title: SREBP cleavage-activating protein (SCAP) is required for increased lipid synthesis in liver induced by cholesterol deprivation and insulin elevation.
abstract: In liver, the synthesis of cholesterol and fatty acids increases in response to cholesterol deprivation and insulin elevation, respectively. This regulatory mechanism underlies the adaptation to cholesterol synthesis inhibitors (statins) and high calorie diets (insulin). In nonhepatic cells, lipid synthesis is controlled by sterol regulatory element-binding proteins (SREBPs), membrane-bound transcription factors whose active domains are released proteolytically to enter the nucleus and activate genes involved in the synthesis and uptake of cholesterol and fatty acids. SCAP (SREBP cleavage-activating protein) is a sterol-regulated escort protein that transports SREBPs from their site of synthesis in the endoplasmic reticulum to their site of cleavage in the Golgi. Here, we produced a conditional deficiency of SCAP in mouse liver by genomic recombination mediated by inducible Cre recombinase. SCAP-deficient mice showed an 80% reduction in basal rates of cholesterol and fatty acid synthesis in liver, owing to decreases in mRNAs encoding multiple biosynthetic enzymes. Moreover, these mRNAs failed to increase normally in response to cholesterol deprivation produced by a cholesterol synthesis inhibitor and to insulin elevation produced by a fasting-refeeding protocol. These data provide in vivo evidence that SCAP and the SREBPs are required for hepatic lipid synthesis under basal and adaptive conditions.
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9046, USA.
authors.forename: M
authors.initials: M
authors.lastname: Matsuda
authors.forename: B S
authors.initials: BS
authors.lastname: Korn
authors.forename: R E
authors.initials: RE
authors.lastname: Hammer
authors.forename: Y A
authors.initials: YA
authors.lastname: Moon
authors.forename: R
authors.initials: R
authors.lastname: Komuro
authors.forename: J D
authors.initials: JD
authors.lastname: Horton
authors.forename: J L
authors.initials: JL
authors.lastname: Goldstein
authors.forename: M S
authors.initials: MS
authors.lastname: Brown
authors.forename: I
authors.initials: I
authors.lastname: Shimomura
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D002784:Cholesterol / Q000172:deficiency*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D015151:Immunoblotting; D007328:Insulin / Q000378:metabolism*; D019426:Integrases / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D050356:Lipid Metabolism; D008055:Lipids / Q000096:biosynthesis*; D008099:Liver / Q000378:metabolism*; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D011995:Recombination, Genetic; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D014764:Viral Proteins
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D008055:Lipids; D008565:Membrane Proteins; D012333:RNA, Messenger; C102196:SREBP cleavage-activating protein; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D014764:Viral Proteins; D002784:Cholesterol; C045073:Cre recombinase; D019426:Integrases