Regulation of GLUT4 gene expression by SREBP-1c in adipocytes

Abstract

Expression of the GLUT4 (glucose transporter type 4 isoform) gene in adipocytes is subject to hormonal or metabolic control. In the present study, we have characterized an adipose tissue transcription factor that is influenced by fasting/refeeding regimens and insulin. Northern blotting showed that refeeding increased GLUT4 mRNA levels for 24 h in adipose tissue. Consistent with an increased GLUT4 gene expression, the mRNA levels of SREBP (sterol-regulatory-element-binding protein)-1c in adipose tissue were also increased by refeeding. In streptozotocin-induced diabetic rats, insulin treatment increased the mRNA levels of GLUT4 in adipose tissue. Serial deletion, luciferase reporter assays and electrophoretic mobility-shift assay studies indicated that the putative sterol response element is located in the region between bases -109 and -100 of the human GLUT4 promoter. Transduction of the SREBP-1c dominant negative form to differentiated 3T3-L1 adipocytes caused a reduction in the mRNA levels of GLUT4, suggesting that SREBP-1c mediates the transcription of GLUT4. In vivo chromatin immunoprecipitation revealed that refeeding increased the binding of SREBP-1 to the putative sterol-response element in the GLUT4. Furthermore, treating streptozotocin-induced diabetic rats with insulin restored SREBP-1 binding. In addition, we have identified an Sp1 binding site adjacent to the functional sterol-response element in the GLUT4 promoter. The Sp1 site appears to play an additive role in SREBP-1c mediated GLUT4 gene upregulation. These results suggest that upregulation of GLUT4 gene transcription might be directly mediated by SREBP-1c in adipose tissue.

Regulation of glucose transporter type 4 isoform gene expression in muscle and adipocytes

“…Recently, we showed a direct relationship between SREBP1c and GLUT4 gene expression. We identified the SREBP responsive element (SRE) in the bases 7109 and 7100 bp region of the human GLUT4 promoter (43). We also confirmed the Sp1 binding site on the human GLUT4 promoter.…”

“…Muscle GLUT4 enhancer factor (mGEF) and myocyte enhancer factor 2 (MEF2), which are regulated by AMP-activated protein kinase (AMPK), also synergistically control GLUT4 gene expression (41). MyoD (42), nuclear factor I (NF-1) family (37), C/EBP-a (29), SREBP-1c (43), and O/E-1 factor (39) are known to be responsible for insulin-mediated GLUT4 gene expression. Those factors, which are responsible for the organization of the tissue specificity of GLUT4 gene, will be described in this section (Figs 2 and 3).…”

Inhibition of cannabinoid CB1 receptor upregulates Slc2a4 expression via nuclear factor-κB and sterol regulatory element-binding protein-1 in adipocytes

“…From another standpoint, it was found that 24 h blockade of the CB1 receptor increases the binding activity of SREBP-1, a positive regulator of Slc2a4 gene expression (Im et al 2006), to the Slc2a4 promoter; thus, this finding contributes to the increased Slc2a4 mRNA expression observed in this condition.…”

“…To address the hypothesis that SREBP-1 may be involved in Slc2a4 upregulation by CB1 receptor, the described SRE site of Slc2a4 promoter was utilized in EMSA experiments (Im et al 2006). To examine the specificity of the nuclear protein binding into the labeled oligonucleotide containing the SRE binding site, a competition with unlabeled SRE oligonucleotide was performed (Fig.…”

Effect of Daxx on cholesterol accumulation in hepatic cells

“…In this case, SREBP inhibits caveolin gene transcription in contrast to its stimulating effect on other gene promoters [27,28] . Caveolin-1, a type of free cholesterolbinding protein, is another significant protein involved in cholesterol homeostasis [29] .…”