Repression and activation of transcription of phosphoenolpyruvate carboxykinase gene during liver development

Transcriptional activation of the hepatic phosphoenolpyruvate carboxykinase (PEPCK) gene at birth is critical since PEPCK appearance initiates hepatic gluconeogenesis. A delayed appearance results in hypoglycemia, while a premature appearance results in neonatal diabetes, both are incompatible with sustaining life. Experiments using transgenic mice and transfected hepatoma cells suggest that both repression and activation underlie the correct onset of hepatic PEPCK gene transcription. In transgenic mice, transgenes driven by the proximal PEPCK promoter are prematurely expressed in the fetal liver and over-expressed in the neonatal liver, indicating that sequences upstream of the proximal promoter restrain perinatal expression. In Hepa1c1c7 cells, which mimic the fetal liver, the proximal PEPCK promoter (597 bp) exhibited a 3.5-10-fold higher activity than longer promoters. Repression of the longer promoter (2000 bp) was diminished upon deletion of the sequence spanning positions -840 to -1116 which contains a PPAR/RXR recognition element, The intact 2000 bp PEPCK promoter could be markedly activated by co-transfecting the transcription factor HNF-1 together with C/EBP, It could be repressed by co-transfection with RXR alpha and adding PPAR alpha relieved this inhibition. (C) 1999 Federation of European Biochemical Societies.