VITAMIN-A REGULATES GENES INVOLVED IN HEPATIC GLUCONEOGENESIS IN MICE- PHOSPHOENOLPYRUVATE CARBOXYKINASE, FRUCTOSE-1,6-BISPHOSPHATASE AND 6-PHOSPHOFRUCTO-2-KINASE FRUCTOSE-2,6-BISPHOSPHATASE/

We examined the effects of vitamin A deficiency and all-trans retinoic acid (RA) supplementation on regulation of three important genes in h epatic gluconeogenesis: the genes for phosphoenolpyruvate carboxykinas e (PEPCK), fructose-1,6-bisphosphatase (Fru-1,6-P(2)ase) and phosphofr ucto-2-kinase/fructose-2,6-bisphosphatase (6-PF-2-K/Fru-2,6-P(2)ase). Mice were made vitamin A deficient in the second generation by initiat ing a vitamin A-deficient diet on d 10 of gestation. At 7 wk of age, V itamin A-deficient mice were treated with all-trans RA or vehicle alon e and killed for RNA analysis. In liver, Vitamin A deficiency resulted in PEPCK mRNA levels that were 74% lower and 6-PF-2-K/Fru-2,6-P(2)ase mRNA levels that were 42% lower than the respective mRNA measured in control mice. The Fru-1,6-P(2)ase mRNA abundance was not affected by v itamin a deficiency, The decrease in hepatic PEPCK and 6-PF-2-K/Fru-2, 6-P(2)ase mRNA levels was reversed by treatment with all-trans RA with in 3 h of administration, In mice fed the control diet, food deprivati on for 15 h resulted in PEPCK mRNA levels that were 3.5-fold higher, F ru-1,6-P(2)ase mRNA levels that were 2-fold higher, and 6-PF-2-K/Fru-2 ,6-P(2)ase mRNA levels that were 3.4-fold higher than in fed mice, Vit amin A-deficient mice did not respond to food deprivation with induced PEPCK mRNA levels, whereas 6-PF-2-K/Fru-2,6-P(2)ase and Fru-1,6-P(2)a se mRNA levels were induced. The pattern of 6-PF-2-K/Fru-2,6-P(2)ase m RNA abundance with vitamin A deficiency and food deprivation was compl ex and different from that for either PEPCK or Fru-1,6-P(2)ase transcr ipts. The cAMP-responsiveness of the PEPCK gene in vitamin A-deficient mice was tested. Vitamin A deficiency caused a significant reduction in cAMP stimulation of PEPCK mRNA levels in liver. These results in th e whole animal indicate that vitamin A regulation of the hepatic PEPCK gene is physiologically important; without adequate vitamin A nutritu re, stimulation of the PEPCK gene by food deprivation or cAMP treatmen t is inhibited in the liver.