Scap is required for sterol synthesis and crypt growth in intestinal mucosa[S]
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 tole...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2015-08-01
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| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520355334 |
| _version_ | 1818735047927136256 |
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| author | Matthew R. McFarlane Mary Jo Cantoria Albert G. Linden Brandon A. January Guosheng Liang Luke J. Engelking |
| author_facet | Matthew R. McFarlane Mary Jo Cantoria Albert G. Linden Brandon A. January Guosheng Liang Luke J. Engelking |
| author_sort | Matthew R. McFarlane |
| collection | DOAJ |
| description | 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-ERT2, 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. |
| first_indexed | 2024-12-18T00:15:03Z |
| format | Article |
| id | doaj.art-59f7ab0a23d04fb9ae3d437573e7459f |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-18T00:15:03Z |
| publishDate | 2015-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-59f7ab0a23d04fb9ae3d437573e7459f2022-12-21T21:27:33ZengElsevierJournal of Lipid Research0022-22752015-08-0156815601571Scap is required for sterol synthesis and crypt growth in intestinal mucosa[S]Matthew R. McFarlane0Mary Jo Cantoria1Albert G. Linden2Brandon A. January3Guosheng Liang4Luke J. Engelking5Department of Molecular Genetics University of Texas Southwestern Medical Center, Dallas, TX 75390-9046Department of Molecular Genetics University of Texas Southwestern Medical Center, Dallas, TX 75390-9046Department of Molecular Genetics University of Texas Southwestern Medical Center, Dallas, TX 75390-9046Department of Molecular Genetics University of Texas Southwestern Medical Center, Dallas, TX 75390-9046Department of Molecular Genetics University of Texas Southwestern Medical Center, Dallas, TX 75390-9046To whom correspondence should be addressed; 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 75390-9046SREBP 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-ERT2, 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.http://www.sciencedirect.com/science/article/pii/S0022227520355334SREBP cleavage-activating proteinnuclear receptors/ sterol regulatory element-binding proteincholesterol/biosynthesisfatty acid/synthesisorganoid, intestinegene expression |
| spellingShingle | Matthew R. McFarlane Mary Jo Cantoria Albert G. Linden Brandon A. January Guosheng Liang Luke J. Engelking Scap is required for sterol synthesis and crypt growth in intestinal mucosa[S] Journal of Lipid Research SREBP cleavage-activating protein nuclear receptors/ sterol regulatory element-binding protein cholesterol/biosynthesis fatty acid/synthesis organoid, intestine gene expression |
| title | Scap is required for sterol synthesis and crypt growth in intestinal mucosa[S] |
| title_full | Scap is required for sterol synthesis and crypt growth in intestinal mucosa[S] |
| title_fullStr | Scap is required for sterol synthesis and crypt growth in intestinal mucosa[S] |
| title_full_unstemmed | Scap is required for sterol synthesis and crypt growth in intestinal mucosa[S] |
| title_short | Scap is required for sterol synthesis and crypt growth in intestinal mucosa[S] |
| title_sort | scap is required for sterol synthesis and crypt growth in intestinal mucosa s |
| topic | SREBP cleavage-activating protein nuclear receptors/ sterol regulatory element-binding protein cholesterol/biosynthesis fatty acid/synthesis organoid, intestine gene expression |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520355334 |
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