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.
Animals ; Brain Stem/metabolism/pathology ; Disease Models, Animal ; Gene Expression Regulation ; Hep G2 Cells ; Hepatocyte Nuclear Factor 4/metabolism ; Humans ; Liver/*metabolism/pathology ; Mice ; Mice, Mutant Strains ; Mitogen-Activated Protein Kinase 3/genetics/*metabolism ; Organ Specificity ; Phenylalanine/metabolism ; Phenylalanine Hydroxylase/deficiency ; Phenylketonurias/*genetics/metabolism/pathology/physiopathology ; Phenylpyruvic Acids/metabolism ; Prealbumin/*biosynthesis/genetics ; p38 Mitogen-Activated Protein Kinases/genetics/*metabolism