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Expression of SREBP-1c requires SREBP-2-mediated generation of a sterol ligand for LXR in livers of mice

  1. Shunxing Rong
  2. Víctor A Cortés
  3. Shirya Rashid
  4. Norma N Anderson
  5. Jeffrey G McDonald
  6. Guosheng Liang
  7. Young-Ah Moon
  8. Robert E Hammer
  9. Jay D Horton  Is a corresponding author
  1. University of Texas Southwestern Medical Center, United States
  2. North South University, Bangladesh
  3. Inha University College of Medicine, Korea (South), Republic of
Research Article
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Cite this article as: eLife 2017;6:e25015 doi: 10.7554/eLife.25015

Abstract

The synthesis of cholesterol and fatty acids (FA) in liver is independently regulated by SREBP-2 and SREBP-1c, respectively. Here we genetically deleted Srebf-2 from hepatocytes and confirmed that SREBP-2 regulates all genes involved in cholesterol biosynthesis, the LDL receptor, and PCSK9; a secreted protein that degrades LDL receptors in liver. Surprisingly, we found that elimination of Srebf-2 in hepatocytes of mice also markedly reduced SREBP-1c and the expression of all genes involved in FA and triglyceride synthesis that are normally regulated by SREBP-1c. The nuclear receptor LXR is necessary for Srebf-1c transcription. The deletion of Srebf-2 and subsequent lower sterol synthesis in hepatocytes eliminated the production of an endogenous sterol ligand required for LXR activity and SREBP-1c expression. These studies demonstrate that cholesterol and FA synthesis in hepatocytes are coupled and that flux through the cholesterol biosynthetic pathway is required for maximal SREBP-1c expression and high rates of FA synthesis.

Article and author information

Author details

  1. Shunxing Rong

    Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Víctor A Cortés

    Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Shirya Rashid

    Department of Public Health, North South University, Dhaka, Bangladesh
    Competing interests
    The authors declare that no competing interests exist.
  4. Norma N Anderson

    Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Jeffrey G McDonald

    Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Guosheng Liang

    Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Young-Ah Moon

    Department of Biomedical Sciences, Inha University College of Medicine, Inharo, Korea (South), Republic of
    Competing interests
    The authors declare that no competing interests exist.
  8. Robert E Hammer

    Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Jay D Horton

    Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    Jay.Horton@utsouthwestern.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7778-1074

Funding

National Institutes of Health (HL-20948)

  • Jay D Horton

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal experiments were performed with approval of the Institutional Animal Care and Research Advisory Committee at UT Southwestern.

Reviewing Editor

  1. Peter Tontonoz, University of California, Los Angeles, United States

Publication history

  1. Received: January 9, 2017
  2. Accepted: February 26, 2017
  3. Accepted Manuscript published: February 28, 2017 (version 1)
  4. Accepted Manuscript updated: March 6, 2017 (version 2)
  5. Version of Record published: March 13, 2017 (version 3)

Copyright

© 2017, Rong et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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