<b>Importance of Hepatocyte Nuclear Factor 4α in Glycerol-induced Glucose-6-phosphatase Expression in </b><b>Liver </b>

Abstract

Glucose-6-phosphatase (G6Pase) is a key regulator of gluconeogenesis. We previously found that administration of glycerol, a substrate for gluconeogenesis, transactivates G6Pase in the mouse liver. To clarify its cell-autonomous transcriptional activation in hepatocytes, we examined the mechanism of expression of the gene G6pc, which encodes G6Pase, in rat hepatoma cell line FAO cells. Endogenous G6pc expression in FAO cells was increased by glycerol administration as well as by the fatty acid oleate. Luciferase reporter assay revealed that the ~2.0 kb mouse G6pc promoter contains the element(s) responsible for glycerol-stimulated G6pc transactivation. Using several deletion-or chimeric-constructs of G6pc promoter, we found that the DNA response element for hepatocyte nuclear factor 4α (HNF4α) (−77/−65) in the G6pc promoter is essential for transactivation by glycerol. Similarly to glycerol, oleate also increased G6pc expression through its action on the HNF4α element (−77/−65). Furthermore, the reporter activities were higher in the cells co-treated with glycerol plus oleate than in those singly treated with glycerol or oleate. In addition, the temporal profiles of G6pc expression differed between glycerol and oleate administration. Our present results suggest that glycerol and oleate induce G6pc expression both via the HNF4α element (−77/−65) and also through other regulatory mechanisms.

Glycerol induces G6pc in primary mouse hepatocytes and is the preferred substrate for gluconeogenesis both in vitro and in vivo

“…Another finding in this study is that glycerol metabolism increases G6pc expression. Previously, glycerol was shown to slightly increase levels of G6pc in a rat hepatoma cell line (46); however, an effect in primary hepatocytes has not been reported. The importance of elevated G6pc mRNA levels in mediating hyperglycemia, however, is still unclear.…”

Tracking the carbons supplying gluconeogenesis

“…One must consider how gluconeogenic precursors regulate enzymes relevant to gluconeogenesis. In vitro studies have shown glycerol induced G6Pase expression in mouse primary hepatocytes [89] and rat hepatoma FAO cells [93]. Yoshida et al showed that glycerol induced G6Pase expression in mouse hepatocytes via binding of the G6Pase promoter region in conjunction with hepatocyte nuclear factor 4α (HNF4α) binding to the promoter region [93].…”

“…In vitro studies have shown glycerol induced G6Pase expression in mouse primary hepatocytes [89] and rat hepatoma FAO cells [93]. Yoshida et al showed that glycerol induced G6Pase expression in mouse hepatocytes via binding of the G6Pase promoter region in conjunction with hepatocyte nuclear factor 4α (HNF4α) binding to the promoter region [93]. Glycerol reduced PEPCK expression in some in vitro studies [89] but not all [93].…”

“…Yoshida et al showed that glycerol induced G6Pase expression in mouse hepatocytes via binding of the G6Pase promoter region in conjunction with hepatocyte nuclear factor 4α (HNF4α) binding to the promoter region [93]. Glycerol reduced PEPCK expression in some in vitro studies [89] but not all [93]. In contrast, lactate and pyruvate did not affect G6Pase and PEPCK expression in mouse primary hepatocytes [89].…”