Prenatal glucocorticoid administration enhances bilirubin metabolic capacity and increases Ugt1a and Abcc2 gene expression via glucocorticoid receptor and PXR in rat fetal liver
Prenatal glucocorticoid administration enhances bilirubin metabolic capacity and increases Ugt1a and Abcc2 gene expression via glucocorticoid receptor and PXR in rat fetal liver
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DOI：
10.1111/jog.15235
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发表时间：
2022-04-20
影响因子：
1.6
通讯作者：
Matsumoto, Naoki
中科院分区：
文献类型：
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作者：
Kobayashi, Tsukasa;Takeba, Yuko;Matsumoto, Naoki
目的黄疸多见于35周以内的早产儿。由于早产儿出生时肝脏发育不完全，胆红素代谢可能不完全。本研究旨在探讨早产大鼠产前应用糖皮质激素（GC）后肝脏胆红素代谢和排泄的变化。方法Wistar孕鼠于孕17、19 d皮下注射地塞米松（DEX），连续2 d。胎儿在妊娠第19天和第21天通过剖宫产分娩。分别采用RT-PCR免疫组化染色和ELISA法检测胎肝组织中胆红素代谢酶和转运蛋白的mRNA水平和蛋白水平。本实验观察了糖皮质激素受体（GR，Nr 3c 1）和Pxr（Nr 1 i2）siRNA对原代胎鼠肝细胞糖皮质激素（DEX）处理后的影响。结果产前应用GC后，胎儿Ugt 1a 1和Bsep（Abcb 11）mRNA水平明显升高。核转录因子Nr 1 i2、Car（Nr 1 i3）和Rxr α（Nr 2b 1）的mRNA水平也显著增加。此外，DEX增加Nr 1 i2，Ugt 1a 1，和Abcc 2（Mrp 2）的mRNA水平在原代胎肝细胞。Nr 3c 1或Nr 1 i2 siRNA抑制DEX诱导的Ugt 1a 1和Abcc 2 mRNA水平的增加，表明DEX在原代胎肝细胞中由GC受体和PXR介导。结论产前应用GC可提高早产儿肝脏胆红素代谢能力，预防新生儿黄疸。
Aim Jaundice is especially common in premature infant born before 35 weeks. Because the premature infant liver is not fully developed at birth it may be incomplete the bilirubin metabolism. The purpose was to evaluate the metabolism and the excretion of bilirubin in the premature infant rat liver following prenatal glucocorticoid (GC) administration. Methods Dexamethasone (DEX) was administered subcutaneously to pregnant Wistar rats for two consecutive days on gestational days 17 and 19. The fetus were delivered by cesarean section in gestational days 19 and 21. The mRNA levels and protein levels of bilirubin-metabolic enzymes and transporters in the fetal liver tissues were analyzed using RT-PCR immunohistochemistry staining and ELISA, respectively. We evaluated that the effect of bilirubin-metabolic enzymes in the primary fetal rat hepatocytes treated with DEX after pretreated with glucocorticoid receptor (GR, Nr3c1) and Pxr (Nr1i2) siRNA. Results Ugt1a1 and Bsep (Abcb11) mRNA levels were significantly increased in the fetuses by prenatal GC administration. The mRNA levels of nuclear transcription factors Nr1i2, Car (Nr1i3), and Rxr alpha (Nr2b1) were also significantly increased in the fetuses by prenatal GC administration. In addition, DEX increased Nr1i2, Ugt1a1, and Abcc2 (Mrp2) mRNA levels in the primary fetal hepatocytes. The Nr3c1 or Nr1i2 siRNA-mediated knockdown suppressed the increases of Ugt1a1, and Abcc2 mRNA levels induced by DEX, indicating that DEX are mediated by GC receptor and PXR in primary fetal hepatocytes. Conclusions These results suggest that prenatal GC administration increases bilirubin-metabolic ability, in the premature liver, which may prevent jaundice in neonates.