title: Scap is required for sterol synthesis and crypt growth in intestinal mucosa.
abstract: SREBP cleavage-activating protein (Scap) is an endoplasmic reticulum membrane protein required for cleavage and activation of sterol regulatory element-binding proteins (SREBPs), which activate the transcription of genes in sterol and fatty acid biosynthesis. Liver-specific loss of Scap is well tolerated; hepatic synthesis of sterols and fatty acids is reduced, but mice are otherwise healthy. To determine whether Scap loss is tolerated in the intestine, we generated a mouse model (Vil-Scap(-)) in which tamoxifen-inducible Cre-ER(T2), a fusion protein of Cre recombinase with a mutated ligand binding domain of the human estrogen receptor, ablates Scap in intestinal mucosa. After 4 days of tamoxifen, Vil-Scap(-) mice succumb with a severe enteropathy and near-complete collapse of intestinal mucosa. Organoids grown ex vivo from intestinal crypts of Vil-Scap(-) mice are readily killed when Scap is deleted by 4-hydroxytamoxifen. Death is prevented when culture medium is supplemented with cholesterol and oleate. These data show that, unlike the liver, the intestine requires Scap to sustain tissue integrity by maintaining the high levels of lipid synthesis necessary for proliferation of intestinal crypts.
authors.affiliation: Department of Molecular Genetics University of Texas Southwestern Medical Center, Dallas, TX 75390-9046.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: McFarlane
authors.affiliation: Department of Molecular Genetics University of Texas Southwestern Medical Center, Dallas, TX 75390-9046.
authors.forename: Mary Jo
authors.initials: MJ
authors.lastname: Cantoria
authors.affiliation: Department of Molecular Genetics University of Texas Southwestern Medical Center, Dallas, TX 75390-9046.
authors.forename: Albert G
authors.initials: AG
authors.lastname: Linden
authors.affiliation: Department of Molecular Genetics University of Texas Southwestern Medical Center, Dallas, TX 75390-9046.
authors.forename: Brandon A
authors.initials: BA
authors.lastname: January
authors.affiliation: Department of Molecular Genetics University of Texas Southwestern Medical Center, Dallas, TX 75390-9046.
authors.forename: Guosheng
authors.initials: G
authors.lastname: Liang
authors.affiliation: Department of Molecular Genetics University of Texas Southwestern Medical Center, Dallas, TX 75390-9046 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046.
authors.forename: Luke J
authors.initials: LJ
authors.lastname: Engelking
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D017353:Gene Deletion; D006801:Humans; D007410:Intestinal Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009928:Organ Specificity; D013261:Sterols / Q000096:biosynthesis*; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C102196:SREBP cleavage-activating protein; D013261:Sterols; D013629:Tamoxifen
keywords: Niemann-Pick C1-like 1 protein; SREBP cleavage-activating protein; cholesterol/biosynthesis; fatty acid/synthesis; gene expression; nuclear receptors/ sterol regulatory element-binding protein; organoid, intestine