SREBP-1 regulates the expression of heme oxygenase 1 and the phosphatidylinositol-3 kinase regulatory subunit p55γ

Patrice D Cani,Jean-Baptiste Demoulin,Anders Kallin,Fabienne Foufelle,Nathalie M Delzenne,Ahmed Essaghir,Pascal Ferré,Catherine Y Marbehant,Carl-Henrik Heldin,Lene E Johannessen

doi:10.1194/jlr.m700136-jlr200

Abstract

Sterol-regulatory element binding proteins (SREBPs) control the expression of genes involved in fatty acid and cholesterol biosynthesis. Using microarrays, we observed that mature SREBP-1 also induced the expression of genes unrelated to lipid metabolism, such as heme oxygenase 1 (HMOX1), plasma glutathione peroxidase, the phosphatidylinositol-3 kinase regulatory subunit p55 gamma, synaptic vesicle glycoprotein 2A, and COTE1. The expression of these genes was repressed upon addition of sterols, which block endogenous SREBP cleavage, and was induced by the statin drug mevinolin. Stimulation of fibroblasts with platelet-derived growth factor, which activates SREBP-1, had a similar effect. Fasted mice that were refed with a high-carbohydrate diet presented an increased expression of HMOX1 and p55 gamma in the liver. Overall, the transcriptional signature of SREBP-1 in fibroblasts stimulated by growth factors was very similar to that described in liver cells. We analyzed the HMOX1 promoter and found one SREBP binding site of the E-box type, which was required for regulation by SREBP-1a and SREBP-1c but was insensitive to SREBP-2. In conclusion, our data suggest that SREBP-1 regulates the expression of stress response and signaling genes, which could contribute to the metabolic response to insulin and growth factors in various tissues.

Highlights

Sterol-regulatory element binding proteins (SREBPs) control the expression of genes involved in fatty acid and cholesterol biosynthesis
Among the genes selected using these criteria, we found six genes that are involved in fatty acid biosynthesis and that have been shown to be regulated by sterol-regulatory element binding protein (SREBP)-1c in liver cells (Table 1)
We identified novel target genes for the SREBP-1 transcription factors, including heme oxygenase 1 (HMOX1), p55g, synaptic vesicle glycoprotein 2A (SV2A), and COTE1, based on the following observations: i) the corresponding transcripts were enriched in human fibroblasts infected with an adenovirus encoding mature SREBP-1c; ii) their expression was upregulated by mevinolin and repressed by sterols, which modulate the processing of endogenous SREBP-1a and SREBP-2; iii) all transcripts were induced by stimulation of AG01518 fibroblasts with platelet-derived growth factor (PDGF), which activates SREBP-1 [9]; iv) expression of HMOX1 and p55g was increased in the liver of fasted mice refed with a high-carbohydrate diet, a condition known to activate SREBP-1c in vivo

Summary

Introduction

Sterol-regulatory element binding proteins (SREBPs) control the expression of genes involved in fatty acid and cholesterol biosynthesis. We observed that mature SREBP-1 induced the expression of genes unrelated to lipid metabolism, such as heme oxygenase 1 (HMOX1), plasma glutathione peroxidase, the phosphatidylinositol-3 kinase regulatory subunit p55g, synaptic vesicle glycoprotein 2A, and COTE1. The expression of these genes was repressed upon addition of sterols, which block endogenous SREBP cleavage, and was induced by the statin drug mevinolin. Sterol-regulatory element binding proteins (SREBPs) are ubiquitous transcription factors that control the expression of the enzymes involved in the biosynthesis of cholesterol and fatty acids [1]. When cells are loaded with cholesterol, SCAP interacts with Insig-1 and Insig-2 in the endoplasmic reticulum, thereby preventing SREBP translocation and processing

Methods

Results

Conclusion