Saarland University, Department of Pharmacy, Pharmaceutical Biology, Saarbrücken, Germany.
J Hepatol. 2011 May;54(5):994-1001. doi: 10.1016/j.jhep.2010.08.034. Epub 2010 Oct 26.
BACKGROUND & AIMS: The insulin-like growth-factor 2 (IGF2) mRNA binding protein p62 is highly expressed in hepatocellular carcinoma tissue. Still, its potential role in liver disease is largely unknown. In this study, we investigated pathophysiological implications of p62 overexpression in mice.
We generated mice overexpressing p62 under a LAP-promotor. mRNA expression levels and stability were examined by real-time RT-PCR. Allele-specific expression of Igf2 and H19 was assessed after crossing mice with SD7 animals. The Igf2 downstream mediators pAKT and PTEN were determined by Western blot.
Hepatic p62 overexpression neither induced inflammatory processes nor liver damage. However, 2.5week old transgenic animals displayed a steatotic phenotype and improved glucose tolerance. p62 overexpression induced the expression of the imprinted genes Igf2 and H19 and their transcriptional regulator Aire (autoimmune regulator). Neither monoallelic expression nor mRNA stability of Igf2 and H19 was affected. Investigating Igf2 downstream signalling pathways showed increased AKT activation and attenuated PTEN expression.
The induction of a steatotic phenotype implies that p62 plays a role in hepatic pathophysiology.
胰岛素样生长因子 2（IGF2）mRNA 结合蛋白 p62 在肝癌组织中高度表达。然而，其在肝脏疾病中的潜在作用在很大程度上尚不清楚。在本研究中，我们研究了 p62 在小鼠中的过表达对生理病理的影响。
我们利用 LAP 启动子在小鼠中过表达 p62。通过实时 RT-PCR 检测 mRNA 表达水平和稳定性。通过与 SD7 动物杂交，评估 Igf2 和 H19 的等位基因特异性表达。通过 Western blot 检测 Igf2 的下游介质 pAKT 和 PTEN。
肝组织中 p62 的过表达既不会诱导炎症过程，也不会导致肝损伤。然而，2.5 周龄的转基因动物表现出脂肪变性表型和改善的葡萄糖耐量。p62 的过表达诱导了印记基因 Igf2 和 H19 及其转录调节剂 Aire（自身免疫调节因子）的表达。Igf2 和 H19 的单等位基因表达或 mRNA 稳定性均不受影响。研究 Igf2 下游信号通路表明 AKT 激活增加，PTEN 表达减弱。
诱导脂肪变性表型表明 p62 在肝脏生理病理中发挥作用。
