Exp Mol Med.  2010 Feb;42(2):105-115. 10.3858/emm.2010.42.2.012.

Tissue-specific activation of mitogen-activated protein kinases for expression of transthyretin by phenylalanine and its metabolite, phenylpyruvic acid

• Park JW
• Lee MH
• Choi JO
• Park HY
• Jung SC

• KMID: 983983
• DOI: http://doi.org/10.3858/emm.2010.42.2.012

Abstract

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.

Keyword

hepatocyte nuclear factor 4; mitogen-activated protein kinases; mouse; phenylketonurias; prealbumin

MeSH Terms

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