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

Shunxing Rong, Víctor A. Cortés, Shirya Rashid, Norma N. Anderson, Jeffrey G McDonald, Guosheng Liang, Young Ah Moon, Robert E Hammer, Jay D Horton

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

The synthesis of cholesterol and fatty acids (FA) in the 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 the 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 the maximal SREBP-1c expression and high rates of FA synthesis.

Original languageEnglish (US)
Article numbere25015
JournaleLife
Volume6
DOIs
StatePublished - Feb 28 2017

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Sterol Regulatory Element Binding Protein 1
Sterols
Liver
Hepatocytes
Ligands
Fatty Acids
Cholesterol
LDL Receptors
Genes
Biosynthesis
Biosynthetic Pathways
Transcription
Cytoplasmic and Nuclear Receptors
Triglycerides
Fluxes
Gene Expression
Proteins

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Expression of SREBP-1c requires SREBP-2-mediated generation of a sterol ligand for LXR in livers of mice. / Rong, Shunxing; Cortés, Víctor A.; Rashid, Shirya; Anderson, Norma N.; McDonald, Jeffrey G; Liang, Guosheng; Moon, Young Ah; Hammer, Robert E; Horton, Jay D.

In: eLife, Vol. 6, e25015, 28.02.2017.

Research output: Contribution to journalArticle

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AU - Cortés, Víctor A.

AU - Rashid, Shirya

AU - Anderson, Norma N.

AU - McDonald, Jeffrey G

AU - Liang, Guosheng

AU - Moon, Young Ah

AU - Hammer, Robert E

AU - Horton, Jay D

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AB - The synthesis of cholesterol and fatty acids (FA) in the 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 the 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 the maximal SREBP-1c expression and high rates of FA synthesis.

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