Scap is required for sterol synthesis and crypt growth in intestinal mucosa

Matthew R. McFarlane, Mary Jo Cantoria, Albert G. Linden, Brandon A. January, Guosheng Liang, Luke J. Engelking

Research output: Contribution to journalArticle

15 Scopus citations

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 <sup>-</sup> ) in which tamoxifen-inducible Cre-ER<sup>T2</sup> , 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 <sup>-</sup> mice succumb with a severe enteropathy and nearcomplete collapse of intestinal mucosa. Organoids grown ex vivo from intestinal crypts of Vil-Scap <sup>-</sup> 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.

Original languageEnglish (US)
Pages (from-to)1560-1571
Number of pages12
JournalJournal of Lipid Research
Volume56
Issue number8
DOIs
StatePublished - Aug 1 2015

Keywords

  • Cholesterol/biosynthesis
  • Fatty acid/synthesis
  • Gene expression
  • Niemann-Pick C1-like 1 protein
  • Nuclear receptors/sterol regulatory element-binding protein
  • Organoid, intestine
  • SREBP cleavage-activating protein

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Endocrinology

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