Structural and Functional Alteration of Full Length PPARα and LXRα by Fatty Acids and their Thioesters
Steven Berberich (Committee Chair), Heather Hostetler (Advisor), Lawrence Prochaska (Committee Member)
Master of Science (MS)
Peroxisome proliferator-activated receptors (PPAR) and liver X receptors (LXR) are known to play important roles in fatty acid metabolism, interact with each other, and function as heterodimeric partners. Although previous studies indicate that PPARα is activated by long chain fatty acyl-CoA thioesters (LCFA-CoA) and polyunsaturated fatty acids, little is known about the effects of these ligands on the function or interaction of PPARα and LXRα. In this study, hPPARα and hLXRα were shown to directly interact by circular dichroism, fluorescent binding assays, and co-immunoprecipitation. Further experiments suggested that although fatty acids resulted in small structural changes, they significantly altered binding affinities; while LCFA-CoAs decreased the binding affinities, no observable trend was seen with respect to the number of carbon atoms or bonds. In addition, transactivation assays in the presence of certain fatty acids suggested that the combination of PPARα and LXRα increased the activity of the PPARα regulated gene - ACOX, while downregulating the LXRα regulated gene SREBP. As high levels of fatty acids are associated with certain metabolic disorders and also serve as natural ligands for PPARα, changes in structure and/or interaction between PPARα and LXRα may have significant effects on the normal functioning of a cell.
Department or Program
Department of Biochemistry and Molecular Biology
Year Degree Awarded
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