| Peroxisome proliferator-activated receptors (PPAR) are members of the nuclear hormone receptor superfamily that serve as ligand-activated transcription factors regulating the expression of genes involved in lipid metabolism (peroxisomal β-oxidation), adipogenesis, inflammation, and glucose metabolism. PPARs are activated by a diverse group of compounds termed peroxisome proliferators, which include the fibrate family of hypolipidemic drugs, eicosanoids, antidiabetic thiazolidinediones, as well as naturally occurring and synthetic mono- and polyunsaturated fatty acids. Upon binding of ligand, PPARs heterodimerize with the 9-cis -retinoic acid receptor (RXRα) and bind to cognate binding sequences termed peroxisome proliferator-response elements (PPRE) found in the promoter regions of target genes. PPAR-mediated gene transcription is a complex and dynamic event involving a myriad of cellular factors. This thesis examines the role of various members of the nuclear hormone receptor superfamily in modulating gene transcription by PPARs. In particular, this thesis focuses on the genes encoding the first two enzymes of the peroxisomal β-oxidation pathway, acyl-CoA oxidase (AOx) and enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase (HD).; The results presented illustrate the involvement of thyroid hormone receptor α, RevErb α, constitutive androstane receptor β (CARβ), and the short heterodimer partner (SBP) in differentially modulating PPARα-mediated gene transcription from both the AOx- and HD-PPREs. Furthermore, subtype- and response element-dependent differences in gene transcription between two PPAR subtypes, α and γ, are also demonstrated. The conclusions drawn from this research further support the hypothesis that PPAR-mediated gene transcription from PPREs is integrated with the transcriptional activities of various members of the nuclear hormone receptor superfamily, as well as with a variety of cellular coactivators and corepressors, and can be influenced by the availability of ligand so as to ensure a correct transcriptional response to extra- and intracellular stimuli from appropriate target genes. The research contained herein establishes a framework for understanding normal and dysfunctional lipid metabolism and provides an impetus for further exploration of the molecular mechanisms of PPAR-mediated gene transcription. |
