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

• Published in: Biochemical journal Vol. 399; no. 1; pp. 131 - 139
• Main Authors: Im, Seung-Soon, Kwon, Sool-Ki, Kang, Seung-Youn, Kim, Tae-Hyun, Kim, Ha-Il, Hur, Man-Wook, Kim, Kyung-Sup, Ahn, Yong-Ho
• Format: Journal Article
• Language: English
• Published: England Portland Press Ltd 01.10.2006
• Subjects: 3T3-L1 Cells; Adipocytes - cytology; Adipocytes - metabolism; Animals; Cell Differentiation; Diabetes Mellitus, Experimental - genetics; Diabetes Mellitus, Experimental - metabolism; Eating; Fasting; Gene Expression Regulation - drug effects; Glucose Transporter Type 4 - genetics; Humans; Insulin - pharmacology; Male; Mice; Promoter Regions, Genetic; Rats; Response Elements - genetics; Sp1 Transcription Factor - metabolism; Sterol Regulatory Element Binding Protein 1 - genetics; Sterol Regulatory Element Binding Protein 1 - metabolism; Up-Regulation - drug effects
• ISSN: 0264-6021; 1470-8728; 1470-8728
• DOI: 10.1042/BJ20060696

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.