SREBP-2-deficient and hypomorphic mice reveal roles for SREBP-2 in embryonic development and SREBP-1c expression

Laurent Vergnes, Robert G. Chin, Thomas Aguiar De Vallim, Loren G. Fong, Timothy F. Osborne, Stephen G. Young, Karen Reue

Research output: Contribution to journalArticlepeer-review

Abstract

Cholesterol and fatty acid biosynthesis are regulated by the sterol regulatory element-binding proteins (SREBPs), encoded by Srebf1 and Srebf2 . We generated mice that were either deficient or hypomorphic for SREBP-2. SREBP-2 deficiency generally caused death during embryonic development. Analyses of Srebf2 -/ - embryos revealed a requirement for SREBP-2 in limb development and expression of morphogenic genes. We encountered only one viable Srebf2 -/ - mouse, which displayed alopecia, attenuated growth, and reduced adipose tissue stores. Hypomorphic SREBP-2 mice (expressing low levels of SREBP-2) survived development, but the female mice exhibited reduced body weight and died between 8 and 12 weeks of age. Male hypomorphic mice were viable but had reduced cholesterol stores in the liver and lower expression of SREBP target genes. Reduced SREBP-2 expression affected SREBP-1 isoforms in a tissue-specific manner. In the liver, reduced SREBP-2 expression nearly abolished Srebf1c transcripts and reduced Srebf1a mRNA levels. In contrast, adipose tissue displayed normal expression of SREBP target genes, likely due to a compensatory increase in Srebf1a expression. Our results establish that SREBP-2 is critical for survival and limb patterning during development. Reduced expression of SREBP-2 from the hypomorphic allele leads to early death in females and reduced cholesterol content in the liver, but not in adipose tissue.

Original languageEnglish (US)
Pages (from-to)410-421
Number of pages12
JournalJournal of Lipid Research
Volume57
Issue number3
DOIs
StatePublished - Mar 2016

Keywords

  • Cholesterol synthesis
  • Gene regulation
  • Sterol regulatory element-binding protein 1c
  • Sterol regulatory element-binding protein 2

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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