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A more recent version of this article appeared on July 1, 2007

Papers In Press, published online ahead of print April 23, 2007
J. Lipid Res., doi:10.1194/jlr.M700136-JLR200
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Submitted on March 19, 2007
Revised on April 16, 2007
Accepted on April 23, 2007

SREBP1 regulates the expression of heme oxygenase 1 and the phosphatidylinositol-3 kinase regulatory subunit p55gamma

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

Christian de Duve Institute of Cellular Pathology, Université catholique de Louvain, Brussels B-1200

Corresponding Author: Jean-Baptiste.Demoulin{at}mexp.ucl.ac.be

Sterol-regulatory element binding proteins (SREBP) 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 glutathion peroxidase (GPx-3), the phosphatidylinositol-3 kinase regulatory subunit p55gamma (PIK3R3), synaptic vesicle glycoprotein 2A (SV2A) and COTE1 (C1orf2). 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 p55gamma 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.


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