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

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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.

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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.
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.
Shirya Rashid

Department of Public Health, North South University, Dhaka, Bangladesh

Competing interests
The authors declare that no competing interests exist.
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.
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.
Guosheng Liang

Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States

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The authors declare that no competing interests exist.
Young-Ah Moon

Department of Biomedical Sciences, Inha University College of Medicine, Inharo, Korea (South), Republic of

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The authors declare that no competing interests exist.
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.
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.

"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.

Copyright

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.