Regulation of GLUT4 gene expression by SREBP-1c in adipocytes.
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.
Im
Seung-Soon
SS
Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemoon-gu, Seoul 120-752, Korea.
Kwon
Sool-Ki
SK
Kang
Seung-Youn
SY
Kim
Tae-Hyun
TH
Kim
Ha-Il
HI
Hur
Man-Wook
MW
Kim
Kyung-Sup
KS
Ahn
Yong-Ho
YH
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism; D004435:Eating; D005215:Fasting; D005786:Gene Expression Regulation / Q000187:drug effects; D051275:Glucose Transporter Type 4 / Q000235:genetics*; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D008297:Male; D051379:Mice; D011401:Promoter Regions, Genetic; D051381:Rats; D020218:Response Elements / Q000235:genetics; D016329:Sp1 Transcription Factor / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
D051275:Glucose Transporter Type 4; D007328:Insulin; D016329:Sp1 Transcription Factor; D051780:Sterol Regulatory Element Binding Protein 1