SREBP-1 regulates the expression of heme oxygenase 1 and the phosphatidylinositol-3 kinase regulatory subunit p55 gamma.
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.
Kallin
Anders
A
Université catholique de Louvain, Christian de Duve Institute of Cellular Pathology, Experimental Medicine Unit, Brussels, Belgium.
Johannessen
Lene E
LE
Cani
Patrice D
PD
Marbehant
Catherine Y
CY
Essaghir
Ahmed
A
Foufelle
Fabienne
F
Ferré
Pascal
P
Heldin
Carl-Henrik
CH
Delzenne
Nathalie M
NM
Demoulin
Jean-Baptiste
JB
D000818:Animals; D045744:Cell Line, Tumor; D005347:Fibroblasts / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology; D008148:Lovastatin / Q000494:pharmacology; D008297:Male; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000502:physiology; D051780:Sterol Regulatory Element Binding Protein 1 / Q000502:physiology*
D006888:Hydroxycholesterols; D010982:Platelet-Derived Growth Factor; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; C007997:25-hydroxycholesterol; D008148:Lovastatin; D051547:Heme Oxygenase-1; D019869:Phosphatidylinositol 3-Kinases; C523442:PIK3R3 protein, human