ADD1/SREBP-1c Is Required in the Activation of Hepatic Lipogenic Gene Expression by Glucose

Foretz, Marc; Pacot, Corinne; Dugail, Isabelle; Lemarchand, Patricia; Guichard, C; Lièpvre, Xavier Le; Berthelier-Lubrano, Cécile; Spiegelman, Bruce M.; Kim, Jae Bum; Ferré, Pascal; Foufelle, Fabienne

doi:10.1128/mcb.19.5.3760

Cited by 490 publications

(431 citation statements)

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“…These experiments provide evidence that SREBP-1c mRNA and nuclear binding to the SRE increase progressively from mid-gestation to late gestation and drop just after birth in parallel with plasma insulin. In the adult liver, SREBP-1c is a major transcriptional mediator of insulin action on glycolytic and lipogenic enzyme genes such as the glucokinase (GK) and FAS genes (12,13,16). A similar pattern as described for SREBP-1c mRNA and binding activity was observed for GK and FAS mRNA expression, characterized by an increase between 16.5 days pc and 19.5 days pc and a drastic fall at birth (Fig.…”

Section: Differential Regulation Of Srebp-1c Transcriptional Activitysupporting

confidence: 54%

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

Bobard¹,

Hainault

Ferré

et al. 2005

Journal of Biological Chemistry

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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.

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Section: Differential Regulation Of Srebp-1c Transcriptional Activitysupporting

confidence: 54%

“…Indeed, previous studies have shown that SREBP-1c expression is transcriptionally stimulated by insulin (11,12). In vivo, a reduction of liver SREBP-1c mRNA is observed during fasting, whereas in mice refed a high carbohydrate diet, a strong increase of the SREBP-1c transcript occurs (11).…”

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confidence: 97%

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

Bobard¹,

Hainault

Ferré

et al. 2005

Journal of Biological Chemistry

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“…Therefore, it is possible that the greater expression of fatty acid-related genes in the WAT was induced by olanzapine through activation of parasympathetic nerves. Although our present knowledge on the regulation of srebp-1 expression in the WTA is far from complete, it has been shown that tissue-specific expression of SREBP-1 is responsible for the differential expressions of lipogenic genes between the liver and adipose tissue (Foretz et al 1999). In addition, the SREBP-1 may play additional roles in adipose tissue.…”

Section: Discussionmentioning

confidence: 98%

Acute effects of oral olanzapine treatment on the expression of fatty acid and cholesterol metabolism-related gene in rats

et al. 2015

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. (2015). Acute effects of oral olanzapine treatment on the expression of fatty acid and cholesterol metabolism-related gene in rats. Life Sciences, Acute effects of oral olanzapine treatment on the expression of fatty acid and cholesterol metabolism-related gene in rats AbstractAims Second-generation antipsychotic drugs (SGAs) have a high risk for serious metabolic side-effects including dyslipidemia. This study aimed to investigate the acute effects of oral olanzapine treatment on the expression of genes for fatty acid and cholesterol biosynthesis in rats. Main methods Female Sprague-Dawley rats were treated orally with olanzapine (1 mg/kg, equivalent to a human clinical dose of 10 mg) via selfadministration aimed to measure pharmacokinetics. Based on the pharmacokinetic analysis, the acute effects of olanzapine on sterol regulatory element binding protein (SREBP)-related fatty acid/cholesterol metabolism genes were investigated in the liver and perirenal white adipose tissue (WAT) by Real-time quantitative PCR. Key findings A pharmacokinetic analysis demonstrated that the maximum concentration of olanzapine in plasma (Cmax) occurred at 6 h with a peak concentration of 276.5 ng/ml after a single oral treatment and with a plasma elimination half-life of 3.5 h after peak. The mRNA expression of SREBP-2 and target genes for cholesterol synthesis and transport was increased 1.9 8.8 fold compared with the control at 6 h after olanzapine administration but returned to basal level at 12 h post-treatment, while the increased mRNA expression of SREBP-1c and its targeted fatty acid-related genes appeared at both 6 h and 12 h post-treatment. Significance The present study provided evidence that olanzapine at a clinically-relevant dose caused abnormal expression of genes involved in lipid metabolism in the liver and WAT. These results suggest that olanzapine may cause dyslipidemia side-effects through direct effects on lipid biosynthesis and efflux genes associated with SREBP-stimulated transcriptional changes. Disciplines Medicine and Health Sciences Publication DetailsLiu, X., Deng, C., Cao, S., Gong, J., Wang, B. & Hu, C. (2015). Acute effects of oral olanzapine treatment on the expression of fatty acid and cholesterol metabolism-related gene in rats. Life Sciences, 128 72-78. Second-generation antipsychotic drugs (SGAs) have a high risk for serious metabolic sideeffects including dyslipidemia. This study aimed to investigate the acute effects of oral olanzapine treatment on the expression of genes for fatty acid and cholesterol biosynthesis in rats. Main methods:Female Sprague-Dawley rats were treated orally with olanzapine (1 mg/kg, equivalent to human clinical dose of 10 mg) via self-administration aimed to measure pharmacokinetics.Based on the pharmacokinetic analysis, the acute effects of olanzapine on SREBP-related fatty acid/cholesterol metabolism genes were investigated in the liver and perirenal white adipose tissue (WAT) by Real-time quantitative PCR. Key findings:A pharmacokinetic analysis demonstrated that ...

