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Journal of Lipid Research, Vol. 48, 1628-1636, July 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

SREBP-1 regulates the expression of heme oxygenase 1 and the phosphatidylinositol-3 kinase regulatory subunit p55

Anders Kallin^1,*, Lene E. Johannessen^1,2,, Patrice D. Cani, Catherine Y. Marbehant^*, Ahmed Essaghir^*, Fabienne Foufelle^**,, Pascal Ferré^**,, Carl-Henrik Heldin, Nathalie M. Delzenne and Jean-Baptiste Demoulin^3,*

^* Université catholique de Louvain, Christian de Duve Institute of Cellular Pathology, Experimental Medicine Unit, Brussels, Belgium
Ludwig Institute for Cancer Research, Uppsala, Sweden
Université catholique de Louvain, School of Pharmacy, Brussels, Belgium
^** Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche S872, Centre de Recherches des Cordeliers, Paris, France
Université Pierre et Marie Curie, Paris, France

Published, JLR Papers in Press, April 23, 2007.

¹ A. Kallin and L. E. Johannessen contributed equally to this work.

² Present address of L. E. Johannessen: National Veterinary Institute, Section of Food and Feed Microbiology, Oslo, Norway.

³ To whom correspondence should be addressed. e-mail: jean-baptiste.demoulin{at}mexp.ucl.ac.be

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, 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 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.

Supplementary key words PIK3R3 • C1orf2 • GPx-3 • PDGF • HO1 • SV2A • stress response • growth factors • fatty acid • phospholipid and cholesterol synthesis • bilirubin • E-box • signal transduction

Abbreviations: GPx-3, plasma glutathione peroxidase; HIF, hypoxia-inducible factor; HMOX1, heme oxygenase 1; PDGF, platelet-derived growth factor; PI3K, phosphatidylinositol-3 kinase; SCAP, sterol-regulatory element binding protein cleavage-activating protein; SCD, stearoyl-coenzyme A desaturase; SREBP, sterol-regulatory element binding protein; SV2A, synaptic vesicle glycoprotein 2A

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