Journal
MOLECULAR THERAPY
Volume 12, Issue 2, Pages 337-344Publisher
CELL PRESS
DOI: 10.1016/j.ymthe.2005.03.025
Keywords
phenylketonuria; phenylalanine; hepatocyte transplantation; mouse model
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Funding
- NIDDK NIH HHS [R01 DK059371-03A3, R01 DK 59371, R01 DK 04252, R01 DK059371-04, K08 DK 02405, R01 DK059371] Funding Source: Medline
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Phenylalanine homeostasis in mammals is primarily controlled by liver phenylalanine hydroxylase (PAH) activity. Inherited PAH deficiency (phenylketonuria or PKU) leads to hyperphenylalaninemia in both mice and humans. A low level of residual liver PAH activity ensures near-normal dietary protein tolerance with normal serum phenylalanine level, but the precise threshold for normal phenylalanine clearance is unknown. We employed hepatocyte transplantation under selective growth conditions to investigate the minimal number of PAH-expressing hepatocytes necessary to prevent hyperphenylalaninemia in mice. Serum phenylalanine levels remained normal in mice exhibiting nearly complete liver repopulation with PAH-deficient hepatocytes (<5% residual wildtype liver PAH activity). Conversely, transplantation of PAH-positive hepatocytes into PAH-deficient pah(enu2) mice, a model of human PKU, yielded a significant decrease in serum phenylalanine (<700 mu M) when liver repopulation exceeded approximately 5%. These data suggest that restoration of phenylalanine homeostasis requires PAH activity in only a minority of hepatocytes.
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