Foxa3 (Hepatocyte Nuclear Factor 3γ) Is Required for the Regulation of Hepatic GLUT2 Expression and the Maintenance of Glucose Homeostasis during a Prolonged Fast

Abstract

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.Recent studies suggest that no single transcription factor on its own controls hepatocyte differentiation and metabolism. Instead, a transcription factor network including HNF-3␣, 1

Orthogonal analysis of C/EBPβ targets in vivo during liver proliferation

“…The identification of Foxa3 as a direct C͞EBP␤ target in the regenerating liver is of particular interest because Foxa3 is required for maintenance of glucose homeostasis during a prolonged fast (36). It is conceivable that decreased activation of Foxa3 may contribute to the prolonged hypoglycemia observed Potential C͞EBP␤ DNA-binding partners were evaluated as described in Materials and Methods.…”

Forkhead box A3 mediates glucocorticoid receptor function in adipose tissue

“…Among them, members of the Foxa subfamily play important roles in early organ development and metabolism (24,25). We recently have shown that Forkhead box protein A3 (Foxa3), previously known to play a role in liver during long-term starvation and in pancreas development (26,27), is involved in the selective expansion of epididymal fat depots during a high-fat diet and in the suppression of energy expenditure during aging (28,29) and that its variants are associated with human metabolic traits (30). Our studies also have revealed that Foxa3 levels are inducible in visceral fat in Significance This paper shows a previously unidentifed relationship between the transcription factor forkhead box a3 (Foxa3) and the glucocorticoid receptor (GR) by demonstrating, for the first time to our knowledge, that Foxa3 is a target of GR and that it is required for GR transcriptional function in fat depots.…”

Role of forkhead box protein A3 in age-associated metabolic decline

“…Among these FOX factors, the members of the forkhead box protein A (Foxa) subfamily play important roles in early development, organogenesis, and metabolism (19,20). Whereas Foxa1-and Foxa2-deficient mice manifest either perinatal or embryonic lethality (21,22), Foxa3-null mice are viable, with no obvious abnormalities (23). We recently demonstrated that Foxa3 is an early regulator of adipocyte differentiation, and that Foxa3-null mice are selectively protected from visceral adipose depot expansion when fed a highfat diet (HFD) (24).…”