title: High concentrations of phenylalanine stimulate peroxisome proliferator-activated receptor gamma: implications for the pathophysiology of phenylketonuria.
abstract: 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.
authors.affiliation: Institute for Anatomy II: Experimental Morphology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Udo
authors.initials: U
authors.lastname: Schumacher
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Lukacs
authors.forename: Christian
authors.initials: C
authors.lastname: Kaltschmidt
authors.forename: Christian
authors.initials: C
authors.lastname: Freudlsperger
authors.forename: Dorothea
authors.initials: D
authors.lastname: Schulz
authors.forename: Kai
authors.initials: K
authors.lastname: Kompisch
authors.forename: Reinhard
authors.initials: R
authors.lastname: Müller
authors.forename: Tanja
authors.initials: T
authors.lastname: Rudolph
authors.forename: René
authors.initials: R
authors.lastname: Santer
authors.forename: Dietrich E
authors.initials: DE
authors.lastname: Lorke
authors.forename: Kurt
authors.initials: K
authors.lastname: Ullrich