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

doi:10.7554/eLife.25015

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

Résultat de recherche: Article › examen par les pairs

107 Citations (Scopus)

Résumé

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.

Langue d'origine	English
Numéro d'article	e25015
Journal	eLife
Volume	6
DOI	https://doi.org/10.7554/eLife.25015
Statut de publication	Published - févr. 28 2017
Publié à l'externe	Oui

Note bibliographique

Funding Information:
We thank Tuyet Dang, Bonne Thompson, Marcus Thornton, and Judy Sanchez, for excellent technical assistance and Jian Yang for assistance in the production of the L-Srebf-2-/- mice. We also thank Drs. Joseph L Goldstein and Michael S Brown for helpful suggestions throughout the project. This work was supported by grants from the National Institutes of Health HL-20948.

Publisher Copyright:
© Rong et al.

ASJC Scopus Subject Areas

General Neuroscience
General Immunology and Microbiology
General Biochemistry,Genetics and Molecular Biology

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10.7554/eLife.25015

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

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.",

author = "Shunxing Rong and Cort{\'e}s, {V{\'i}ctor A.} and Shirya Rashid and Anderson, {Norma N.} and McDonald, {Jeffrey G.} and Guosheng Liang and Moon, {Young Ah} and Hammer, {Robert E.} and Horton, {Jay D.}",

note = "Funding Information: We thank Tuyet Dang, Bonne Thompson, Marcus Thornton, and Judy Sanchez, for excellent technical assistance and Jian Yang for assistance in the production of the L-Srebf-2-/- mice. We also thank Drs. Joseph L Goldstein and Michael S Brown for helpful suggestions throughout the project. This work was supported by grants from the National Institutes of Health HL-20948. Publisher Copyright: {\textcopyright} Rong et al.",

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AU - Rong, Shunxing

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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PY - 2017/2/28

Y1 - 2017/2/28

N2 - 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.

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

Résumé

Note bibliographique

ASJC Scopus Subject Areas

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