Prenatal programming of hepatocyte nuclear factor 4α in the rat: a key mechanism in the ‘foetal origins of hyperglycaemia’?

Abstract

Aims/hypothesis: Prenatal glucocorticoid exposure causes lifelong hyperglycaemia in rat offspring, associated with permanently increased hepatic phosphoenolpyruvate carboxykinase 2 (PCK2), the rate-controlling enzyme of gluconeogenesis. To elucidate the mechanisms underlying the 'programming' of PCK2, this study examined the effect of prenatal dexamethasone treatment on expression of transcription factors that regulate Pck2. Materials and Methods: Real-time RT-PCR and in situ hybridisation were used to measure and localise hepatic mRNA transcribed from the genes for PCK2, hepatocyte nuclear factor 4, alpha (HNF4A), transcription factor 1 (TCF1), CCAAT/enhancer binding protein, alpha (CEBPA), CEBPB, the glucocorticoid receptor (NR3C1) and peroxisome proliferative activated receptor, gamma, coactivator 1 alpha (PPARGC1A) in foetal and adult offspring of dams treated with dexamethasone or vehicle during the last week of gestation. Results: Prenatal dexamethasone exposure significantly elevated Hnf4a mRNA expression in foetal and adult liver. This resulted from increased expression of isoforms derived from the 'adult' (P1) Hnf4a promoter. In contrast, isoforms from the 'foetal' (P2) promoter were markedly suppressed by dexamethasone. Like Pck2, the increase in hepatic Hnf4a mRNA occurred exclusively in the periportal zone. Foetal Tcf1 expression was also increased by dexamethasone treatment, but this did not persist into adulthood. Prenatal dexamethasone did not affect the amounts of foetal and/or adult Cebpa, Cebpb, Nr3c1 or Ppargc1a mRNA. Conclusions/interpretation: Prenatal dexamethasone exposure caused a permanent increase in hepatic Hnf4a mRNA. This increase, which was associated with a premature switch from foetal to adult promoter predominance, was congruent with changes in Pck2 expression. These data suggest that HNF4A might mediate Pck2 overexpression and subsequent hyperglycaemia.

Antenatal Dexamethasone Treatment Leads to Changes in Gene Expression in a Murine Late Placenta

“…PEPCK is a key regulator of gluconeogenesis and hyperglycemia is a well-known side effect of steroid use. Antenatal DEX treatment has been shown to up-regulate hepatocyte nuclear factor 4 alpha which in turn up-regulates PEPCK gene and this phenomenon has been linked to prenatal foetal programming and hyperglycemia later in life [52].…”

Early foetal programming of hepatic gluconeogenesis: glucocorticoids strike back

“…In this issue of Diabetologia, Nyirenda et al [17] report an exciting new potential mechanism for glucocorticoidinduced foetal programming of hyperglycaemia. The authors' previous work demonstrated that exposure to prenatal dexamethasone resulted in persistent upregulation of the mRNA and activity of the cytosolic form of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PCK) in adult offspring [18].…”

“…Furthermore, these changes in PCK expression in adult offspring could not be attributed to altered postnatal maternal behaviour, suggesting that excess foetal glucocorticoid exposure has a permanent effect, programming increased gluconeogenesis [19]. Nyirenda et al [17] have now followed up this work by investigating the effects of supraphysiological levels of glucocorticoids, administered to female rats during the last week of pregnancy, on key hepatic transcription factors known to regulate PCK expression in the rat foetus and adult offspring. Prenatal dexamethasone resulted in an early increase in the transcription of the gene encoding foetal hepatic nuclear factor 4 (Hnf4a), which remained elevated into adulthood, and paralleled the rise in Pck1 expression and hyperglycaemia.…”

“…HNF4A has been associated with recruiting coactivator protein (CREB binding protein/ p300) and the ability to mediate chromatin remodelling [26][27][28]. Whether these other regulators are also involved in stimulating PCK gene transcription directly in response to early glucocorticoid exposure was not explored in the report by Nyirenda et al [17]. A more thorough and direct analysis of the DNA binding factors at the protein level could be explored using foetal rat liver nuclear extracts and DNA binding assays.…”

Comment on: Nyirenda MJ, Dean S, Lyons V, Chapman KE, Seckl JR (2006) Prenatal programming of hepatocyte nuclear factor 4a in the rat: a key mechanism in the ‘foetal origins of hyperglycaemia’? Diabetologia 49: 1412–1420, and on: McCurdy CE, Friedman JE (2006) Early foetal programming of hepatic gluconeogenesis: glucocorticoids strike back. Diabetologia 49:1138–1141

“…Nyirenda et al present compelling new evidence on the mechanism of fetal programming of gluconeogenesis by glucocorticoid administration during the last third of pregnancy in rats [1], a study that is commented on by McCurdy and Friedman [2]. Nyirenda et al focus on a fluxgenerating enzyme of gluconeogenesis (phosphoenolpyruvate carboxykinase [PCK]) and the factors involved in its transcription, showing how PCK mRNA and that of its controlling transcription factors are localised within the hepatic acinus.…”