Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut, United States of America.
Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut, United States of America.
PLoS One. 2017 Nov 3;12(11):e0187557. doi: 10.1371/journal.pone.0187557. eCollection 2017.
H19 RNA is highly expressed at early postnatal ages and precipitously decreases at a specific time corresponding with increases in expression of genes important for mature liver function, such as drug metabolizing enzymes. H19's role in the regulation of liver maturation is currently unknown. Using an H19 knockout mouse model to determine the role of H19 in liver development, we quantified gene expression for insulin growth factor signaling, Wnt signaling, key cytochrome P450 (P450) enzymes known to change as the liver develops, and fetal and adult plasma protein produced in liver. In mice lacking H19 expression, liver weights were significantly increased immediately after birth and significant increases were found in the number of actively proliferating cells. Increases in cell proliferation may be due to increases in β-catenin protein affecting Wnt signaling, increases in insulin-like growth factor 2 (IGF2) expression, and/or increases in insulin-like growth factor 1 receptor (IGF1R) expression at the protein level. Loss of targeted inhibition of IGF1R by microRNA 675 (miR-675) may be the cause of IGF1R increases, as miR-675 expression is also abrogated with loss of H19 expression in our model. P450 expression patterns were largely unchanged. No change in the production of plasma proteins was found, indicating H19 may not be important for liver maturation despite its role in controlling cell proliferation during liver growth. H19 may be important for normal liver development, and understanding how the liver matures will assist in predicting drug efficacy and toxicity in pediatric populations.
H19 RNA 在出生后早期高度表达，并在特定时间急剧下降，此时与成熟肝功能相关的基因表达增加，如药物代谢酶。H19 在调节肝脏成熟中的作用尚不清楚。我们使用 H19 敲除小鼠模型来确定 H19 在肝脏发育中的作用，定量检测了胰岛素生长因子信号、Wnt 信号、已知在肝脏发育过程中发生变化的关键细胞色素 P450（P450）酶以及在肝脏中产生的胎儿和成人血浆蛋白的基因表达。在缺乏 H19 表达的小鼠中，出生后立即肝脏重量显著增加，并且发现活跃增殖细胞的数量显著增加。细胞增殖的增加可能是由于 β-连环蛋白蛋白增加影响 Wnt 信号、胰岛素样生长因子 2（IGF2）表达增加，和/或胰岛素样生长因子 1 受体（IGF1R）表达增加。针对 IGF1R 的 microRNA 675（miR-675）的靶向抑制丧失可能是 IGF1R 增加的原因，因为在我们的模型中，miR-675 表达也随着 H19 表达的丧失而被废除。P450 表达模式基本不变。未发现血浆蛋白产生的变化，表明尽管 H19 在控制肝脏生长期间的细胞增殖中起作用，但它对于肝脏成熟可能不重要。H19 可能对正常肝脏发育很重要，了解肝脏如何成熟将有助于预测儿科人群的药物疗效和毒性。
