Nyirenda M J, Dean S, Lyons V, Chapman K E, Seckl J R
Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
Diabetologia. 2006 Jun;49(6):1412-20. doi: 10.1007/s00125-006-0188-5. Epub 2006 Mar 29.
AIMS/HYPOTHESIS: 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.
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.
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/INTERPRETATION: 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.
目的/假设：产前暴露于糖皮质激素会导致大鼠后代出现终身高血糖，这与糖异生的限速酶——肝磷酸烯醇式丙酮酸羧激酶2（PCK2）的永久性增加有关。为阐明PCK2“编程”的潜在机制，本研究检测了产前地塞米松治疗对调节Pck2的转录因子表达的影响。
采用实时逆转录-聚合酶链反应（RT-PCR）和原位杂交技术，检测并定位妊娠最后一周接受地塞米松或赋形剂处理的母鼠的胎儿及成年后代肝脏中PCK2、肝细胞核因子4α（HNF4A）、转录因子1（TCF1）、CCAAT/增强子结合蛋白α（CEBPA）、CEBPB、糖皮质激素受体（NR3C1）和过氧化物酶体增殖物激活受体γ共激活因子1α（PPARGC1A）基因转录的mRNA。
产前暴露于地塞米松显著提高了胎儿和成年肝脏中Hnf4a mRNA的表达。这是由于源自“成年”（P1）Hnf4a启动子的异构体表达增加所致。相反，地塞米松显著抑制了源自“胎儿”（P2）启动子的异构体。与Pck2一样，肝脏中Hnf4a mRNA的增加仅发生在门静脉周围区域。地塞米松治疗也增加了胎儿Tcf1的表达，但这种增加在成年后并未持续。产前地塞米松不影响胎儿和/或成年Cebpa、Cebpb、Nr3c1或Ppargc1a mRNA的量。
结论/解读：产前暴露于地塞米松导致肝脏中Hnf4a mRNA永久性增加。这种增加与从胎儿启动子优势向成年启动子优势的过早转变有关，与Pck2表达的变化一致。这些数据表明，HNF4A可能介导Pck2的过表达及随后的高血糖。
