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Diabetes 54:1684-1691, 2005
© 2005 by the American Diabetes Association, Inc.

Glucose-Stimulated Upregulation of GLUT2 Gene Is Mediated by Sterol Response Element–Binding Protein-1c in the Hepatocytes

Seung-Soon Im1,2,3, Seung-Youn Kang1,3, So-Youn Kim1,2,3, Ha-il Kim2,3, Jae-Woo Kim2,4, Kyung-Sup Kim1,2,3,4, and Yong-Ho Ahn1,2,3

1 Brain Korea 21 Project for Medical Sciences, Yonsei University, Seoul, Korea
2 Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, Korea
3 Center for Chronic Metabolic Disease Research, Yonsei University College of Medicine, Seoul, Korea
4 Institute of Genetic Science, Yonsei University College of Medicine, Seoul, Korea

GLUT2 is mainly expressed in the liver, ß-cells of the pancreas, and the basolateral membrane of kidney proximal tubules and plays an important role in glucose homeostasis in living organisms. The transcription of the GLUT2 gene is known to be upregulated in the liver during postprandial hyperglycemic states or in type 2 diabetes. However, a molecular mechanism by which glucose activates GLUT2 gene expression is not known. In this study, we report evidence that sterol response element–binding protein (SREBP)-1c plays a key role in glucose-stimulated GLUT2 gene expression. The GLUT2 promoter reporter is activated by SREBP-1c, and the activation is inhibited by a dominant-negative form of SREBP-1c (SREBP-1c DN). Adenoviral expression of SREBP-1c DN suppressed glucose-stimulated GLUT2 mRNA level in primary hepatocytes. An electrophoretic mobility shift assay and mutational analysis of the GLUT2 promoter revealed that SREBP-1c binds to the –84/–76 region of the GLUT2 promoter. Chromatin immunoprecipitation revealed that the binding of SREBP-1c to the –84/–76 region was increased by glucose concentration in a dose-dependent manner. These results indicate that SREBP-1c mediates glucose-stimulated GLUT2 gene expression in hepatocytes.

Address correspondence and reprint requests to Yong-Ho Ahn, MD, PhD, Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemoon-gu, Seoul 120-752, Korea. E-mail: yha111{at}yumc.yonsei.ac.kr

Abbreviations: ChIP, chromatin immunoprecipitation; DMEM, Dulbecco’s modified Eagles’ medium; EMSA, electrophoretic mobility shift assay; FBS, fetal bovine serum; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GFP, green fluorescent protein; SRE, SREBP response element; SREBP, sterol response element–binding protein; SREBP-1c DN, dominant-negative form of SREBP-1c


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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Diabetes Diabetes Care Clinical Diabetes Diabetes Spectrum
Copyright © 2005 by the American Diabetes Association.