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

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

doi:10.1194/jlr.m064022

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.

Highlights

Cholesterol and fatty acid biosynthesis are regulated by the sterol regulatory element-binding proteins (SREBPs), encoded by Srebf1 and Srebf2
There is overlap in the activities of the SREBP isoforms, but it is generally held that SREBP-1c primarily targets genes implicated in fatty acid synthesis, whereas SREBP-2 preferentially regulates genes involved in cholesterol synthesis [5,6,7,8]
To generate mouse models with absent or reduced SREBP-2, we used a gene-trap allele containing an insertional mutation in intron 1 of Srebf2

Summary

Introduction

Cholesterol and fatty acid biosynthesis are regulated by the sterol regulatory element-binding proteins (SREBPs), encoded by Srebf and Srebf. Male hypomorphic mice were viable but had reduced cholesterol stores in the liver and lower expression of SREBP target genes. 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.—Vergnes, L., R. Cholesterol biosynthesis and homeostasis are regulated by the sterol regulatory element-binding protein (SREBP) transcription factor family. SREBP-1a is a potent activator of both triglyceride and cholesterol biosynthetic pathways, but is expressed at low levels in metabolic tissues, making the physiological role of the protein unclear [9].

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Results

Conclusion