title: PPARγ population shift produces disease-related changes in molecular networks associated with metabolic syndrome.
abstract: Peroxisome proliferator-activated receptor gamma (PPARγ) is a key regulator of adipocyte differentiation and has an important role in metabolic syndrome. Phosphorylation of the receptor's ligand-binding domain at serine 273 has been shown to change the expression of a large number of genes implicated in obesity. The difference in gene expression seen when comparing wild-type phosphorylated with mutant non-phosphorylated PPARγ may have important consequences for the cellular molecular network, the state of which can be shifted from the healthy to a stable diseased state. We found that a group of differentially expressed genes are involved in bi-stable switches and form a core network, the state of which changes with disease progression. These findings support the idea that bi-stable switches may be a mechanism for locking the core gene network into a diseased state and for efficiently propagating perturbations to more distant regions of the network. A structural analysis of the PPARγ-RXRα dimer complex supports the hypothesis of a major structural change between the two states, and this may represent an important mechanism leading to the differential expression observed in the core network.
authors.affiliation: Luxembourg Center for Systems Biomedicine (LCSB), University of Luxembourg, Campus Limpertsberg, USA.
authors.forename: W
authors.initials: W
authors.lastname: Jurkowski
authors.forename: K
authors.initials: K
authors.lastname: Roomp
authors.forename: I
authors.initials: I
authors.lastname: Crespo
authors.forename: J G
authors.initials: JG
authors.lastname: Schneider
authors.forename: A
authors.initials: A
authors.lastname: Del Sol
mesh_terms: D019281:Dimerization; D005786:Gene Expression Regulation; D006801:Humans; D053858:Metabolic Networks and Pathways; D024821:Metabolic Syndrome / Q000378:metabolism*; D047495:PPAR gamma / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D047490:Retinoid X Receptor alpha / Q000378:metabolism
chemical_list: D047495:PPAR gamma; D047490:Retinoid X Receptor alpha