High concentrations of phenylalanine stimulate peroxisome proliferator-activated receptor gamma: implications for the pathophysiology of phenylketonuria.
If left untreated, the common inherited metabolic disorder phenylketonuria (PKU) presents with mental retardation and reduced brain weight. The underlying molecular reasons for these deficits are unknown so far. Using human neuroblastoma cells as a model for normal human neuroblasts, elevated phenylalanine concentrations suppressed proliferation of these cells in culture. Furthermore, microarray and functional assays of these cells revealed that both phenylalanine and the known PPARgamma agonist rosiglitazone regulated the same set of genes causing subsequently similar changes in the functional assays. The lowered brain weight of PKU patients may thus be the result of reduced neuroblast proliferation caused by phenylalanine-induced stimulation of PPARgamma receptors. The observation that high concentrations of small substrates can activate receptors may serve as a new paradigm for other metabolic diseases and provides a new approach for the treatment of these disorders by application of specific receptor antagonists.
Schumacher
Udo
U
Institute for Anatomy II: Experimental Morphology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Lukacs
Zoltan
Z
Kaltschmidt
Christian
C
Freudlsperger
Christian
C
Schulz
Dorothea
D
Kompisch
Kai
K
Müller
Reinhard
R
Rudolph
Tanja
T
Santer
René
R
Lorke
Dietrich E
DE
Ullrich
Kurt
K