PPAR[gamma] population shift produces disease-related changes in molecular networks associated with metabolic syndrome

• Published in: Cell death & disease Vol. 2; p. e192
• Main Authors: Jurkowski, W, Roomp, K, Crespo, I, Schneider, J G, Del Sol, A
• Format: Journal Article
• Language: English
• Published: London Springer Nature B.V 01.08.2011
• DOI: 10.1038/cddis.2011.74

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.