Prostate Apoptosis Response-4 (Par-4) is a conserved and ubiquitous tumor-suppressor factor which can selectively induce apoptosis in tumor cells, while leaving normal cells unaffected. While Par-4 is well established as a tumor-suppressor, there have yet been no formal investigations as to whether it has a physiologic role in normal tissues.
Early observations of Par-4 knockout mouse lines yielded that the adult mice displayed significant weight gain and fat accumulation compared to their wild-type counterparts while on a conventional chow diet. Interestingly, obese mouse and human subjects were found to exhibit reduced expression of Par-4 in adipose tissue as well as lower levels of secreted Par-4 in their plasma, compared to samples collected from lean human subjects.
Subsequent in vitro experiments would show that loss of Par-4 has significant impact upon adipogenesis. Mechanistically, Par-4 loss during adipogenesis in cell culture correlated inversely with expression of the adipogenic transcription factor PPARγ. Subsequent experiments would demonstrate that Par-4 transcriptionally represses PPARγ at the promoter level.
Thereby, we conclude that Par-4 regulates adipogenesis and lipid accumulation through transcriptional repression of the PPARγ promoter. This research utilizes novel models and may be used as the basis for Par-4-mediated therapies for obesity and metabolic disease.
| Identifer | oai:union.ndltd.org:uky.edu/oai:uknowledge.uky.edu:toxicology_etds-1020 |
| Date | 01 January 2018 |
| Creators | Sledziona, James |
| Publisher | UKnowledge |
| Source Sets | University of Kentucky |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Theses and Dissertations--Toxicology and Cancer Biology |
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