Abstract
Glucose constitutes a major fuel for the heart, and high glucose uptake during fetal development is coincident with the highest level of expression of the glucose transporter GLUT-1 during life. We have previously reported that GLUT-1 is repressed perinatally in rat heart, and GLUT-4, which shows a low level of expression in the fetal stage, becomes the main glucose transporter in the adult. Here, we show that the perinatal expression of GLUT-1 and GLUT-4 glucose transporters in heart is controlled directly at the level of gene transcription. Transient transfection assays show that the -99/-33 fragment of the GLUT-1 gene is sufficient to drive transcriptional activity in rat neonatal cardiomyocytes. Electrophoretic mobility shift assays demonstrate that the transcription factor Sp1, a trans-activator of GLUT-1 promoter, binds to the -102/-82 region of GLUT-1 promoter during the fetal state but not during adulthood. Mutation of the Sp1 site in this region demonstrates that Sp1 is essential for maintaining a high transcriptional activity in cardiac myocytes. Sp1 is markedly down-regulated both in heart and in skeletal muscle during neonatal life, suggesting an active role for Sp1 in the regulation of GLUT-1 transcription. In all, these results indicate that the expression of GLUT-1 and GLUT-4 in heart during perinatal development is largely controlled at a transcriptional level by mechanisms that might be related to hyperplasia and that are independent from the signals that trigger cell hypertrophy in the developing heart. Furthermore, our results provide the first functional insight into the mechanisms regulating muscle GLUT-1 gene expression in a live animal.
Highlights
Glucose constitutes a major fuel for the heart, and high glucose uptake during fetal development is coincident with the highest level of expression of the glucose transporter GLUT-1 during life
GLUT-1 and GLUT-4 Transcriptional Activity Is Regulated during Development—We have previously shown [16] that both GLUT-4 and GLUT-1 glucose transporters are strongly regulated during perinatal development in heart, skeletal muscle, and brown adipose tissue
The above observations led us to consider that the induction of GLUT-4 mRNA and repression of GLUT-1 during perinatal development may be due to transcriptional control
Summary
Vol 274, No 25, Issue of June 18, pp. 17626 –17634, 1999 Printed in U.S.A. Factors Involved in GLUT-1 Glucose Transporter Gene Transcription in Cardiac Muscle*. The expression of GLUT-1 and GLUT-4 glucose transporters is strongly regulated during the perinatal development of rat heart, skeletal muscle, and brown adipose tissue. We have described [16] that around birth and during the first weeks of neonatal life, glucose transporter expression is characterized by a dramatic change in the accumulations of GLUT-1 and GLUT-4, both mRNA and protein, in rat heart, in skeletal muscle, and in brown adipose tissue. We show that this reduced binding is due to a reduced Sp1 protein abundance in nuclear extracts from heart and muscle in the adult Together, these findings suggest that Sp1 contributes to the high level of expression of GLUT-1 in the fetal heart
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