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“…Because insulin is known to stimulate transcription of the SREBP-1c gene (17,(37)(38)(39), activity of the SREBP-1c promoter was stimulated with insulin in the presence or absence of a p38 inhibitor. As shown in Fig.…”

Section: Inhibition Of P38 Leads To Elevation Of Plasma Lipids and Fatmentioning

confidence: 99%

p38 Mitogen-activated Protein Kinase Plays an Inhibitory Role in Hepatic Lipogenesis

Xiong

Collins

et al. 2007

Journal of Biological Chemistry

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Hepatic lipogenesis is the principal route to convert excess carbohydrates into fatty acids and is mainly regulated by two opposing hormones, insulin and glucagon. Although insulin stimulates hepatic lipogenesis, glucagon inhibits it. However, the mechanism by which glucagon suppresses lipogenesis remains poorly understood. In this study, we have observed that p38 mitogen-activated protein kinase plays an inhibitory role in hepatic lipogenesis. Levels of plasma triglyceride and triglyceride accumulation in the liver were both elevated when p38 activation was blocked. Expression levels of central lipogenic genes, including sterol regulatory element-binding protein-1 (SREBP-1), fatty acid synthase, hydroxy-3-methylglutaryl coenzyme A reductase, farnesyl pyrophosphate synthase, and cytochrome P-450-51, were decreased in liver by fasting and in primary hepatocytes by glucagon but increased by the inhibition of p38. In addition, we have shown that p38 can inhibit insulin-induced expression of key lipogenic genes in isolated hepatocytes. Our results in hepatoma cells demonstrate that p38 plays an inhibitory role in the activation of the SREBP-1c promoter. Finally, we have shown that transcription of the PGC-1␤ gene, a key coactivator of SREBP-1c, was reduced in liver by fasting and in isolated hepatocytes by glucagon. This reduction was significantly reversed by the blockade of p38. Insulin-induced expression of the PGC-1␤ gene was enhanced by the inhibition of p38 but suppressed by the activation of p38. Together, we have identified an inhibitory role for p38 in the transcription of central lipogenic genes, SREBPs, and PGC-1␤ and hepatic lipogenesis.Hepatic lipogenesis is essential for maintaining energy balance (1). Disorders of hepatic lipogenesis may lead to fatty liver, dyslipidemia, type II diabetes mellitus, and complications such as atherosclerosis (2). Lipogenesis in liver includes de novo synthesis of fatty acids and cholesterols. As a major site for synthesis of fatty acids, the liver converts excess carbohydrates into fat storage in the fed state. Fatty acids synthesized in the liver are converted into triglycerides and secreted as very low density lipoproteins, which transport fatty acids to the storage sites in adipocytes. Cholesterols synthesized in the liver are also transported to other tissues via very low density lipoproteins as essential building materials for steroid hormones and cellular membranes. However, excess production of fatty acids and cholesterols from the liver may contribute to a variety of lipid disorders. The lipogenic process in the liver is primarily regulated by central lipogenic transcription factors, sterol regulatory element-binding proteins (SREBPs) 2 (reviewed in Refs. 3 and 4).The SREBPs are basic helix-loop-helix-leucine zipper-containing transcription factors (5). Among three known SREBPs, SREBP-1a and -1c are encoded by the same gene; SREBP-1c lacks the N-terminal exon compared with SREBP-1a (6). SREBP-2 is encoded by a separate gene (7). Although SREBPs share similar lip...

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ADD1/SREBP-1c Is Required in the Activation of Hepatic Lipogenic Gene Expression by Glucose

Cited by 490 publications

References 37 publications

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

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

Acute effects of oral olanzapine treatment on the expression of fatty acid and cholesterol metabolism-related gene in rats

p38 Mitogen-activated Protein Kinase Plays an Inhibitory Role in Hepatic Lipogenesis

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