Foxa3 (hepatocyte nuclear factor 3 gamma) is required for the regulation of hepatic GLUT2 expression and the maintenance of glucose homeostasis during a prolonged fast

The winged helix transcription factors, hepatocyte nuclear factors 3 alpha, -beta, and -gamma (HN-F-3, encoded by the Foxa1, -a2, and -a3 genes, respe ctively), are expressed early in embryonic endoderm and play important role s in the regulation of gene expression in liver and pancreas. Foxa1 has bee n shown to be required for glucagon secretion in the pancreas, whereas Foxa 2 is critical for the regulation of insulin secretion in pancreatic beta -c ells. Here we address the role of Foxa3 in the maintenance of glucose homeo stasis. Mice homozygous for a null mutation in Foxa3 appear normal under fe d conditions. However, when fasted, Foxa3(-/-) mice have a significantly lo wer blood glucose compared with control mice. The fasting hypoglycemia in F oxa3(-/-) mice could not be attributed to defects in pancreatic hormone sec retion, ketone production, or hepatic glycogen breakdown. Surprisingly, mRN A levels for several gluconeogenic enzymes were up-regulated appropriately in fasted Foxa3(-/-) mice, despite the fact that the corresponding genes ha d been shown to be activated by FOXA proteins in vitro. However, the mRNA f or the plasma membrane glucose transporter GLUT2 was decreased by 64% in th e fasted and 93% in the fed state, suggesting that efflux of newly synthesi zed glucose is limiting in Foxa3(-/-) hepatocytes. Thus, Foxa3 is the domin ating transcriptional regulator of GLUT2 expression in hepatocytes in vivo. In addition, we investigated the hepatic transcription factor network in F oxa3(-/-) mice and found that the normal activation of HNF-4 alpha, HNF-1 a lpha, and PGC-1 induced by fasting is attenuated in mice lacking Foxa3.