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 hepatic gluconeogenesis: the genes for phosphoenolpyruvate carboxykinase (PEPCK), fructose-1,6-bisphosphatase (Fru-1,6-P2ase) and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (6-PF-2-K/Fru-2,6-P2ase). Mice were made vitamin A deficient in the second generation by initiating a vitamin A-deficient diet on d 10 of gestation. At 7 wk of age, vitamin A-deficient mice were treated with all-trans RA or vehicle alone 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-P2ase mRNA levels that were 42% lower than the respective mRNA measured in control mice. The Fru-1,6-P2ase mRNA abundance was not affected by vitamin A deficiency. The decrease in hepatic PEPCK and 6-PF-2-K/Fru-2,6-P2ase mRNA levels was reversed by treatment with all-trans RA within 3 h of administration. In mice fed the control diet, food deprivation for 15 h resulted in PEPCK mRNA levels that were 3.5-fold higher, Fru-1,6-P2ase mRNA levels that were 2-fold higher, and 6-PF-2-K/Fru-2,6-P2ase mRNA levels that were 3.4-fold higher than in fed mice. Vitamin A-deficient mice did not respond to food deprivation with induced PEPCK mRNA levels, whereas 6-PF-2-K/Fru-2,6-P2ase and Fru-1,6-P2ase mRNA levels were induced. The pattern of 6-PF-2-K/Fru-2,6-P2ase mRNA abundance with vitamin A deficiency and food deprivation was complex and different from that for either PEPCK or Fru-1,6-P2ase transcripts. 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 the whole animal indicate that vitamin A regulation of the hepatic PEPCK gene is physiologically important; without adequate vitamin A nutriture, stimulation of the PEPCK gene by food deprivation or cAMP treatment is inhibited in the liver.
Shin
D J
DJ
Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA.
McGrane
M M
MM
D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D005508:Food Deprivation / Q000502:physiology; D006597:Fructose-Bisphosphatase / Q000096:biosynthesis / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D005943:Gluconeogenesis / Q000187:drug effects* / Q000235:genetics; D008099:Liver / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000096:biosynthesis / Q000235:genetics*; D010732:Phosphofructokinase-1 / Q000096:biosynthesis / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology; D014801:Vitamin A / Q000494:pharmacology*; D014802:Vitamin A Deficiency / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology
D012333:RNA, Messenger; D014801:Vitamin A; D014212:Tretinoin; D003994:Bucladesine; D010732:Phosphofructokinase-1; D006597:Fructose-Bisphosphatase; D010729:Phosphoenolpyruvate Carboxykinase (GTP)