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J. Biol. Chem., Vol. 276, Issue 46, 42812-42817, November 16, 2001
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) Is
Required for the Regulation of Hepatic GLUT2 Expression and the
Maintenance of Glucose Homeostasis during a Prolonged Fast*
From the Department of Genetics, School of Medicine, University of
Pennsylvania, Philadelphia, Pennsylvania 19104
The winged helix transcription factors,
hepatocyte nuclear factors 3
, -
, and -
(HNF-3, encoded
by the Foxa1, -a2, and -a3 genes, respectively), are expressed early in embryonic endoderm and
play important roles in the regulation of gene expression in liver and
pancreas. Foxa1 has been shown to be required for glucagon
secretion in the pancreas, whereas Foxa2 is critical for
the regulation of insulin secretion in pancreatic -cells. Here we
address the role of Foxa3 in the maintenance of glucose homeostasis. Mice homozygous for a null mutation in Foxa3
appear normal under fed conditions. However, when fasted,
Foxa3
/ mice have a significantly lower
blood glucose compared with control mice. The fasting hypoglycemia in
Foxa3/ mice could not be attributed to
defects in pancreatic hormone secretion, ketone production, or hepatic
glycogen breakdown. Surprisingly, mRNA levels for several
gluconeogenic enzymes were up-regulated appropriately in fasted
Foxa3/ mice, despite the fact that the
corresponding genes had been shown to be activated by FOXA
proteins in vitro. However, the mRNA for the plasma
membrane glucose transporter GLUT2 was decreased by 64% in the fasted
and 93% in the fed state, suggesting that efflux of newly synthesized
glucose is limiting in Foxa3/ hepatocytes.
Thus, Foxa3 is the dominating transcriptional regulator of
GLUT2 expression in hepatocytes in vivo. In addition, we
investigated the hepatic transcription factor network in
Foxa3/ mice and found that the normal
activation of HNF-4, HNF-1, and PGC-1 induced by fasting is
attenuated in mice lacking Foxa3.
To whom correspondence should be addressed: 560 Clinical Research
Bldg., Dept. of Genetics, School of Medicine, University of
Pennsylvania, 415 Curie Blvd., Philadelphia, PA 19104. Tel.: 215-898-8759; Fax: 215-573-5892; E-mail:
kaestner@mail.med.upenn.edu.
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