A Combination of HNF-4 and Foxo1 Is Required for Reciprocal Transcriptional Regulation of Glucokinase and Glucose-6-phosphatase Genes in Response to Fasting and Feeding

Abstract

Glucokinase (GK) and glucose-6-phosphatase (G6Pase) regulate rate-limiting reactions in the physiologically opposed metabolic cascades, glycolysis and gluconeogenesis, respectively. Expression of these genes is conversely regulated in the liver in response to fasting and feeding. We explored the mechanism of transcriptional regulation of these genes by nutritional condition and found that reciprocal function of HNF-4 and Foxo1 plays an important role in this process. In the GK gene regulation, Foxo1 represses HNF-4-potentiated transcription of the gene, whereas it synergizes with HNF-4 in activating the G6Pase gene transcription. These opposite actions of Foxo1 concomitantly take place in the cells under no insulin stimulus, and such gene-specific action was promoter context-dependent. Interestingly, HNF-4-binding elements (HBEs) in the GK and G6Pase promoters were required both for the insulin-stimulated GK gene activation and insulin-mediated G6Pase gene repression. Indeed, mouse in vivo imaging showed that mutating the HBEs in the GK and G6Pase promoters significantly impaired their reactivity to the nutritional states, even in the presence of intact Foxo1-binding sites (insulin response sequences). Thus, in the physiological response of the GK and G6Pase genes to fasting/feeding conditions, Foxo1 distinctly decodes the promoter context of these genes and differently modulates the function of HBE, which then leads to opposite outcomes of gene transcription.The liver plays an important role in maintaining plasma glucose homeostasis by adjusting a delicate balance between hepatic glucose utilization and production via the glycolytic and gluconeogenic pathways. These physiologically opposed cascades are regulated, at least in part, at the transcriptional level of the glucokinase (GK) 2 and glucose-6-phosphatase (G6Pase) genes, which catalyze the first and last rate-limiting steps in glycolysis and gluconeogenesis, respectively.

Alternative human liver transcripts of TCF7L2 bind to the gluconeogenesis regulator HNF4α at the protein level

“…Glucose-6-phosphatase gene expression is repressed by TCF7L2 independently of FOXO1 Expression of G6PC is regulated by FOXO1 and HNF4α [30], and the β-catenin-FOXO1 complex stimulates G6PC only in the absence of insulin [24]. We observed that in HepG2 cells with reduced TCF7L2 expression, G6PC mRNA expression was increased independently of the presence or absence of insulin (Fig.…”

“…4a). To further characterise the effect of TCF7L2 on G6PC expression, we measured G6PC promoter activity by using luciferase reporter constructs previously used to analyse the synergistic activation of HNF4α and FOXO1 [30]. In HepG2 cells treated with TCF7L2 siRNA, both the wild-type G6PC promoter and the G6PC promoter construct lacking the FOXO1 binding region (G6PCΔ123) showed a Representative western blots of total cell lysate from HepG2 cells cultured as above (a-f) similar increase in luciferase activity (Fig.…”

Novel Polymorphisms of Nuclear Receptor SHP Associated with Functional and Structural Changes

“…Glutathione S-Transferase (GST) Pulldown Assays-GST-ERR␥ (Dr. Uwe Borgmeyer), GST-LRH-1 (Dr. Timothy Osborne), GST-HNF4␣ (Dr. Akiyoshi Fukamizu), and GST-EID1 (Dr. Eckardt Treuter) were generously provided as indicated (23)(24)(25)(26). MagneGST TM Pull-Down System (catalog #V8872, Promega) was used in this experiment.…”

Mechanisms of lifespan extension and preventive effects of calorie restriction on tumor development: Possible link between central neuroendocrine system and peripheral metabolic adaptation

“…This effect may be regulated by FoxO1 35) and Nrf2 36) transcription factors. Interestingly, HNF-4α can interact with FoxO1 and modulate its transcriptional activity 37) . Moreover, levels of Nrf2 may be regulated by HNF-4α 38) .…”

“…This is probably because, in the absence of DNA damage, HNF-4α is activated by PGC-1α; whereas, under DNA damage conditions, HNF-4α would switch its interaction partner for FoxO1, p53, or Rad50 to activate the DNA damage response. Indeed, HNF-4α interaction with FoxO1 has been shown to decrease transcriptional activity for certain target genes 37) .…”