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J. Biol. Chem., Vol. 280, Issue 1, 199-206, January 7, 2005

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Differential Regulation of Sterol Regulatory Element-binding Protein 1c Transcriptional Activity by Insulin and Liver X Receptor during Liver Development^*

Alexandre Bobard, Isabelle Hainault, Pascal Ferré, Fabienne Foufelle, and Pascale Bossard

From the INSERM U465, 15 rue de l'Ecole de médecine, 75006, Paris, France and the Université Pierre et Marie Curie, 15 rue de l'Ecole de Médecine, 75006, Paris, France

Sterol regulatory element-binding proteins (SREBPs) are transcription factors involved in the synthesis of cholesterol and fatty acids. In adults, the isoform SREBP-1c is the predominant transcript in the liver of fed animals, and it activates triglyceride production from glucose when diet is enriched in carbohydrates. Studies have shown that SREBP-1c expression is dependent on insulin but also on the availability of oxysterols, ligands of the nuclear liver X receptor (LXR). The aim of this study was to investigate the regulation of the hepatic SREBP-1c expression in vivo in situations where drastic nutritional and hormonal changes occur, from the gestation to the weaning period. In this paper, we report the discovery of LXR-independent SREBP-1c transcriptional activity during late gestation. In utero insulin injection prior to the natural rise in insulin in late gestation triggers SREBP-1c mRNA elevation, nuclear SREBP-1c binding activity, and expression of its target genes independently of LXR transactivation. On the other hand, during suckling, we observed strong SREBP-1c mRNA expression despite very low plasma insulin, an expression that may be due to LXR transactivation. In contrast to insulin, LXR is not sufficient to trigger nuclear SREBP-1c binding activity and target gene induction. This could be due to the concomitant induction of INSIG-2a by LXR and subsequent retention of SREBP-1c in the endoplasmic reticulum.

Received for publication, June 11, 2004 , and in revised form, October 26, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of a doctoral fellowship from the Ministère de l'Enseignement Supérieur et de la Recherche.

To whom correspondence should be addressed: INSERM U465, 15 rue de l'Ecole de Médecine, 75270, Paris cedex 06, France. Tel.: 33-1-42-34-69-23; Fax: 33-1-40-51-85-86; E-mail: pbossard{at}bhdc.jussieu.fr.

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