Ghoshal Saheli, Pasham Saritha, Odom Daniel P, Furr Harold C, McGrane Mary M
Department of Nutritional Sciences and Molecular and Cell Biology, University of Connecticut, Storrs, CT 06269, USA.
J Nutr. 2003 Jul;133(7):2131-6. doi: 10.1093/jn/133.7.2131.
Expression of the phosphoenolpyruvate carboxykinase (PEPCK) gene is repressed during fetal liver development and activated at birth. It has been shown that the PEPCK gene is a retinoid-responsive gene, but whether it is regulated by vitamin A in the fetus has not been established. In this study, we found that PEPCK mRNA can be detected in the murine fetal liver as early as gestational d 17. In addition, expression and cAMP induction of the PEPCK gene during late gestation and at birth require vitamin A sufficiency in the fetus and neonate. The PEPCK promoter contains several regulatory elements that bind a diverse array of transcription factors and nuclear coregulators, although it is largely unknown which of these factors are expressed early in liver development. Expression of some of these nuclear factors in livers of fetal mice was investigated by immunohistochemistry (IHC). Fetuses were from dams that were fed from the beginning of gestation diets that were adequate or devoid of vitamin A. Hepatocyte nuclear factor 4alpha (HNF4alpha) was expressed at the earliest stage of liver development on d 11, whereas retinoid X receptor alpha (RXRalpha) and nuclear coactivator CREB-binding protein (CBP) were expressed from d 16 onward. Although expressions of RXRalpha and CBP in livers of vitamin A-sufficient and vitamin A-depleted fetal mice did not differ, the level of HNF4alpha was consistently lower in the latter. Our findings strongly suggest that vitamin A is required during liver development for staged expression of the PEPCK gene and that HNF4alpha may be involved in mediating vitamin A regulation of the PEPCK gene at these critical periods.
磷酸烯醇丙酮酸羧激酶（PEPCK）基因的表达在胎儿肝脏发育过程中受到抑制，并在出生时被激活。研究表明，PEPCK基因是一种视黄酸反应性基因，但它在胎儿中是否受维生素A调控尚未明确。在本研究中，我们发现早在妊娠第17天就能在小鼠胎儿肝脏中检测到PEPCK mRNA。此外，在妊娠后期和出生时，PEPCK基因的表达及cAMP诱导需要胎儿和新生儿体内维生素A充足。PEPCK启动子包含多个调控元件，可结合多种转录因子和核共调节因子，尽管目前尚不清楚这些因子中哪些在肝脏发育早期表达。通过免疫组织化学（IHC）研究了其中一些核因子在胎儿小鼠肝脏中的表达。胎儿来自从妊娠开始就喂食充足或缺乏维生素A日粮的母鼠。肝细胞核因子4α（HNF4α）在肝脏发育的最早阶段即第11天表达，而视黄酸X受体α（RXRα）和核共激活因子CREB结合蛋白（CBP）从第16天起开始表达。尽管维生素A充足和缺乏的胎儿小鼠肝脏中RXRα和CBP的表达没有差异，但后者中HNF4α的水平始终较低。我们的研究结果强烈表明，肝脏发育过程中需要维生素A来实现PEPCK基因的阶段性表达，并且HNF4α可能在这些关键时期参与介导维生素A对PEPCK基因的调控。
