNA mediates both activation and repression of immune response genes. Science 341, 789–792 (2013)

  14. 14.

    , , & Reciprocal regulation of HIF-1alpha and lincRNA-p21 modulates the Warburg effect. Mol. Cell 53, 88–100 (2014)

  15. 15.

    et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet 375, 998–1006 (2010)

  16. 16.

    et al. Targeting APOC3 in the familial chylomicronemia syndrome. N. Engl. J. Med. 371, 2200–2206 (2014)

  17. 17.

    & Genome regulation by long noncoding RNAs. Annu. Rev. Biochem. 81, 145–166 (2012)

  18. 18.

    , & Chromatin isolation by RNA purification (ChIRP). J. Vis. Exp . 61, 3912 (2012)

  19. 19.

    , , & The embryonic lethality of homozygous lethal yellow mice (Ay/Ay) is associated with the disruption of a novel RNA-binding protein. Genes Dev. 7, 1203–1213 (1993)

  20. 20.

    , & Four distinct regions in the auxiliary domain of heterogeneous nuclear ribonucleoprotein C-related proteins. Biochim. Biophys. Acta 1399, 229–233 (1998)

  21. 21.

    et al. COXPRESdb in 2015: coexpression database for animal species by DNA-microarray and RNAseq-based expression data with multiple quality assessment systems. Nucleic Acids Res. 43, D82–D86 (2015)

  22. 22.

    et al. Genome-wide localization of SREBP-2 in hepatic chromatin predicts a role in autophagy. Cell Metab. 13, 367–375 (2011)

  23. 23.

    , , , & The Phyre2 web portal for protein modeling, prediction and analysis. Nature Protocols 10, 845–858 (2015)

  24. 24.

    et al. CoAA, a nuclear receptor coactivator protein at the interface of transcriptional coactivation and RNA splicing. Mol. Cell. Biol. 24, 442–453 (2004)

  25. 25.

    et al. Genetic compensation induced by deleterious mutations but not gene knockdowns. Nature 524, 230–233 (2015)

  26. 26.

    , , , & Conserved function of lincRNAs in vertebrate embryonic development despite rapid sequence evolution. Cell 147, 1537–1550 (2011)

  27. 27.

    et al. The macrophage LBP gene is an LXR target that promotes macrophage survival and atherosclerosis. J. Lipid Res. 55, 1120–1130 (2014)

  28. 28.

    et al. LXRs regulate ER stress and inflammation through dynamic modulation of membrane phospholipid composition. Cell Metab. 18, 685–697 (2013)

  29. 29.

    , & The nuclear receptor FXR uncouples the actions of miR-33 from SREBP-2. Arterioscler. Thromb. Vasc. Biol. 35, 787–795 (2015)

  30. 30.

    et al. LXRα is uniquely required for maximal reverse cholesterol transport and atheroprotection in ApoE-deficient mice. J. Lipid Res. 53, 1126–1133 (2012)

  31. 31.

    et al. Short antisense oligonucleotides with novel 2′–4′ conformationaly restricted nucleoside analogues show improved potency without increased toxicity in animals. J. Med. Chem. 52, 10–13 (2009)

  32. 32.

    et al. Ligand activation of LXR β reverses atherosclerosis and cellular cholesterol overload in mice lacking LXR α and apoE. J. Clin. Invest. 117, 2337–2346 (2007)

  33. 33.

    et al. Transcript dynamics of proinflammatory genes revealed by sequence analysis of subcellular RNA fractions. Cell 150, 279–290 (2012)

  34. 34.

    , & TopHat: discovering splice junctions with RNA-Seq. Bioinformatics 25, 1105–1111 (2009)

  35. 35.

    et al. Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nature Biotechnol. 28, 511–515 (2010)

  36. 36.

    , & Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nature Protocols 4, 44–57 (2009)

  37. 37.

    , & Chromatin immunoprecipitation (ChIP). Cold Spring Harb. Protoc. 2009, pdb.prot5279 (2009)

  38. 38.

    & Detection of individual endogenous RNA transcripts in situ using multiple singly labeled probes. Methods Enzymol. 472, 365–386 (2010)

Download references


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.


  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


  1. Search for Tamer Sallam in:

  2. Search for Marius C. Jones in:

  3. Search for Thomas Gilliland in:

  4. Search for Li Zhang in:

  5. Search for Xiaohui Wu in:

  6. Search for Ascia Eskin in:

  7. Search for Jaspreet Sandhu in:

  8. Search for David Casero in:

  9. Search for Thomas Q. de Aguiar Vallim in:

  10. Search for Cynthia Hong in:

  11. Search for Melanie Katz in:

  12. Search for Richard Lee in:

  13. Search for Julian Whitelegge in:

  14. Search for Peter Tontonoz in:


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

PDF files

  1. 1.

    Supplementary Information

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

About this article

Publication history






Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.