Abstract
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.
Highlights
During development, the organism must continuously adapt its metabolism to the nutritional environment because the availability and quality of the nutrients varies widely throughout the different developmental stages
Liver SREBP-1c Binding Activity Increases with Plasma Insulin during Fetal Development—To investigate the mechanisms involved in the regulation of SREBP-1c expression during development, we first measured hepatic SREBP-1c mRNA in fetal livers from 16.5 days pc to day 1 after birth
We have shown that insulin stimulates SREBP-1c transcriptional activity in the absence of liver X receptor (LXR) binding activity, and this results in the increased expression of SREBP-1c target genes during the late gestation period
Summary
The organism must continuously adapt its metabolism to the nutritional environment because the availability and quality of the nutrients varies widely throughout the different developmental stages. Toward the end of the suckling period the milk is progressively replaced by the solid food diet of the adult, enriched in carbohydrates The adaptation to these changes in nutrition requires important modifications of glucose and fatty acid metabolism in the liver orchestrated mainly through hormonal variations. The transcription factor sterol regulatory element-binding protein 1c (SREBP-1c) has been shown to play a key role for the control of glucose and fatty acid metabolism in the liver [4, 5]. The current experiments were designed to explore the in vivo regulation of SREBP-1c levels in the liver during late gestation, suckling, and the weaning period and the respective roles of LXR and insulin on SREBP-1c transcriptional activity throughout these developmental stages
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