Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul 158-710, Korea.
Exp Mol Med. 2010 Feb 28;42(2):105-15. doi: 10.3858/emm.2010.42.2.012.
Phenylketonuria is an autosomal recessive disorder caused by a deficiency of phenylalanine hydroxylase. Transthyretin has been implicated as an indicator of nutritional status in phenylketonuria patients. In this study, we report that phenylalanine and its metabolite, phenylpyruvic acid, affect MAPK, changing transthyretin expression in a cell- and tissue-specific manner. Treatment of HepG2 cells with phenylalanine or phenylpyruvic acid decreased transcription of the TTR gene and decreased the transcriptional activity of the TTR promoter site, which was partly mediated through HNF4alpha. Decreased levels of p38 MAPK were detected in the liver of phenylketonuria-affected mice compared with wild-type mice. In contrast, treatment with phenylalanine increased transthyretin expression and induced ERK1/2 activation in PC-12 cells; ERK1/2 activation was also elevated in the brainstem of phenylketonuria-affected mice. These findings may explain between-tissue differences in gene expression, including Ttr gene expression, in the phenylketonuria mouse model.
苯丙酮尿症是一种常染色体隐性遗传疾病，由苯丙氨酸羟化酶缺乏引起。转甲状腺素蛋白已被认为是苯丙酮尿症患者营养状况的指标。在这项研究中，我们报告苯丙氨酸及其代谢产物苯丙酮酸以细胞和组织特异性的方式影响 MAPK，改变转甲状腺素蛋白的表达。用苯丙氨酸或苯丙酮酸处理 HepG2 细胞会降低 TTR 基因的转录，并降低 TTR 启动子位点的转录活性，这部分是通过 HNF4alpha 介导的。与野生型小鼠相比，苯丙酮尿症小鼠肝脏中 p38 MAPK 的水平降低。相比之下，用苯丙氨酸处理可增加 PC-12 细胞中转甲状腺素蛋白的表达，并诱导 ERK1/2 激活；苯丙酮尿症小鼠脑干中的 ERK1/2 激活也升高。这些发现可以解释苯丙酮尿症小鼠模型中包括 Ttr 基因表达在内的不同组织之间基因表达的差异。
