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

• Published in: The Journal of biological chemistry Vol. 280; no. 1; pp. 199 - 206
• Main Authors: Bobard, Alexandre, Hainault, Isabelle, Ferré, Pascal, Foufelle, Fabienne, Bossard, Pascale
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07-01-2005; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; CCAAT-Enhancer-Binding Proteins - genetics; CCAAT-Enhancer-Binding Proteins - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Endoplasmic Reticulum - metabolism; Female; Gene Expression Regulation, Developmental; Insulin - metabolism; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Liver - embryology; Liver - metabolism; Liver X Receptors; Male; Mice; Orphan Nuclear Receptors; Pregnancy; Protein Binding; Protein Transport; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Sterol Regulatory Element Binding Protein 1; Transcription Factors - genetics; Transcription Factors - metabolism; Transcriptional Activation
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M406522200

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.