Erschienen:
[Erscheinungsort nicht ermittelbar]: [Verlag nicht ermittelbar], 2013
Sprache:
Englisch
Entstehung:
Hochschulschrift:
Dissertation, 2013
Anmerkungen:
Beschreibung:
Transcription is a fundamental cellular process which is tightly regulated by transcription factors and cofactors to maintain homeostasis, even under changing conditions. The family of peroxisome proliferator-activated receptor (PPAR) coactivator (PGC) 1 transcription cofactors comprises PGC-1, PGC-1 and PRC, which all induce oxidative metabolism including mitochondrial biogenesis and fatty acid oxidation. PGC-1 and PGC-1 have been studied in greater detail than PRC and are predominantly expressed in tissues with high oxidative capacity like brown adipose tissue (BAT), heart and skeletal muscle. Inflammation is the protective response of the body to infection and injury involving tissue as well as immune cells. During this process, a complex cytokine network governs communication between cells, coordinates elimination of pathogens, regeneration and finally drives resolution of the inflammatory reaction. If persistently active, inflammation however becomes detrimental and in fact, accompanies a large number of chronic diseases like type 2 diabetes. In skeletal muscle of diabetic patients, levels of PGC-1 and PGC-1 are diminished and a mouse model with skeletal muscle-specific deletion of PGC-1 shows elevated inflammatory markers both locally and systemically. These findings suggest a causal role of PGC-1 coactivators in counteracting inflammation. The work presented here explored the relationship of those coactivators with inflammatory reactions in skeletal muscle in vitro and in vivo. In vitro, PGC-1 and PGC-1 were expressed using adenoviral vectors in a C2C12 myotube model. Tumour necrosis factor (TNF) , different toll-like receptor agonists and free fatty acids all elicited pro-inflammatory cytokine expression that was diminished by both coactivators in a stimulus- and gene-dependent manner. To further elucidate the mechanism behind this repressive action, TNtreatment was chosen as paradigm. A microarray experiment with subsequent bioinformatic analysis revealed that the NF-B pathway, which is a major driver of inflammatory reactions, plays an important role in PGC-1-controlled inflammatory gene expression. This prediction was validated as NF-B reporter gene activity was inhibited by both PGC-1 and PGC-1. However, neither changes in mRNA nor in protein expression of components of the NF-B signalling pathway explained the repression. Rather, PGC-1 coactivators affected the post-translational modification of p65, a NF-B subunit. Diminished phosphorylation at serine 536 precluded complete transcriptional activation by p65 leading to lower cytokine levels. .