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 deletedSrebf-2from 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 ofSrebf-2in 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 forSrebf-1ctranscription. The deletion ofSrebf-2and 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.
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Shunxing
authors.identifier: 0000-0002-4948-7222
authors.initials: S
authors.lastname: Rong
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Víctor A
authors.initials: VA
authors.lastname: Cortés
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Shirya
authors.initials: S
authors.lastname: Rashid
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Norma N
authors.initials: NN
authors.lastname: Anderson
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: McDonald
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Guosheng
authors.initials: G
authors.lastname: Liang
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Young-Ah
authors.initials: YA
authors.lastname: Moon
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hammer
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States.|Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Jay D
authors.identifier: 0000-0002-7778-1074
authors.initials: JD
authors.lastname: Horton
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D008099:Liver / Q000502:physiology*; D000071518:Liver X Receptors / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D051780:Sterol Regulatory Element Binding Protein 1 / Q000096:biosynthesis*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D005227:Fatty Acids; D000071518:Liver X Receptors; C497388:Srebf1 protein, mouse; C497391:Srebf2 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D002784:Cholesterol
keywords: LXR; SREBP; cholesterol; fatty acids; human biology; medicine; mouse