Prenatal programming of hepatocyte nuclear factor 4alpha in the rat: A key mechanism in the 'foetal origins of hyperglycaemia'?
OBJECTIVE
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.


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
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.
Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK. m.nyirenda@ed.ac.uk
M J
MJ
Nyirenda
S
S
Dean
V
V
Lyons
K E
KE
Chapman
J R
JR
Seckl
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D003907:Dexamethasone / Q000494:pharmacology; D047108:Embryonic Development; D005260:Female; D047109:Fetal Development; D018507:Gene Expression Regulation, Developmental; D005938:Glucocorticoids / Q000494:pharmacology; D051557:Hepatocyte Nuclear Factor 4 / Q000187:drug effects / Q000235:genetics*; D006943:Hyperglycemia / Q000196:embryology*; D008099:Liver / Q000196:embryology*; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D014158:Transcription, Genetic
D017931:DNA Primers; D005938:Glucocorticoids; D051557:Hepatocyte Nuclear Factor 4; D012333:RNA, Messenger; D003907:Dexamethasone