The peroxisome proliferator-activated receptor a (PPARalpha) plays a central role in energy homeostasis by initiating transcription of multiple genes in fatty add and glucose metabolism, while concomitantaly downregulating genes in insulin signaling. In liver, PPARa induces transcription of many genes involved in fatty acid degradation by b-oxidation, fatty acid uptake and transport, and lipoprotein metabolism. Thus, PPARalpha is responsible for control of a number of lipid metabolic proteins that may contribute to obesity, diabetes, lipotoxicity, and subsequent cardiovascular disorders. However, relatively little is known regarding either the mechanisms that regulate the availability of endogenous fatty acyl-CoA ligands to the nucleus for interaction with PPARa or the effect of these ligands on PPARalpha interaction with heterodimer partners. Although it is known that PPARa must heterodimerize with either the retinoid X receptor (RXR) or the liver X receptor (LXR) prior to bidning DNA response elements for transcriptional regulation, surprisingly little is known about the effect of endogenous ligands on the choice of heterodimer partners. Furthermore, the effect of PPARalpha ligands on heterodimer partners is incompletely resolved. In order to address these issues, this proposal is focused in two phases: First, the 'mentored phase'will: 1. Resolve whether PPARa-mediated transcription of genes is regulated by long-chain fatty acyl-CoAs (LCFA-CoA). 2. Determine the effect of LCFA-CoA on the molecular interaction of PPARa with L-FABP. Second, the 'independent phase'w^ill: 3. Determine if LXRa binds LCFA-CoA with high affinity, in the physiological range of nulcear LCFA-CoA levels. 4. Elucidate the effect of LCFA-CoA on the molecular interaction of PPARa with LXRa. It is hoped tha the results of this work will provide a mechanistic role of LCFA-CoA in nuclear receptor regulation.
This work aims at studying a protein whose abnormal expression/regulation is associated with obesity, diabetes, and cardiovascular disease. This research is a step towards the development of new methods and more efficient dmgs for the treatment of such disorders.
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